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Dong H, Lyu Y, Huang CY, Tsai SY. Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle. Autophagy 2025; 21:1212-1227. [PMID: 39878121 PMCID: PMC12087647 DOI: 10.1080/15548627.2025.2457925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 01/21/2025] [Accepted: 01/21/2025] [Indexed: 01/31/2025] Open
Abstract
Postmitotic skeletal muscle critically depends on tightly regulated protein degradation to maintain proteomic stability. Impaired macroautophagy/autophagy-lysosomal or ubiquitin-proteasomal protein degradation causes the accumulation of damaged proteins, ultimately accelerating muscle dysfunction with age. While in vitro studies have demonstrated the complementary nature of these systems, their interplay at the organism levels remains poorly understood. Here, our study reveals novel insights into this complex relationship in autophagy-deficient skeletal muscle. We demonstrated that despite a compensatory increase in proteasome level in response to autophagy impairment, 26S proteasome activity was not proportionally enhanced in autophagy-deficient skeletal muscle. This functional deficit was partly attributed to reduced ATP levels to fuel the 26S proteasome. Remarkably, we found that activation of EIF4EBP1, a crucial inhibitor of cap-dependent translation, restored and even augmented proteasomal function through dual mechanisms. First, genetically activating EIF4EBP1 enhanced both ATP-dependent 26S proteasome and ATP-independent 20S proteasome activities, thereby expanding overall protein degradation capacity. Second, EIF4EBP1 activation caused muscle fiber transformation and increased mitochondrial biogenesis, thus replenishing ATP levels for 26S proteasome activation. Notably, the improved performance of the 20S proteasome in EIF4EBP1-activated skeletal muscle was attributed to an increased abundance of the immunoproteasome, a subtype specially adapted to function under oxidative stress conditions. This dual action of EIF4EBP1 activation preserved proteomic integrity in autophagy-deficient skeletal muscle. Our findings uncover a novel role of EIF4EBP1 in improving protein quality control, presenting a promising therapeutic strategy for autophagy-related muscular disorders and potentially other conditions characterized by proteostatic imbalance.Abbreviations: 3-MA: 3-methyladenine; ACAC/ACC: acetyl-Coenzyme A carboxylase; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATP: adenosine triphosphate; ATP5F1A/ATP5A: ATP synthase F1 subunit alpha; CKM-Cre: creatine kinase, muscle-Cre; CMA: chaperone-mediated autophagy; CTSB: cathepsin B; CTSK: cathepsin K; CTSL: cathepsin L; CUL3: cullin 3; EDL: extensor digitorum longus; EIF4E: eukaryotic translation initiation factor 4E; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EIF4F: eukaryotic translation initiation factor 4F complex; FBXO32/ATROGIN1/MAFbx: F-box protein 32; GFP: green fluorescent protein; IFNG/IFN-γ: interferon gamma; KEAP1: kelch-like ECH-associated protein 1; LAMP1: lysosomal-associated membrane protein 1; LAMP2: lysosomal-associated membrane protein 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; Myl1/Mlc1f-Cre: myosin, light polypeptide 1 (promoter driving Cre recombinase); mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; NFE2L1/NRF1: nuclear factor, erythroid derived 2, like 1; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; NFKB1/NFκB1: nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105; OXPHOS: oxidative phosphorylation; PPARGC1A/PGC1α: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; PSMB5: proteasome (prosome, macropain) subunit, beta type 5; PSMB6: proteasome (prosome, macropain) subunit, beta type 6; PSMB7: proteasome (prosome, macropain) subunit, beta type 7; PSMB8: proteasome (prosome, macropain) subunit, beta type 8 (large multifunctional peptidase 7); PSMB9: proteasome (prosome, macropain) subunit, beta type 9 (large multifunctional peptidase 2); PSMB10: proteasome (prosome, macropain) subunit, beta type 10; PSME1: proteasome (prosome, macropain) activator subunit 1 (PA28 alpha); PSME2: proteasome (prosome, macropain) activator subunit 2 (PA28 beta); RBX1: ring-box 1; SQSTM1/p62: sequestosome 1; SREBF1/SREBP1: sterol regulatory element binding transcription factor 1; STAT3: signal transducer and activator of transcription 3; TRIM63/MURF1: tripartite motif-containing 63; ULK1: unc-51 like kinase 1; UPS: ubiquitin-proteasome system.
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Affiliation(s)
- Han Dong
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yifan Lyu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Chien-Yung Huang
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Shih-Yin Tsai
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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2
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Shero JA, Lindholm ME, Sandri M, Stanford KI. Skeletal Muscle as a Mediator of Interorgan Crosstalk During Exercise: Implications for Aging and Obesity. Circ Res 2025; 136:1407-1432. [PMID: 40403102 PMCID: PMC12101524 DOI: 10.1161/circresaha.124.325614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 03/09/2025] [Accepted: 03/10/2025] [Indexed: 05/24/2025]
Abstract
Physical exercise is critical for preventing and managing chronic conditions, such as cardiovascular disease, type 2 diabetes, hypertension, and sarcopenia. Regular physical activity significantly reduces cardiovascular and all-cause mortality. Exercise also enhances metabolic health by promoting muscle growth, mitochondrial biogenesis, and improved nutrient storage while preventing age-related muscle dysfunction. Key metabolic benefits include increased glucose uptake, enhanced fat oxidation, and the release of exercise-induced molecules called myokines, which mediate interorgan communication and improve overall metabolic function. These myokines and other exercise-induced signaling molecules hold promise as therapeutic targets for aging and obesity-related conditions.
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Affiliation(s)
- Julia A. Shero
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
- Division of General and Gastrointestinal Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
| | - Maléne E. Lindholm
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California, United States
| | - Marco Sandri
- Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy
| | - Kristin I. Stanford
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
- Division of General and Gastrointestinal Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
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3
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Teixeira AM, Nosrani SE, Parvani M, Viola J, Mohammadi S. Sarcopenia: an Aging Perspective and Management Options. Int J Sports Med 2025. [PMID: 40199507 DOI: 10.1055/a-2577-2577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
There is no doubt that sarcopenia is one of the most defining characteristics of aging that negatively impacts the people's health and quality of life. The condition is characterized by the progressive and generalized loss of muscle mass and strength, affecting physical performance. It is part of aging but can be exacerbated by pathophysiological conditions like cancer and several factors such as a sedentary lifestyle, poor nutrition, chronic diseases, falls and immobilization. Numerous cellular mechanisms have been implicated in its pathogenesis, including hormonal changes, mitochondrial dysfunctions, altered apoptotic and autophagic signaling, muscle fiber composition, and inflammatory pathways. To prevent sarcopenia, exercise is one of the most effective strategies as it has a strong influence on both anabolic and catabolic muscle pathways and helps improve skeletal muscle function. A well-rounded, multicomponent exercise program that targets muscle strength, aerobic capacity, and balance is recommended for optimal results. While nutrition is essential for muscle maintenance, relying solely on dietary interventions is unlikely to fully address sarcopenia. Therefore, a combination of adequate nutrition and regular exercise is recommended to promote muscle health and function. The purpose of this study is to review sarcopenia from an aging viewpoint and discuss the role of exercise and nutrition as prevention and management options.
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Affiliation(s)
- Ana M Teixeira
- Faculty of Sport Sciences and Physical Education, University of Coimbra, Coimbra, Portugal
- Research Center for Sport and Physical Activity (doi: 10.54499/UIDP/04213/2020), CIDAF-UC, Coimbra, Portugal
| | - Shiva E Nosrani
- Faculty of Sport Sciences and Physical Education, University of Coimbra, Coimbra, Portugal
- Research Center for Sport and Physical Activity (doi: 10.54499/UIDP/04213/2020), CIDAF-UC, Coimbra, Portugal
| | - Mohsen Parvani
- Faculty of Sport Sciences and Physical Education, University of Coimbra, Coimbra, Portugal
- Research Center for Sport and Physical Activity (doi: 10.54499/UIDP/04213/2020), CIDAF-UC, Coimbra, Portugal
| | - João Viola
- Faculty of Sport Sciences and Physical Education, University of Coimbra, Coimbra, Portugal
| | - Shaghayegh Mohammadi
- Faculty of Physical Education, Department of Pathology and Corrective Exercises, University of Guilan, Rasht, Iran (the Islamic Republic of)
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4
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Conjard-Duplany A, Osseni A, Lamboux A, Mouradian S, Picard F, Moncollin V, Angleraux C, Dorel-Dubois T, Puccio H, Leblanc P, Galy B, Balter V, Schaeffer L, Gangloff YG. Muscle mTOR controls iron homeostasis and ferritinophagy via NRF2, HIFs and AKT/PKB signaling pathways. Cell Mol Life Sci 2025; 82:178. [PMID: 40293459 PMCID: PMC12037468 DOI: 10.1007/s00018-025-05695-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 03/28/2025] [Accepted: 04/03/2025] [Indexed: 04/30/2025]
Abstract
Balanced mTOR activity and iron levels are crucial for muscle integrity, with evidence suggesting mTOR regulates cellular iron homeostasis. In this study, we investigated iron metabolism in muscle-specific mTOR knockout mice (mTORmKO) and its relation to their myopathy. The mTORmKO mice exhibited distinct iron content patterns across muscle types and ages. Slow-twitch soleus muscles initially showed reduced iron levels in young mice, which increased with the dystrophy progression but remained within control ranges. In contrast, the less affected fast-twitch muscles maintained near-normal iron levels from a young age. Interestingly, both mTORmKO muscle types exhibited iron metabolism markers indicative of iron excess, including decreased transferrin receptor 1 (TFR1) and increased levels of ferritin (FTL) and ferroportin (FPN) proteins. Paradoxically, these changes were accompanied by downregulated Ftl and Fpn mRNA levels, indicating post-transcriptional regulation. This discordant regulation resulted from disruption of key iron metabolism pathways, including NRF2/NFE2L2, HIFs, and AKT/PKB signaling. Mechanistically, mTOR deficiency impaired transcriptional regulation of iron-related genes mediated by NRF2 and HIFs. Furthermore, it triggered ferritin accumulation through two NRF2 mechanisms: (1) derepression of ferritin translation via suppression of the FBXL5-IRP axis, and (2) autophagosomal sequestration driven by NCOA4-dependent ferritin targeting to autophagosomes, coupled with age-related impairments of autophagy linked to chronic AKT/PKB activation. Three-week spermidine supplementation in older mTORmKO mice was associated with normalized AKT/PKB-FOXO signaling, increased endolysosomal FTL and reduced total FTL levels in the dystrophic soleus muscle. These findings underscore mTOR's crucial role in skeletal muscle iron metabolism and suggest spermidine as a potential strategy to address impaired ferritinophagy due to autophagy blockade in dystrophic muscle.
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Affiliation(s)
- Agnès Conjard-Duplany
- Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (PGNM), Institut NeuroMyoGène, Université Claude Bernard Lyon 1, INSERM U1315, CNRS UMR 5261, 8 avenue Rockefeller, Lyon, 69008, France.
| | - Alexis Osseni
- Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (PGNM), Institut NeuroMyoGène, Université Claude Bernard Lyon 1, INSERM U1315, CNRS UMR 5261, 8 avenue Rockefeller, Lyon, 69008, France
| | - Aline Lamboux
- Laboratoire de Géologie de Lyon: Terre, Planètes, Environnement, UMR 5276, Ecole Normale Supérieure de Lyon, 46, allée d'Italie, Lyon, Cedex 07, 69364, France
| | - Sandrine Mouradian
- Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (PGNM), Institut NeuroMyoGène, Université Claude Bernard Lyon 1, INSERM U1315, CNRS UMR 5261, 8 avenue Rockefeller, Lyon, 69008, France
| | - Flavien Picard
- Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (PGNM), Institut NeuroMyoGène, Université Claude Bernard Lyon 1, INSERM U1315, CNRS UMR 5261, 8 avenue Rockefeller, Lyon, 69008, France
| | - Vincent Moncollin
- Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (PGNM), Institut NeuroMyoGène, Université Claude Bernard Lyon 1, INSERM U1315, CNRS UMR 5261, 8 avenue Rockefeller, Lyon, 69008, France
| | - Céline Angleraux
- Université Claude Bernard Lyon 1, CNRS UAR3444, Inserm US8, ENS de Lyon, AniRA-PBES, SFR Biosciences, Lyon, 69007, France
| | - Tiphaine Dorel-Dubois
- Université Claude Bernard Lyon 1, CNRS UAR3444, Inserm US8, ENS de Lyon, AniRA-PBES, SFR Biosciences, Lyon, 69007, France
| | - Hélène Puccio
- Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (PGNM), Institut NeuroMyoGène, Université Claude Bernard Lyon 1, INSERM U1315, CNRS UMR 5261, 8 avenue Rockefeller, Lyon, 69008, France
| | - Pascal Leblanc
- Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (PGNM), Institut NeuroMyoGène, Université Claude Bernard Lyon 1, INSERM U1315, CNRS UMR 5261, 8 avenue Rockefeller, Lyon, 69008, France
| | - Bruno Galy
- German Cancer Research Center (DKFZ), Division of Virus-associated Carcinogenesis (F170), Heidelberg, Germany
- IB-Cancer Research Foundation, Science Park 2, 66123, Saarbrücken, Germany
| | - Vincent Balter
- Laboratoire de Géologie de Lyon: Terre, Planètes, Environnement, UMR 5276, Ecole Normale Supérieure de Lyon, 46, allée d'Italie, Lyon, Cedex 07, 69364, France
| | - Laurent Schaeffer
- Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (PGNM), Institut NeuroMyoGène, Université Claude Bernard Lyon 1, INSERM U1315, CNRS UMR 5261, 8 avenue Rockefeller, Lyon, 69008, France
- Centre de Biotechnologie Cellulaire, Hospices Civils de Lyon, Lyon, France
| | - Yann-Gaël Gangloff
- Laboratoire Physiopathologie et Génétique du Neurone et du Muscle (PGNM), Institut NeuroMyoGène, Université Claude Bernard Lyon 1, INSERM U1315, CNRS UMR 5261, 8 avenue Rockefeller, Lyon, 69008, France.
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5
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Riccardi V, Viscomi CF, Sandri M, D'Alessandro A, Dzieciatkowska M, Stephenson D, Federti E, Hermann A, Salviati L, Siciliano A, Andolfo I, Alper SL, Ceolan J, Iolascon A, Vattemi G, Danek A, Walker RH, Mensch A, Otto M, Deschauer M, Armbrust M, Beninca' C, Salari V, Fabene P, Peikert K, De Franceschi L. Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy. Acta Neuropathol Commun 2025; 13:83. [PMID: 40275365 PMCID: PMC12023462 DOI: 10.1186/s40478-025-01997-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 04/03/2025] [Indexed: 04/26/2025] Open
Abstract
VPS13A disease (chorea-acanthocytosis), is an ultra-rare autosomal recessive neurodegenerative disorder caused by mutations of the VPS13A gene encoding Vps13A. Increased serum levels of the muscle isoform of creatine kinase associated with often asymptomatic muscle pathology are among the poorly understood early clinical manifestations of VPS13A disease. Here, we carried out an integrated analysis of skeletal muscle from Vps13a-/- mice and from VPS13A disease patient muscle biopsies. The absence of Vps13A impaired autophagy, resulting in pathologic metabolic remodeling characterized by cellular energy depletion, increased protein/lipid oxidation and a hyperactivated unfolded protein response. This was associated with defects in myofibril stability and the myofibrillar regulatory proteome, with accumulation of the myocyte senescence marker, NCAM1. In Vps13a-/- mice, the impairment of autophagy was further supported by the lacking effect of starvation alone or in combination with colchicine on autophagy markers. As a proof of concept, we showed that rapamycin treatment rescued the accumulation of terminal phase autophagy markers LAMP1 and p62 as well as NCAM1, supporting a connection between impaired autophagy and accelerated aging in the absence of VPS13A. The premature senescence was also corroborated by local activation of pro-inflammatory NF-kB-related pathways in both Vps13a-/- mice and patients with VPS13A disease. Our data link for the first time impaired autophagy and inflammaging with muscle dysfunction in the absence of VPS13A. The biological relevance of our mouse findings, supported by human muscle biopsy data, shed new light on the role of VPS13A in muscle homeostasis.
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Affiliation(s)
- Veronica Riccardi
- Department of Engineering for Innovative Medicine- DIMI, University of Verona, Verona, Italy
| | | | - Marco Sandri
- Department of Bomedical Sciences, University of Padua, Padua, Italy
- Venetian Institute of Molecular Medicine, Padova, Italy
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Monika Dzieciatkowska
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Daniel Stephenson
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Enrica Federti
- Department of Engineering for Innovative Medicine- DIMI, University of Verona, Verona, Italy
| | - Andreas Hermann
- Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
- Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, Rostock, Germany
- United Neuroscience Campus Lund-Rostock (UNC), Rostock site, Rostock, Germany
| | - Leonardo Salviati
- Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy
- Pediatric Research Institute (IRP) - Fondazione Città della Speranza, Padova, Italy
| | - Angela Siciliano
- Department of Engineering for Innovative Medicine- DIMI, University of Verona, Verona, Italy
- Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Immacolata Andolfo
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy
- CEINGE Biotecnologie Avanzate Franco Salvatore, Napoli, Italy
| | - Seth L Alper
- Division of Nephrology, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Jacopo Ceolan
- Department of Engineering for Innovative Medicine- DIMI, University of Verona, Verona, Italy
- Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Achille Iolascon
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy
- CEINGE Biotecnologie Avanzate Franco Salvatore, Napoli, Italy
| | - Gaetano Vattemi
- Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
- Department of Neuroscience, Biomedicine and Movement Science, University of Verona, Verona, Italy
| | - Adrian Danek
- Neurologische Klinik und Poliklinik, LMU Klinikum, LMU München, München, Germany
| | - Ruth H Walker
- Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA
- Department of Neurology, Mount Sinai School of Medicine, New York City, NY, USA
| | - Alexander Mensch
- Department of Neurology, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany
| | - Markus Otto
- Department of Neurology, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany
| | - Marcus Deschauer
- Department of Neurology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, München, Germany
| | - Moritz Armbrust
- Goethe University, University Hospital Frankfurt, Neurological Institute (Edinger Institute), Frankfurt am Main, Germany
- Goethe University, University Hospital Frankfurt, University Cancer Center (UCT) Frankfurt-Marburg, Frankfurt am Main, Germany
- Goethe University, University Hospital Frankfurt, Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany
- German Cancer Consortium (DKTK), Partner site Frankfurt / Mainz and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Cristiane Beninca'
- Mitochondria and Metabolism Imaging Core, Department of Endocrinology, University of California, Los Angeles, USA
| | - Valentina Salari
- Department of Engineering for Innovative Medicine- DIMI, University of Verona, Verona, Italy
| | - Paolo Fabene
- Department of Engineering for Innovative Medicine- DIMI, University of Verona, Verona, Italy
- Section of Anatomy and Histology, Department of Excellence in Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Kevin Peikert
- Translational Neurodegeneration Section "Albrecht Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany
- Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, Rostock, Germany
- United Neuroscience Campus Lund-Rostock (UNC), Rostock site, Rostock, Germany
| | - Lucia De Franceschi
- Department of Engineering for Innovative Medicine- DIMI, University of Verona, Verona, Italy.
- Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.
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Li E, Wang R, Li Y, Zan X, Wu S, Yin Y, Yang X, Yin L, Zhang Y, Li J, Zhao X, Zhang C. A Novel Research Paradigm for Sarcopenia of Limb Muscles: Lessons From the Perpetually Working Diaphragm's Anti-Aging Mechanisms. J Cachexia Sarcopenia Muscle 2025; 16:e13797. [PMID: 40223287 PMCID: PMC11994741 DOI: 10.1002/jcsm.13797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 02/16/2025] [Accepted: 02/27/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND Skeletal muscle function and mass continuously decrease during aging. Most studies target limb muscles owing to their direct impact on mobility and falls risk. The diaphragm (DIA), also a type of skeletal muscle with different phenotype, has received less attention. Comparative research of the DIA and limb muscles can reveal their distinct aging characteristics. Critically, the potential endogenous anti-aging mechanisms of DIA that may provide new insights into the mechanisms of sarcopenia in limb muscles remain scarce. METHODS Treadmill and grip tests assessed limb muscle function, while a lung function system evaluated respiratory function in both adult (6-month-old) and old (22-month-old) mice. Histological assessments evaluated muscle mass in both the DIA and tibialis anterior (TA). Transcriptome sequencing identified differentially expressed genes (DEGs) between the DIA and TA with aging. Adeno-associated virus (AAV)-encoding short hairpin (sh) RNA targeting gene was injected into adult mice's TA muscles to knockdown target gene level in TA, and AAV-gene was injected into old mice's TA to overexpress target gene level. RESULTS Old mice displayed significantly reduced running distance (p = 0.0026), maximal speed (p = 0.0019), time to exhaustion (p = 0.0033) and grip strength (p = 0.0055) compared with adult mice, alongside TA's weight loss, decreased myofibre cross-sectional area (CSA) and autophagy deficiency. However, lung function indicators (respiratory rate, tidal volume, minute ventilation volume, forced vital capacity and ratio of forced expiratory volume in 100 or 200 ms to forced vital capacity), as well as DIA weight and morphology remained stable in old mice. Transcriptional analysis revealed 61 DEGs, with significant upregulation or downregulation observed in TA, but without changes in DIA during aging. Smox (spermine oxidase) is one of the DEGs, responsible for catalysing the conversion of spermine to spermidine. It was reported that in muscle atrophy models such as limb immobilisation, fasting and denervation, Smox's levels are positively correlated with muscle mass and function. Additionally, an increase in Smox also promotes mitochondrial biogenesis. In our study, AAV-shSmox adult mice decreased running distance, speed and time, myofibre CSA alongside mitochondrial function, compared with controls. In contrast, old mice with Smox overexpression showed enhanced mitochondrial function. CONCLUSIONS In conclusion, this study reveals aging diversities of TA and DIA, explores the sarcopenia of limb muscles based on the anti-aging properties of DIA, which offers a novel perspective on limb sarcopenia. Our findings suggest Smox as a potential target for developing strategies to mitigate sarcopenia progression.
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Affiliation(s)
- Enhui Li
- Key Laboratory of Cellular Physiology, Ministry of Education, Department of PhysiologyShanxi Medical UniversityTaiyuanShanxiChina
| | - Rui Wang
- Department of NeurologyFirst Hospital of Shanxi Medical UniversityTaiyuanShanxiChina
| | - Yanli Li
- Department of NeurologyFirst Hospital of Shanxi Medical UniversityTaiyuanShanxiChina
| | - Xiang Zan
- The Neurosurgery Department of Shanxi Provincial People's HospitalShanxi Medical UniversityTaiyuanShanxiChina
| | - Shufen Wu
- Key Laboratory of Cellular Physiology, Ministry of Education, Department of PhysiologyShanxi Medical UniversityTaiyuanShanxiChina
| | - Yiru Yin
- Key Laboratory of Cellular Physiology, Ministry of Education, Department of PhysiologyShanxi Medical UniversityTaiyuanShanxiChina
| | - Xiaorong Yang
- Key Laboratory of Cellular Physiology, Ministry of Education, Department of PhysiologyShanxi Medical UniversityTaiyuanShanxiChina
| | - Litian Yin
- Key Laboratory of Cellular Physiology, Ministry of Education, Department of PhysiologyShanxi Medical UniversityTaiyuanShanxiChina
| | - Yu Zhang
- Key Laboratory of Cellular Physiology, Ministry of Education, Department of PhysiologyShanxi Medical UniversityTaiyuanShanxiChina
| | - Jianguo Li
- Key Laboratory of Cellular Physiology, Ministry of Education, Department of PhysiologyShanxi Medical UniversityTaiyuanShanxiChina
| | - Xin Zhao
- Key Laboratory of Cellular Physiology, Ministry of Education, Department of PhysiologyShanxi Medical UniversityTaiyuanShanxiChina
| | - Ce Zhang
- Key Laboratory of Cellular Physiology, Ministry of Education, Department of PhysiologyShanxi Medical UniversityTaiyuanShanxiChina
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7
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Poudel S, Chuang CL, Shrestha HK, Demontis F. Pan-PTM profiling identifies post-translational modifications associated with exceptional longevity and preservation of skeletal muscle function in Drosophila. NPJ AGING 2025; 11:23. [PMID: 40159514 PMCID: PMC11955564 DOI: 10.1038/s41514-025-00215-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 03/18/2025] [Indexed: 04/02/2025]
Abstract
Skeletal muscle weakness is a major component of age-associated frailty, but the underlying mechanisms are not completely understood. Drosophila has emerged as a useful model for studying skeletal muscle aging. In this organism, previous lab-based selection established strains with increased longevity and reduced age-associated muscle functional decline compared to a parental strain. Here, we have applied a computational pipeline (JUMPptm) for retrieving information on 8 post-translational modifications (PTMs) from the skeletal muscle proteomes of 2 long-lived strains and the corresponding parental strain in young and old age. This pan-PTM analysis identified 2470 modified sites (acetylation, carboxylation, deamidation, dihydroxylation, mono-methylation, oxidation, phosphorylation, and ubiquitination) in several classes of proteins, including evolutionarily conserved muscle contractile proteins and metabolic enzymes. PTM consensus sequences further highlight the amino acids that are enriched adjacent to the modified site, thus providing insight into the flanking residues that influence distinct PTMs. Altogether, these analyses identify PTMs associated with muscle functional decline during aging and that may underlie the longevity and negligible functional senescence of lab-evolved Drosophila strains.
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Affiliation(s)
- Suresh Poudel
- Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Chia-Lung Chuang
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Him K Shrestha
- Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Fabio Demontis
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
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8
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Wang ZZ, Xu Q, Zhang YH, Wu RR, Cui JL, Zhou J, Hong JF. Oxidative balance score is associated with increased risk of sarcopenia and sarcopenic obesity in non-elderly adults: results from NHANES 2011-2018. Nutr Metab (Lond) 2025; 22:23. [PMID: 40069772 PMCID: PMC11899308 DOI: 10.1186/s12986-025-00914-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Sarcopenia and obesity, two prevalent health conditions, often coexist and exacerbate each other's impact, increasing the risk of chronic diseases and mortality. This dual condition is termed "sarcopenic obesity." The correlation between oxidative stress (OS) and sarcopenia or obesity was established, and the oxidative balance score (OBS) can serve as an indicator of overall dietary or lifestyle-related OS exposure within an individual. Prior reports have not addressed the relationship between OBS and sarcopenia or sarcopenic obesity in adults under 60. This study endeavors to explore these associations and to identify potential dietary and lifestyle risk factors. METHODS We performed a cross-sectional analysis utilizing data from 4,241 participants in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. OBS is a cumulative score derived from 16 dietary components and 4 lifestyle components, where higher scores indicate greater exposure to antioxidants and lower exposure to pro-oxidant factors, reflecting a reduced oxidative stress burden. Weighted multivariate logistic regression was employed to investigate the association of OBS and sarcopenia and sarcopenic obesity. Further subgroup analyses was conducted to examine interactions with various covariates. The least absolute shrinkage and selection operator (LASSO) regression was applied to identify significant components of OBS associated with sarcopenia and sarcopenic obesity, which were subsequently integrated into a risk prediction nomogram model. The model's predictive accuracy was evaluated using the receiver operating characteristic (ROC) curve. RESULTS After adjusting for potential confounders, the weighted logistic regression analyses demonstrated a significant negative association between OBS and the prevalence of sarcopenia (odds ratio [OR] = 0.954, 95% confidence interval [CI] = 0.925-0.984, P = 0.004) and sarcopenic obesity (OR = 0.948, 95% CI = 0.918-0.980, P = 0.002). The nomogram models, informed by key OBS components identified through LASSO regression, exhibited considerable predictive value for sarcopenia (area under the ROC curve [AUC] = 0.813, 95% CI = 0.792-0.833) and sarcopenic obesity (AUC = 0.894, 95% CI = 0.879-0.909). CONCLUSION This study reveals a robust inverse correlation between OBS and both sarcopenia and sarcopenic obesity in adults aged 20-59. These results suggest that an antioxidant-rich diet and healthy lifestyle practices, including low-fat diets, adequate vitamin B intake, regular physical activity, and weight management, may help mitigate the risk of sarcopenia and sarcopenic obesity. Further research is warranted to confirm these associations and determine causality.
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Affiliation(s)
- Zhu-Zhu Wang
- The First Affiliated Hospital of Anhui Medical University, No, 218 Ji Xi Road, Shu Shan District, Hefei City, Anhui Province, 230022, China
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, 230032, China
| | - Qin Xu
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, 230032, China
| | - Yu-Han Zhang
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, 230032, China
| | - Rong-Rong Wu
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, 230032, China
| | - Jun-Ling Cui
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, 230032, China
| | - Ji Zhou
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, 230032, China
- Department of Epidemiology and Health Statistics, School of Public Health, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, 2300032, China
| | - Jing-Fang Hong
- School of Nursing, Anhui Medical University, No. 81 Mei Shan Road, Shu Shan District, Hefei City, Anhui Province, 230032, China.
- Nursing International Collaboration Research Center of Anhui Province, Hefei City, Anhui Province, 230601, China.
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9
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Cocchiararo I, Castets P. Recent advances in the clinical spectrum and pathomechanisms associated with X-linked myopathy with excessive autophagy and other VMA21-related disorders. J Neuromuscul Dis 2025:22143602251314767. [PMID: 40033998 DOI: 10.1177/22143602251314767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
X-linked myopathy with excessive autophagy (XMEA) is a rare neuromuscular disorder caused by mutations in the VMA21 gene, encoding a chaperone protein present in the endoplasmic reticulum (ER). In yeast and human, VMA21 has been shown to chaperone the assembly of the vacuolar (v)-ATPase proton pump required for the acidification of lysosomes and other organelles. In line with this, VMA21 deficiency in XMEA impairs autophagic degradation steps, which would be key in XMEA pathogenesis. Recent years have witnessed a surge of interest in VMA21, with the identification of novel mutations causing a congenital disorder of glycosylation (CDG) with liver affection, and its potent implication in cancer predisposition. With this, VMA21 deficiency has been further linked to defective glycosylation, lipid metabolism dysregulation and ER stress. Moreover, the identification of two VMA21 isoforms, namely VMA21-101 and VMA21-120, has opened novel avenues regarding the pathomechanisms leading to XMEA and VMA21-CDG. In this review, we discuss recent advances on the clinical spectrum associated with VMA21 deficiency and on the pathophysiological roles of VMA21.
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Affiliation(s)
- Ilaria Cocchiararo
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Perrine Castets
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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10
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Then AA, Goenawan H, Lesmana R, Christoper A, Sylviana N, Gunadi JW. Exploring the potential regulation of DUOX in thyroid hormone‑autophagy signaling via IGF‑1 in the skeletal muscle (Review). Biomed Rep 2025; 22:39. [PMID: 39781041 PMCID: PMC11704872 DOI: 10.3892/br.2024.1917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 09/16/2024] [Indexed: 01/11/2025] Open
Abstract
Dual oxidases (DUOX) are enzymes that have the main function in producing reactive oxygen species (ROS) in various tissues. DUOX also play an important role in the synthesis of H2O2, which is essential for the production of thyroid hormone. Thyroid hormones can influence the process of muscle development through direct stimulation of ROS, 5' AMP-activated protein kinase (AMPK) and mTOR and indirect effect autophagy and the insulin-like growth factor 1 (IGF-1) pathway. IGF-1 signaling controls autophagy in two ways: Inhibiting autophagy through activation of the PI3K/AKT/mTOR/MAPK pathway and promoting mitophagy through the nuclear factor erythroid 2-related factor 2-binding receptor Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3. Thyroid hormone deficiency caused by the absence of DUOX should be considered because it might have a significant effect on the growth of skeletal muscle. The effect of DUOX regulation on thyroid hormone autophagy via IGF-1 in skeletal muscle has not been well investigated. The present review discussed the regulatory interactions between DUOX, thyroid hormone, IGF-1 and autophagy, which can influence skeletal muscle development.
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Affiliation(s)
- Andreas Adiwinata Then
- Master's Program in Basic Biomedical Sciences, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java 40161, Indonesia
| | - Hanna Goenawan
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Jatinangor-Sumedang, West Java 45363, Indonesia
- Biological Activity Division, Central Laboratory, Universitas Padjadjaran, Jatinangor-Sumedang, West Java 45363, Indonesia
| | - Ronny Lesmana
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Jatinangor-Sumedang, West Java 45363, Indonesia
- Biological Activity Division, Central Laboratory, Universitas Padjadjaran, Jatinangor-Sumedang, West Java 45363, Indonesia
| | - Andreas Christoper
- Doctoral Program in Medical Science, PMDSU Program Batch VI, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java 40161, Indonesia
| | - Nova Sylviana
- Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Jatinangor-Sumedang, West Java 45363, Indonesia
| | - Julia Windi Gunadi
- Department of Physiology, Faculty of Medicine, Maranatha Christian University, Bandung, West Java 40164, Indonesia
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11
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Ru Q, Li Y, Zhang X, Chen L, Wu Y, Min J, Wang F. Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects. Bone Res 2025; 13:27. [PMID: 40000618 PMCID: PMC11861620 DOI: 10.1038/s41413-024-00398-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/23/2024] [Accepted: 12/16/2024] [Indexed: 02/27/2025] Open
Abstract
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
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Affiliation(s)
- Qin Ru
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xi Zhang
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Lin Chen
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yuxiang Wu
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China.
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
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12
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Wu Y, Yang Y, Du C, Peng X, Fan W, Chang B, Shan C. Berberine attenuates obesity-induced skeletal muscle atrophy via regulation of FUNDC1 in skeletal muscle of mice. Sci Rep 2025; 15:4918. [PMID: 39930016 PMCID: PMC11811154 DOI: 10.1038/s41598-025-89297-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 02/04/2025] [Indexed: 02/13/2025] Open
Abstract
Skeletal muscle atrophy is a complication of obesity, partially induced by impaired mitophagy. This study investigates whether Berberine(BBR) protects mice from obese skeletal muscle atrophy and the underlying molecular mechanism. Twenty C57BL/6 mice were fed a high-fat diet until they weighed more than 20% of the average body weight of the control group. The mice were then divided into two groups and gavaged with BBR or vehicle for 8 weeks. 10 mice were used as controls. Fasting blood glucose was measured, an oral glucose tolerance test was performed, and the mice were measured for grip strength and exercise capacity. H&E and Oil Red O staining were used to observe the pathological changes of skeletal muscle. MURF1, FBXO32, BAX, BCL2, P62, LC3 and mitophagy receptor FUNDC1 were observed in mice. BBR was intervened in C2C12 myotubes. The role of FUNDC1 was verified by RNA interference. We found that BBR treatment increased grip strength and improved muscle function. BBR not only reduced weight gain, excessive lipid accumulation and hyperlipidemia, but also ameliorated obesity-induced skeletal muscle atrophy and apoptosis. BBR promoted autophagy and increased FUNDC1 protein expression. The same positive effects were observed after BBR intervening on C2C12 myotubes, whereas FUNDC1 RNA interference attenuated the anti-skeletal muscle atrophy effect of BBR. These results suggest that BBR ameliorated obesity-induced skeletal muscle atrophy in mice by modulating the skeletal muscle mitophagy receptor FUNDC1, which may be a potential therapeutic target for obesity-induced skeletal muscle atrophy.
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Affiliation(s)
- Yijie Wu
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, 300134, China, No.6 North Huanrui Rd, Beichen District, Tianjin, P.R China
| | - Yanhui Yang
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, 300134, China, No.6 North Huanrui Rd, Beichen District, Tianjin, P.R China
| | - Caixia Du
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, 300134, China, No.6 North Huanrui Rd, Beichen District, Tianjin, P.R China
| | - Xiaoyue Peng
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, 300134, China, No.6 North Huanrui Rd, Beichen District, Tianjin, P.R China
| | - Wenying Fan
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, 300134, China, No.6 North Huanrui Rd, Beichen District, Tianjin, P.R China
| | - Baocheng Chang
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, 300134, China, No.6 North Huanrui Rd, Beichen District, Tianjin, P.R China.
| | - Chunyan Shan
- NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin, 300134, China, No.6 North Huanrui Rd, Beichen District, Tianjin, P.R China.
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13
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Cheng Y, Lin S, Cao Z, Yu R, Fan Y, Chen J. The role of chronic low-grade inflammation in the development of sarcopenia: Advances in molecular mechanisms. Int Immunopharmacol 2025; 147:114056. [PMID: 39799736 DOI: 10.1016/j.intimp.2025.114056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 12/16/2024] [Accepted: 01/06/2025] [Indexed: 01/15/2025]
Abstract
With the exacerbation of global population aging, sarcopenia has become an increasingly recognized public health issue. Sarcopenia, characterized by a progressive decline in skeletal muscle mass, strength, and function, significantly impacts the quality of life in the elderly. Herein, we explore the role of chroniclow-gradeinflammation in the development of sarcopenia and its underlying molecular mechanisms, including chronic inflammation-associated signaling pathways, immunosenescence, obesity and lipid infiltration, gut microbiota dysbiosis and intestinal barrier disruption, and the decline of satellite cells. The interplay and interaction of these molecular mechanisms provide new perspectives on the complexity of the pathogenesis of sarcopenia and offer a theoretical foundation for the development of future therapeutic strategies.
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Affiliation(s)
- Ying Cheng
- Department of Gastroenterology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040 China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 200040 China
| | - Shangjin Lin
- Department of Orthopedics, Huadong Hospital Affiliated to Fudan University, Shanghai 200040 China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 200040 China
| | - Ziyi Cao
- Department of Gastroenterology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040 China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 200040 China
| | - Runzhi Yu
- Department of Gastroenterology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040 China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 200040 China
| | - Yongqian Fan
- Department of Orthopedics, Huadong Hospital Affiliated to Fudan University, Shanghai 200040 China.
| | - Jie Chen
- Department of Gastroenterology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040 China.
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14
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Brown JL, Xu H, Duggan E, Rosenfeld CS, Remmen HV. Pharmacological reduction of lipid hydroperoxides as a potential modulator of sarcopenia. J Physiol 2025; 603:837-854. [PMID: 39777675 PMCID: PMC12042244 DOI: 10.1113/jp287090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
We previously reported that elevated expression of phospholipid hydroperoxide glutathione peroxidase 4, an enzyme that regulates membrane lipid hydroperoxides, can mitigate sarcopenia in mice. However, it is still unknown whether a pharmacological intervention designed to modulate lipid hydroperoxides might be an effective strategy to reduce sarcopenia in aged mice. Here we asked whether a newly developed compound, CMD-35647 (CMD), can reduce muscle atrophy induced by sciatic nerve transection. We treated mice daily with vehicle or CMD (15 mg/kg, i.p. injection) starting 1 day prior to denervation. CMD treatment reduced hydroperoxide generation and blunted muscle atrophy by over 17% in denervated muscle. To test whether CMD can reduce ageing-induced muscle atrophy and weakness, we treated mice with either vehicle or CMD (15 mg/kg, i.p. injection) 3 days per week for 8 months, starting at 18 months of age until 26 months of age. We measured muscle mass, functional status of neuromuscular junctions, muscle contractile function and mitochondrial function in control and CMD-treated 26-month-old female mice. Treatment with CMD conferred protection against muscle atrophy in both tibialis anterior and extensor digitorum longus that was associated with maintenance of fibre size of MHC 2b and 2x fibres. Mitochondrial respiration was also protected in CMD-treated mice. We also found that muscle force generation was protected with CMD treatment despite denervation in ∼25% of the muscle fibres. Overall, this study shows that pharmacological interventions designed to reduce lipid hydroperoxides might be effective for preventing sarcopenia. KEY POINTS: Sarcopenia in aged mice is associated with muscle loss, contractile dysfunction, denervation, and reduced mitochondrial respiration. CMD-35647 is a pharmocological compound that can neutralize lipid hydroperoxides. 8 month treatment of CMD-35647 mitigated muscle atrophy in tibialis anterior and extensor digitorum longus. 8 month treatment of CMD-35647 improved muscle function in aged mice independent of the neuromuscular junction. Aged mice treated with CMD-35647 had greater respiration in red gastrocnemius muscle when compared to vehicle treated mice.
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Affiliation(s)
- Jacob L. Brown
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States
- Oklahoma City VA Medical Center, Oklahoma City, OK 73104, United States
| | - Hongyang Xu
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States
| | - Elizabeth Duggan
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States
- Oklahoma City VA Medical Center, Oklahoma City, OK 73104, United States
| | | | - Holly Van Remmen
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States
- Oklahoma City VA Medical Center, Oklahoma City, OK 73104, United States
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15
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Tu H, Hakim A, Kim J, Zhu Z, Tian Y, Pipinos I, Li Y. Neuromuscular Junction Damage in the Calf Muscles of Patients With Advanced Peripheral Artery Disease. Neuropathol Appl Neurobiol 2025; 51:e70008. [PMID: 39989162 PMCID: PMC11848508 DOI: 10.1111/nan.70008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 01/19/2025] [Accepted: 02/14/2025] [Indexed: 02/25/2025]
Abstract
AIMS Peripheral artery disease (PAD) reduces blood flow to the legs and causes severe muscle and leg dysfunction for PAD patients. Skeletal muscle contractile function is dependent on the health of the muscle itself and that of the neuromuscular junction (NMJ) on the muscle membrane. METHODS To determine whether the NMJ, including the motor nerve terminals and nicotinic acetylcholine receptors (nAChR), is damaged in PAD, gastrocnemius muscles were collected from 3 controls and 13 PAD patients to capture images from 331 control NMJs and 512 PAD NMJs. RESULTS For the motor nerve terminals, there were more denervated nAChR clusters and fewer nerve terminal occupancies in NMJs in PAD patients, compared with controls. For the nAChR clusters in the NMJs, the area per nAChR cluster was 369.3 ± 6.7 versus 225.2 ± 5.3 μm2, the area per fragment was 195.9 ± 9.2 versus 107.1 ± 3.1 μm2, the number of fragments per nAChR cluster was 2.3 ± 0.1 versus 3.2 ± 0.1, the nAChR cluster area per endplate area was 75.7 ± 1.6 versus 55.7 ± 1.1%, total distance of fragments per nAChR cluster was 4.6 ± 0.4 versus 8.8 ± 0.8 μm, and the fragmented nAChR clusters were 7.6% versus 21.6% of total nAChR clusters in controls versus PAD patients, respectively (p < 0.05 in all parameters). CONCLUSIONS Our data demonstrate deterioration of the motor nerve terminals and nAChR clusters, which may compromise neuromuscular transmission, and contribute to the severe leg dysfunction observed in patients with PAD.
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Affiliation(s)
- Huiyin Tu
- Department of Emergency MedicineUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Ali H. Hakim
- Department of SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Julian K. Kim
- Department of SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Zhen Zhu
- Department of SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Yuqian Tian
- Department of SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Iraklis I. Pipinos
- Department of SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA
- Department of Surgery and VA Research ServiceVA Nebraska‐Western Iowa Health Care SystemOmahaNebraskaUSA
| | - Yu‐Long Li
- Department of Emergency MedicineUniversity of Nebraska Medical CenterOmahaNebraskaUSA
- Department of Cellular and Integrative Physiology, University of Nebraska Medical CenterOmahaNebraskaUSA
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16
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Normand-Gravier T, Solsona R, Dablainville V, Racinais S, Borrani F, Bernardi H, Sanchez AMJ. Effects of thermal interventions on skeletal muscle adaptations and regeneration: perspectives on epigenetics: a narrative review. Eur J Appl Physiol 2025; 125:277-301. [PMID: 39607529 PMCID: PMC11829912 DOI: 10.1007/s00421-024-05642-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/12/2024] [Indexed: 11/29/2024]
Abstract
Recovery methods, such as thermal interventions, have been developed to promote optimal recovery and maximize long-term training adaptations. However, the beneficial effects of these recovery strategies remain a source of controversy. This narrative review aims to provide a detailed understanding of how cold and heat interventions impact long-term training adaptations. Emphasis is placed on skeletal muscle adaptations, particularly the involvement of signaling pathways regulating protein turnover, ribosome and mitochondrial biogenesis, as well as the critical role of satellite cells in promoting myofiber regeneration following atrophy. The current literature suggests that cold interventions can blunt molecular adaptations (e.g., protein synthesis and satellite cell activation) and oxi-inflammatory responses after resistance exercise, resulting in diminished exercise-induced hypertrophy and lower gains in isometric strength during training protocols. Conversely, heat interventions appear promising for mitigating skeletal muscle degradation during immobilization and atrophy. Indeed, heat treatments (e.g., passive interventions such as sauna-bathing or diathermy) can enhance protein turnover and improve the maintenance of muscle mass in atrophic conditions, although their effects on uninjured skeletal muscles in both humans and rodents remain controversial. Nonetheless, heat treatment may serve as an important tool for attenuating atrophy and preserving mitochondrial function in immobilized or injured athletes. Finally, the potential interplay between exercise, thermal interventions and epigenetics is discussed. Future studies must be encouraged to clarify how repeated thermal interventions (heat and cold) affect long-term exercise training adaptations and to determine the optimal modalities (i.e., method of application, temperature, duration, relative humidity, and timing).
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Affiliation(s)
- Tom Normand-Gravier
- UMR866, Dynamique du Muscle et Métabolisme (DMeM), INRAE, University of Montpellier, Montpellier, France
- Laboratoire Interdisciplinaire Performance Santé Environnement de Montagne (LIPSEM), Faculty of Sports Sciences, University of Perpignan Via Domitia, UR 4640, 7 Avenue Pierre de Coubertin, 66120, Font-Romeu, France
| | - Robert Solsona
- Laboratoire Interdisciplinaire Performance Santé Environnement de Montagne (LIPSEM), Faculty of Sports Sciences, University of Perpignan Via Domitia, UR 4640, 7 Avenue Pierre de Coubertin, 66120, Font-Romeu, France
| | - Valentin Dablainville
- UMR866, Dynamique du Muscle et Métabolisme (DMeM), INRAE, University of Montpellier, Montpellier, France
- Research and Scientific Support Department, Aspetar Orthopedic and Sports Medicine Hospital, 29222, Doha, Qatar
| | - Sébastien Racinais
- Environmental Stress Unit, CREPS Montpellier-Font-Romeu, Montpellier, France
| | - Fabio Borrani
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland
| | - Henri Bernardi
- UMR866, Dynamique du Muscle et Métabolisme (DMeM), INRAE, University of Montpellier, Montpellier, France
| | - Anthony M J Sanchez
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland.
- Laboratoire Interdisciplinaire Performance Santé Environnement de Montagne (LIPSEM), Faculty of Sports Sciences, University of Perpignan Via Domitia, UR 4640, 7 Avenue Pierre de Coubertin, 66120, Font-Romeu, France.
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17
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Ting HC, Guo YT, Su HL, Chen YS, Lin SZ, Harn HJ, Chang CY. Rapid iPSC-derived neuromuscular junction model uncovers motor neuron dominance in amyotrophic lateral sclerosis cytopathy. Cell Death Discov 2025; 11:23. [PMID: 39863573 PMCID: PMC11762734 DOI: 10.1038/s41420-025-02302-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 12/23/2024] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
The neuromuscular junction (NMJ) is essential for transmitting signals from motor neurons (MNs) to skeletal muscles (SKMs), and its dysfunction can lead to severe motor disorders. However, our understanding of the NMJ is limited by the absence of accurate human models. Although human induced pluripotent stem cell (iPSC)-derived models have advanced NMJ research, their application is constrained by challenges such as limited differentiation efficiency, lengthy generation times, and cryopreservation difficulties. To overcome these limitations, we developed a rapid human NMJ model using cryopreserved MNs and SKMs derived from iPSCs. Within 12 days of coculture, we successfully recreated NMJ-specific connectivity that closely mirrors in vivo synapse formation. Using this model, we investigated amyotrophic lateral sclerosis (ALS) and replicated ALS-specific NMJ cytopathies with SOD1 mutant and corrected isogenic iPSC lines. Quantitative analysis of 3D confocal microscopy images revealed a critical role of MNs in initiating ALS-related NMJ cytopathies, characterized by alterations in the volume, number, intensity, and distribution of acetylcholine receptors, ultimately leading to impaired muscle contractions. Our rapid and precise in vitro NMJ model offers significant potential for advancing research on NMJ physiology and pathology, as well as for developing treatments for NMJ-related diseases.
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Affiliation(s)
- Hsiao-Chien Ting
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yun-Ting Guo
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Hong-Lin Su
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
- The iEGG and Animal Biotechnology Research Center, National Chung Hsing University, Taichung, Taiwan
| | - Yu-Shuan Chen
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Neuroscience Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Center for General Education, Tzu Chi University, Hualien, Taiwan
| | - Shinn-Zong Lin
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Horng-Jyh Harn
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Department of Pathology, Hualien Tzu Chi Hospital and Tzu Chi University, Hualien, Taiwan
| | - Chia-Yu Chang
- Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
- Neuroscience Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
- Center for General Education, Tzu Chi University, Hualien, Taiwan.
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18
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Wang T, Zhou D, Hong Z. Sarcopenia and cachexia: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2025; 6:e70030. [PMID: 39764565 PMCID: PMC11702502 DOI: 10.1002/mco2.70030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 03/17/2025] Open
Abstract
Sarcopenia is defined as a muscle-wasting syndrome that occurs with accelerated aging, while cachexia is a severe wasting syndrome associated with conditions such as cancer and immunodeficiency disorders, which cannot be fully addressed through conventional nutritional supplementation. Sarcopenia can be considered a component of cachexia, with the bidirectional interplay between adipose tissue and skeletal muscle potentially serving as a molecular mechanism for both conditions. However, the underlying mechanisms differ. Recognizing the interplay and distinctions between these disorders is essential for advancing both basic and translational research in this area, enhancing diagnostic accuracy and ultimately achieving effective therapeutic solutions for affected patients. This review discusses the muscle microenvironment's changes contributing to these conditions, recent therapeutic approaches like lifestyle modifications, small molecules, and nutritional interventions, and emerging strategies such as gene editing, stem cell therapy, and gut microbiome modulation. We also address the challenges and opportunities of multimodal interventions, aiming to provide insights into the pathogenesis and molecular mechanisms of sarcopenia and cachexia, ultimately aiding in innovative strategy development and improved treatments.
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Affiliation(s)
- Tiantian Wang
- Department of NeurologyWest China Hospital of Sichuan UniversityChengduSichuanChina
- Institute of Brain Science and Brain‐Inspired Technology of West China HospitalSichuan UniversityChengduSichuanChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduSichuanChina
| | - Dong Zhou
- Department of NeurologyWest China Hospital of Sichuan UniversityChengduSichuanChina
- Institute of Brain Science and Brain‐Inspired Technology of West China HospitalSichuan UniversityChengduSichuanChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduSichuanChina
| | - Zhen Hong
- Department of NeurologyWest China Hospital of Sichuan UniversityChengduSichuanChina
- Institute of Brain Science and Brain‐Inspired Technology of West China HospitalSichuan UniversityChengduSichuanChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduSichuanChina
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19
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Ng SY, Mikhail AI, Mattina SR, Mohammed SA, Khan SK, Desjardins EM, Lim C, Phillips SM, Steinberg GR, Ljubicic V. AMPK regulates the maintenance and remodelling of the neuromuscular junction. Mol Metab 2025; 91:102066. [PMID: 39571900 PMCID: PMC11646796 DOI: 10.1016/j.molmet.2024.102066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/31/2024] [Accepted: 11/08/2024] [Indexed: 11/27/2024] Open
Abstract
OBJECTIVE The molecular mechanisms underlying the maintenance and adaptability of the neuromuscular junction (NMJ) remain poorly understood. This study aimed to investigate the role of AMP-activated protein kinase (AMPK) as a key regulator of NMJ stability and plasticity. METHOD A comprehensive, multifaceted approach was employed, integrating genetic, physiological, and pharmacological methodologies to elucidate the role of skeletal muscle AMPK in modulating the neuromuscular synapse. RESULTS Our findings reveal an increased abundance of AMPK transcripts within the NMJ and an age-associated decline in AMPK activity and synapse-specific mitochondrial gene expression. Young mice null for skeletal muscle AMPK displayed a neuromuscular phenotype akin to aged animals. Pharmacological AMPK stimulation facilitated its localization in subsynaptic myonuclei, preceded the induction of several NMJ-related transcripts, and enhanced myotube acetylcholine receptor clustering. Exercise-induced AMPK activation in mouse muscle elicited a broad NMJ-related gene response, consistent with human exercise data. CONCLUSIONS These findings highlight a critical role for AMPK in the maintenance and remodeling of the NMJ, highlighting its potential as a therapeutic target for age-related and neuromuscular disorders.
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Affiliation(s)
- Sean Y Ng
- Department of Kinesiology, McMaster University, 1280 Main St. W., Hamilton, ON, Canada
| | - Andrew I Mikhail
- Department of Kinesiology, McMaster University, 1280 Main St. W., Hamilton, ON, Canada
| | - Stephanie R Mattina
- Department of Kinesiology, McMaster University, 1280 Main St. W., Hamilton, ON, Canada
| | - Salah A Mohammed
- Department of Kinesiology, McMaster University, 1280 Main St. W., Hamilton, ON, Canada
| | - Shahzeb K Khan
- Department of Kinesiology, McMaster University, 1280 Main St. W., Hamilton, ON, Canada
| | - Eric M Desjardins
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main St. W., Hamilton, ON, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, ON, Canada
| | - Changhyun Lim
- Department of Kinesiology, McMaster University, 1280 Main St. W., Hamilton, ON, Canada
| | - Stuart M Phillips
- Department of Kinesiology, McMaster University, 1280 Main St. W., Hamilton, ON, Canada
| | - Gregory R Steinberg
- Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1280 Main St. W., Hamilton, ON, Canada; Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, ON, Canada
| | - Vladimir Ljubicic
- Department of Kinesiology, McMaster University, 1280 Main St. W., Hamilton, ON, Canada.
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20
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Haynes J, Joshi A, Larue RC, Eisenmann ED, Govindarajan R. Nucleoside Reverse Transcriptase Inhibitor (NRTI)-Induced Neuropathy and Mitochondrial Toxicity: Limitations of the Poly-γ Hypothesis and the Potential Roles of Autophagy and Drug Transport. Pharmaceutics 2024; 16:1592. [PMID: 39771570 PMCID: PMC11677988 DOI: 10.3390/pharmaceutics16121592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/28/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of highly active antiretroviral therapy (HAART)-the current standard of care for treating human immunodeficiency virus (HIV) infection. Despite their efficacy, NRTIs cause numerous treatment-limiting adverse effects, including a distinct peripheral neuropathy, called antiretroviral toxic neuropathy (ATN). ATN primarily affects the extremities with shock-like tingling pain, a pins-and-needles prickling sensation, and numbness. Despite its negative impact on patient quality of life, ATN remains poorly understood, which limits treatment options and potential interventions for people living with HIV (PLWH). Elucidating the underlying pathophysiology of NRTI-induced ATN will facilitate the development of effective treatment strategies and improved patient outcomes. In this article, we will comprehensively review ATN in the setting of NRTI treatment for HIV infection.
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Affiliation(s)
- John Haynes
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (J.H.); (A.J.); (E.D.E.)
| | - Arnav Joshi
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (J.H.); (A.J.); (E.D.E.)
| | - Ross C. Larue
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA;
| | - Eric D. Eisenmann
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (J.H.); (A.J.); (E.D.E.)
- Translational Therapeutics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Rajgopal Govindarajan
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; (J.H.); (A.J.); (E.D.E.)
- Translational Therapeutics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
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21
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Motanova E, Pirazzini M, Negro S, Rossetto O, Narici M. Impact of ageing and disuse on neuromuscular junction and mitochondrial function and morphology: Current evidence and controversies. Ageing Res Rev 2024; 102:102586. [PMID: 39557298 DOI: 10.1016/j.arr.2024.102586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/01/2024] [Accepted: 11/12/2024] [Indexed: 11/20/2024]
Abstract
Inactivity and ageing can have a detrimental impact on skeletal muscle and the neuromuscular junction (NMJ). Decreased physical activity results in muscle atrophy, impaired mitochondrial function, and NMJ instability. Ageing is associated with a progressive decrease in muscle mass, deterioration of mitochondrial function in the motor axon terminals and in myofibres, NMJ instability and loss of motor units. Focusing on the impact of inactivity and ageing, this review examines the consequences on NMJ stability and the role of mitochondrial dysfunction, delving into their complex relationship with ageing and disuse. Evidence suggests that mitochondrial dysfunction can be a pathogenic driver for NMJ alterations, with studies revealing the role of mitochondrial defects in motor neuron degeneration and NMJ instability. Two perspectives behind NMJ instability are discussed: one is that mitochondrial dysfunction in skeletal muscle triggers NMJ deterioration, the other envisages dysfunction of motor terminal mitochondria as a primary contributor to NMJ instability. While evidence from these studies supports both perspectives on the relationship between NMJ dysfunction and mitochondrial impairment, gaps persist in the understanding of how mitochondrial dysfunction can cause NMJ deterioration. Further research, both in humans and in animal models, is essential for unravelling the mechanisms and potential interventions for age- and inactivity-related neuromuscular and mitochondrial alterations.
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Affiliation(s)
- Evgeniia Motanova
- Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy.
| | - Marco Pirazzini
- Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy; CIR-MYO Myology Center, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy
| | - Samuele Negro
- Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy; CIR-MYO Myology Center, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy
| | - Ornella Rossetto
- Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy; CIR-MYO Myology Center, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy; Institute of Neuroscience, National Research Council, Via Ugo Bassi 58/B, Padova 35131, Italy
| | - Marco Narici
- Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy; CIR-MYO Myology Center, University of Padova, Via U. Bassi 58/B, Padova 35131, Italy
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22
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Grima-Terrén M, Campanario S, Ramírez-Pardo I, Cisneros A, Hong X, Perdiguero E, Serrano AL, Isern J, Muñoz-Cánoves P. Muscle aging and sarcopenia: The pathology, etiology, and most promising therapeutic targets. Mol Aspects Med 2024; 100:101319. [PMID: 39312874 DOI: 10.1016/j.mam.2024.101319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 09/13/2024] [Accepted: 09/16/2024] [Indexed: 09/25/2024]
Abstract
Sarcopenia is a progressive muscle wasting disorder that severely impacts the quality of life of elderly individuals. Although the natural aging process primarily causes sarcopenia, it can develop in response to other conditions. Because muscle function is influenced by numerous changes that occur with age, the etiology of sarcopenia remains unclear. However, recent characterizations of the aging muscle transcriptional landscape, signaling pathway disruptions, fiber and extracellular matrix compositions, systemic metabolomic and inflammatory responses, mitochondrial function, and neurological inputs offer insights and hope for future treatments. This review will discuss age-related changes in healthy muscle and our current understanding of how this can deteriorate into sarcopenia. As our elderly population continues to grow, we must understand sarcopenia and find treatments that allow individuals to maintain independence and dignity throughout an extended lifespan.
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Affiliation(s)
- Mercedes Grima-Terrén
- Altos Labs, San Diego Institute of Science, San Diego, CA, 92121, USA; Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, 08003, Spain
| | - Silvia Campanario
- Altos Labs, San Diego Institute of Science, San Diego, CA, 92121, USA; Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, 08003, Spain
| | - Ignacio Ramírez-Pardo
- Altos Labs, San Diego Institute of Science, San Diego, CA, 92121, USA; Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, 08003, Spain
| | - Andrés Cisneros
- Altos Labs, San Diego Institute of Science, San Diego, CA, 92121, USA; Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, 08003, Spain
| | - Xiaotong Hong
- Altos Labs, San Diego Institute of Science, San Diego, CA, 92121, USA
| | | | - Antonio L Serrano
- Altos Labs, San Diego Institute of Science, San Diego, CA, 92121, USA
| | - Joan Isern
- Altos Labs, San Diego Institute of Science, San Diego, CA, 92121, USA
| | - Pura Muñoz-Cánoves
- Altos Labs, San Diego Institute of Science, San Diego, CA, 92121, USA; Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, 08003, Spain.
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23
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Matteini F, Montserrat‐Vazquez S, Florian MC. Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan. FEBS Lett 2024; 598:2776-2787. [PMID: 38604982 PMCID: PMC11586596 DOI: 10.1002/1873-3468.14865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 02/03/2024] [Accepted: 03/07/2024] [Indexed: 04/13/2024]
Abstract
Aging is associated with a global decline in stem cell function. To date, several strategies have been proposed to rejuvenate aged stem cells: most of these result in functional improvement of the tissue where the stem cells reside, but the impact on the lifespan of the whole organism has been less clearly established. Here, we review some of the most recent work dealing with interventions that improve the regenerative capacity of aged somatic stem cells in mammals and that might have important translational possibilities. Overall, we underscore that somatic stem cell rejuvenation represents a strategy to improve tissue homeostasis upon aging and present some recent approaches with the potential to affect health span and lifespan of the whole organism.
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Affiliation(s)
- Francesca Matteini
- Stem Cell Aging Group, Regenerative Medicine ProgramThe Bellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
- Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia (P‐CMR[C])BarcelonaSpain
| | - Sara Montserrat‐Vazquez
- Stem Cell Aging Group, Regenerative Medicine ProgramThe Bellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
- Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia (P‐CMR[C])BarcelonaSpain
| | - M. Carolina Florian
- Stem Cell Aging Group, Regenerative Medicine ProgramThe Bellvitge Institute for Biomedical Research (IDIBELL)BarcelonaSpain
- Program for Advancing the Clinical Translation of Regenerative Medicine of Catalonia (P‐CMR[C])BarcelonaSpain
- Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER‐BBN)MadridSpain
- The Catalan Institution for Research and Advanced Studies (ICREA)BarcelonaSpain
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24
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Wang C, Liu X, Hu X, Wu T, Duan R. Therapeutic targeting of GDF11 in muscle atrophy: Insights and strategies. Int J Biol Macromol 2024; 279:135321. [PMID: 39236952 DOI: 10.1016/j.ijbiomac.2024.135321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 07/29/2024] [Accepted: 09/02/2024] [Indexed: 09/07/2024]
Abstract
The exploration of novel therapeutic avenues for skeletal muscle atrophy is imperative due to its significant health impact. Recent studies have spotlighted growth differentiation factor 11 (GDF11), a TGFβ superfamily member, for its rejuvenating role in reversing age-related tissue dysfunction. This review synthesizes current findings on GDF11, elucidating its distinct biological functions and the ongoing debates regarding its efficacy in muscle homeostasis. By addressing discrepancies in current research outcomes and its ambiguous role due to its homological identity to myostatin, a negative regulator of muscle mass, this review aims to clarify the role of GDF11 in muscle homeostasis and its potential as a therapeutic target for muscle atrophy. Through a thorough examination of GDF11's mechanisms and effects, this review provides insights that could pave the way for innovative treatments for muscle atrophy, emphasizing the need and strategies to boost endogenous GDF11 levels for therapeutic potential.
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Affiliation(s)
- Chuanzhi Wang
- Lab of Regenerative Medicine in Sports Science, School of Physical Education and Sports Science, South China Normal University, Guangzhou, China
| | - Xiaocao Liu
- Lab of Regenerative Medicine in Sports Science, School of Physical Education and Sports Science, South China Normal University, Guangzhou, China
| | - Xilong Hu
- Lab of Regenerative Medicine in Sports Science, School of Physical Education and Sports Science, South China Normal University, Guangzhou, China
| | - Tao Wu
- Lab of Regenerative Medicine in Sports Science, School of Physical Education and Sports Science, South China Normal University, Guangzhou, China
| | - Rui Duan
- Lab of Regenerative Medicine in Sports Science, School of Physical Education and Sports Science, South China Normal University, Guangzhou, China.
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25
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Xiao L, Chen J, He X, Zhang X, Luo W. Whole-transcriptome sequencing revealed the ceRNA regulatory network during the proliferation and differentiation of goose myoblast. Poult Sci 2024; 103:104173. [PMID: 39153268 PMCID: PMC11471125 DOI: 10.1016/j.psj.2024.104173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 07/13/2024] [Accepted: 07/31/2024] [Indexed: 08/19/2024] Open
Abstract
The Shitou goose, the largest meat-type goose breed, is an ideal model for offering insights into enhancing meat production efficiency through understanding its genetic regulation of muscle development. Here, through whole-transcriptomic analysis of embryonic leg muscles, we identified 847 differentially expressed genes (DEG), 244 differentially expressed lncRNAs (DEL), 37 differentially expressed circRNAs (DEC), and 84 differentially expressed miRNAs (DEM). Gene ontology (GO) analysis highlighted the significant enrichment of differentially expressed RNAs in muscle structure development, actin filament-based processes, and the actin cytoskeleton pathway. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified pathways associated with the FoxO signaling pathway, AMPK signaling pathway, Wnt signaling pathway and calcium signaling pathway. Furthermore, we utilized Miranda, TargetScan, and miRDB to identify regulatory networks that involve interactions between lncRNA-mRNA, circRNA-mRNA, miRNA-mRNA, lncRNA-miRNA-mRNA, and circRNA-miRNA-mRNA, which regulated the growth and development of skeletal muscle. Notably, differentially expressed genes within the ceRNA network were most significantly enriched in the regulation of actin cytoskeletal organization. Additionally, a lncRNA/circRNA-miRNA-mRNA ceRNA network related to muscle growth and development was constructed based on protein-protein interaction (PPI) analysis and hub genes selection using Cytoscape. This further elucidated the regulatory roles of noncoding RNAs (ncRNA) in the formation of muscle fibers in Shitou goose. In summary, this study provides a valuable transcriptional regulatory network for goose muscle development laying the groundwork for further exploration of the molecular regulatory mechanisms underlying the excellent meat production performance of Shitou goose.
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Affiliation(s)
- Liangchao Xiao
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Jiahui Chen
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Xueying He
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Xiquan Zhang
- State Key Laboratory of Livestock and Poultry Breeding, and Lingnan Guangdong Laboratory of Agriculture, South China Agricultural University, Guangzhou 510642, China; Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China
| | - Wen Luo
- State Key Laboratory of Livestock and Poultry Breeding, and Lingnan Guangdong Laboratory of Agriculture, South China Agricultural University, Guangzhou 510642, China; Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affair, South China Agricultural University, Guangzhou 510642, China.
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26
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Rahman FA, Baechler BL, Quadrilatero J. Key considerations for investigating and interpreting autophagy in skeletal muscle. Autophagy 2024; 20:2121-2132. [PMID: 39007805 PMCID: PMC11423691 DOI: 10.1080/15548627.2024.2373676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/13/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Skeletal muscle plays a crucial role in generating force to facilitate movement. Skeletal muscle is a heterogenous tissue composed of diverse fibers with distinct contractile and metabolic profiles. The intricate classification of skeletal muscle fibers exists on a continuum ranging from type I (slow-twitch, oxidative) to type II (fast-twitch, glycolytic). The heterogenous distribution and characteristics of fibers within and between skeletal muscles profoundly influences cellular signaling; however, this has not been broadly discussed as it relates to macroautophagy/autophagy. The growing interest in skeletal muscle autophagy research underscores the necessity of comprehending the interplay between autophagic responses among skeletal muscles and fibers with different contractile properties, metabolic profiles, and other related signaling processes. We recommend approaching the interpretation of autophagy findings with careful consideration for two key reasons: 1) the distinct behaviors and responses of different skeletal muscles or fibers to various perturbations, and 2) the potential impact of alterations in skeletal muscle fiber type or metabolic profile on observed autophagic outcomes. This review provides an overview of the autophagic profile and response in skeletal muscles/fibers of different types and metabolic profiles. Further, this review discusses autophagic findings in various conditions and diseases that may differentially affect skeletal muscle. Finally, we provide key points of consideration to better enable researchers to fine-tune the design and interpretation of skeletal muscle autophagy experiments.Abbreviation: AKT1: AKT serine/threonine kinase 1; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATG4: autophagy related 4 cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CS: citrate synthase; DIA: diaphragm; EDL: extensor digitorum longus; FOXO3/FOXO3A: forkhead box O3; GAS; gastrocnemius; GP: gastrocnemius-plantaris complex; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MYH: myosin heavy chain; PINK1: PTEN induced kinase 1; PLANT: plantaris; PRKN: parkin RBR E3 ubiquitin protein ligase; QUAD: quadriceps; RA: rectus abdominis; RG: red gastrocnemius; RQ: red quadriceps; SOL: soleus; SQSTM1: sequestosome 1; TA: tibialis anterior; WG: white gastrocnemius; WQ: white quadriceps; WVL: white vastus lateralis; VL: vastus lateralis; ULK1: unc-51 like autophagy activating kinase 1.
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Affiliation(s)
- Fasih A. Rahman
- Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, Ontario, Canada
| | - Brittany L. Baechler
- Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, Ontario, Canada
| | - Joe Quadrilatero
- Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, Ontario, Canada
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Su M, Qiu F, Li Y, Che T, Li N, Zhang S. Mechanisms of the NAD + salvage pathway in enhancing skeletal muscle function. Front Cell Dev Biol 2024; 12:1464815. [PMID: 39372950 PMCID: PMC11450036 DOI: 10.3389/fcell.2024.1464815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 09/09/2024] [Indexed: 10/08/2024] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) is crucial for cellular energy production, serving as a coenzyme in oxidation-reduction reactions. It also supports enzymes involved in processes such as DNA repair, aging, and immune responses. Lower NAD+ levels have been associated with various diseases, highlighting the importance of replenishing NAD+. Nicotinamide phosphoribosyltransferase (NAMPT) plays a critical role in the NAD+ salvage pathway, which helps sustain NAD+ levels, particularly in high-energy tissues like skeletal muscle.This review explores how the NAMPT-driven NAD+ salvage pathway influences skeletal muscle health and functionality in aging, type 2 diabetes mellitus (T2DM), and skeletal muscle injury. The review offers insights into enhancing the salvage pathway through exercise and NAD+ boosters as strategies to improve muscle performance. The findings suggest significant potential for using this pathway in the diagnosis, monitoring, and treatment of skeletal muscle conditions.
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Affiliation(s)
- Mengzhu Su
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, China
- School of Physical Education, Qingdao University, Qingdao, China
| | - Fanghui Qiu
- School of Physical Education, Qingdao University, Qingdao, China
| | - Yansong Li
- School of Physical Education, Qingdao University, Qingdao, China
| | - Tongtong Che
- School of Physical Education, Qingdao University, Qingdao, China
| | - Ningning Li
- School of Physical Education, Qingdao University, Qingdao, China
| | - Shuangshuang Zhang
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, China
- School of Physical Education, Qingdao University, Qingdao, China
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28
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Zhao C, Wu Y, Zhu S, Liu H, Xu S. Irisin Protects Musculoskeletal Homeostasis via a Mitochondrial Quality Control Mechanism. Int J Mol Sci 2024; 25:10116. [PMID: 39337601 PMCID: PMC11431940 DOI: 10.3390/ijms251810116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/23/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Irisin, a myokine derived from fibronectin type III domain-containing 5 (FNDC5), is increasingly recognized for its protective role in musculoskeletal health through the modulation of mitochondrial quality control. This review synthesizes the current understanding of irisin's impact on mitochondrial biogenesis, dynamics, and autophagy in skeletal muscle, elucidating its capacity to bolster muscle strength, endurance, and resilience against oxidative-stress-induced muscle atrophy. The multifunctional nature of irisin extends to bone metabolism, where it promotes osteoblast proliferation and differentiation, offering a potential intervention for osteoporosis and other musculoskeletal disorders. Mitochondrial quality control is vital for cellular metabolism, particularly in energy-demanding tissues. Irisin's influence on this process is highlighted, suggesting its integral role in maintaining cellular homeostasis. The review also touches upon the regulatory mechanisms of irisin secretion, predominantly induced by exercise, and its systemic effects as an endocrine factor. While the therapeutic potential of irisin is promising, the need for standardized measurement techniques and further elucidation of its mechanisms in humans is acknowledged. The collective findings underscore the burgeoning interest in irisin as a keystone in musculoskeletal health and a candidate for future therapeutic strategies.
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Affiliation(s)
| | | | | | - Haiying Liu
- Department of Spinal Surgery, Peking University People’s Hospital, Peking University, Beijing 100871, China
| | - Shuai Xu
- Department of Spinal Surgery, Peking University People’s Hospital, Peking University, Beijing 100871, China
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29
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Gao X, Chen Y, Cheng P. Unlocking the potential of exercise: harnessing myokines to delay musculoskeletal aging and improve cognitive health. Front Physiol 2024; 15:1338875. [PMID: 39286235 PMCID: PMC11402696 DOI: 10.3389/fphys.2024.1338875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 08/20/2024] [Indexed: 09/19/2024] Open
Abstract
Objectives This review aims to summarize the common physiological mechanisms associated with both mild cognitive impairment (MCI) and musculoskeletal aging while also examining the relevant literature on how exercise regulation influences the levels of shared myokines in these conditions. Methods The literature search was conducted via databases such as PubMed (including MEDLINE), EMBASE, and the Cochrane Library of Systematic Reviews. The searches were limited to full-text articles published in English, with the most recent search conducted on 16 July 2024. The inclusion criteria for this review focused on the role of exercise and myokines in delaying musculoskeletal aging and enhancing cognitive health. The Newcastle‒Ottawa Scale (NOS) was utilized to assess the quality of nonrandomized studies, and only those studies with moderate to high quality scores, as per these criteria, were included in the final analysis. Data analysis was performed through narrative synthesis. Results The primary outcome of this study was the evaluation of myokine expression, which included IL-6, IGF-1, BDNF, CTSB, irisin, and LIF. A total of 16 studies involving 633 older adults met the inclusion criteria. The current exercise modalities utilized in these studies primarily consisted of resistance training and moderate-to high-intensity cardiovascular exercise. The types of interventions included treadmill training, elastic band training, aquatic training, and Nordic walking training. The results indicated that both cardiovascular exercise and resistance exercise could delay musculoskeletal aging and enhance the cognitive functions of the brain. Additionally, different types and intensities of exercise exhibited varying effects on myokine expression. Conclusion Current evidence suggests that exercise mediates the secretion of specific myokines, including IL-6, IGF-1, BDNF, CTSB, irisin, and LIF, which establish self-regulatory circuits between the brain and muscle. This interaction enhances cognitive function in the brain and improves skeletal muscle function. Future research should focus on elucidating the exact mechanisms that govern the release of myokines, the correlation between the intensity of exercise and the secretion of these myokines, and the distinct processes by which myokines influence the interaction between muscle and the brain.
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Affiliation(s)
- Xing Gao
- Graduate School, Wuhan Sports University, Wuhan, China
| | - Yiyan Chen
- Department of Physical Education, Suzhou Vocational University, Suzhou, China
| | - Peng Cheng
- Department of Basic Teaching, Suzhou City University, Suzhou, China
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30
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Geppert J, Rohm M. Cancer cachexia: biomarkers and the influence of age. Mol Oncol 2024; 18:2070-2086. [PMID: 38414161 PMCID: PMC11467804 DOI: 10.1002/1878-0261.13590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 12/01/2023] [Accepted: 01/15/2024] [Indexed: 02/29/2024] Open
Abstract
Cancer cachexia (Ccx) is a complex metabolic condition characterized by pronounced muscle and fat wasting, systemic inflammation, weakness and fatigue. Up to 30% of cancer patients succumb directly to Ccx, yet therapies that effectively address this perturbed metabolic state are rare. In recent decades, several characteristics of Ccx have been established in mice and humans, of which we here highlight adipose tissue dysfunction, muscle wasting and systemic inflammation, as they are directly linked to biomarker discovery. To counteract cachexia pathogenesis as early as possible and mitigate its detrimental impact on anti-cancer treatments, identification and validation of clinically endorsed biomarkers assume paramount importance. Ageing was recently shown to affect both the validity of Ccx biomarkers and Ccx development, but the underlying mechanisms are still unknown. Thus, unravelling the intricate interplay between ageing and Ccx can help to counteract Ccx pathogenesis and tailor diagnostic and treatment strategies to individual needs.
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Affiliation(s)
- Julia Geppert
- Institute for Diabetes and CancerHelmholtz MunichNeuherbergGermany
- Joint Heidelberg‐IDC Translational Diabetes Program, Inner Medicine 1Heidelberg University HospitalGermany
- German Center for Diabetes Research (DZD)NeuherbergGermany
| | - Maria Rohm
- Institute for Diabetes and CancerHelmholtz MunichNeuherbergGermany
- Joint Heidelberg‐IDC Translational Diabetes Program, Inner Medicine 1Heidelberg University HospitalGermany
- German Center for Diabetes Research (DZD)NeuherbergGermany
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31
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Jahanian S, Pareja-Cajiao M, Gransee HM, Sieck GC, Mantilla CB. Autophagy markers LC3 and p62 in aging lumbar motor neurons. Exp Gerontol 2024; 194:112483. [PMID: 38885913 PMCID: PMC11326290 DOI: 10.1016/j.exger.2024.112483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 06/03/2024] [Accepted: 06/06/2024] [Indexed: 06/20/2024]
Abstract
Autophagy is a ubiquitous process through which damaged cytoplasmic structures are recycled and degraded within cells. Aging can affect autophagy regulation in different steps leading to the accumulation of damaged organelles and proteins, which can contribute to cell dysfunction and death. Motor neuron (MN) loss and sarcopenia are prominent features of neuromuscular aging. Previous studies on phrenic MNs showed increased levels of the autophagy proteins LC3 and p62 in 24 month compared to 6 month old mice, consistent with the onset of diaphragm muscle sarcopenia. In the present study, we hypothesized that aging leads to increased expression of the autophagy markers LC3 and p62 in single lumbar MNs. Expression of LC3 and p62 in lumbar MNs (spinal levels L1-L6) was assessed using immunofluorescence and confocal imaging of male and female mice at 6, 18 and 24 months of age, reflecting 100 %, 90 % and 75 % survival, respectively. A mixed linear model with animal as a random effect was used to compare relative LC3 and p62 expression in choline acetyl transferase-positive MNs across age groups. Expression of LC3 and p62 decreased in the white matter of the lumbar spinal cord with aging, with ~29 % decrease in LC3 and ~ 7 % decrease in p62 expression at 24 months of age compared to 6 months of age. There was no change in LC3 or p62 expression in the gray matter with age. LC3 expression in MNs relative to white matter increased significantly with age, with 150 % increase at 24 months of age compared to 6 months of age. Similarly, p62 expression in MNs relative to white matter increased significantly with age, with ~14 % increase at 24 months of age compared to 6 months of age. No effect of sex or MN pool was observed in LC3 and p62 expression in MNs. Overall, these data suggest autophagy impairment during elongation (increased LC3) and degradation (increased p62) phases with aging in lumbar MNs.
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Affiliation(s)
- Sepideh Jahanian
- Department of Anesthesiology & Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Miguel Pareja-Cajiao
- Department of Anesthesiology & Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Heather M Gransee
- Department of Anesthesiology & Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Gary C Sieck
- Department of Anesthesiology & Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Carlos B Mantilla
- Department of Anesthesiology & Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Physiology & Biomedical Engineering, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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32
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Tsitkanou S, Lindsay A, Abbott G, Foletta V, Walker AK, Russell AP, Della Gatta PA. Exercise training induces mild skeletal muscle adaptations without altering disease progression in a TDP-43 mouse model. J Appl Physiol (1985) 2024; 137:728-745. [PMID: 39008617 DOI: 10.1152/japplphysiol.00192.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 07/17/2024] Open
Abstract
Exercise training is considered a nonpharmacological therapeutic approach for many diseases. Mild-to-moderate endurance exercise training is suggested to improve the mental and physical state of people with amyotrophic lateral sclerosis (ALS). The aim of the present study was to determine the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TAR DNA-binding protein 43 (TDP-43) pathology and motor dysfunction, to perform mild-to-moderate intensity treadmill exercise training and to evaluate the effects of this training on skeletal muscle health and disease progression. Symptomatic rNLS8 mice were able to complete 4 wk of mild-to-moderate treadmill running (30 min at 6-13 m/min, 3 days a week). Exercise training induced an increase in the percentage of type IIA fibers in the tibialis anterior muscle as well as minor adaptations in molecular markers of myogenic, mitochondrial, and neuromuscular junction health in some forelimb and hindlimb muscles. However, this exercise training protocol did not attenuate the loss in motor function or delay disease progression. Alternative exercise regimens need to be investigated to better understand the role exercise training may play in alleviating symptoms of ALS.NEW & NOTEWORTHY This is the first study to investigate the capacity of symptomatic rNLS8 mice, which develop ALS-reminiscent TDP-43 pathology and motor dysfunction, to perform exercise training. We demonstrate that despite the ALS-reminiscent aggressive disease progression characterizing the rNLS8 mouse model, rNLS8 mice are capable of performing mild-to-moderate endurance treadmill training for at least 3-4 wk. We demonstrate that exercise training induces several minor skeletal muscle adaptations without delaying disease progression in rNLS8 mice.
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Affiliation(s)
- Stavroula Tsitkanou
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Faculty of Health, Deakin University, Geelong, Victoria, Australia
- Cachexia Research Laboratory, Exercise Science Research Center, Department of Health, Human Performance and Recreation, University of Arkansas, Fayetteville, Arkansas, United States
| | - Angus Lindsay
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Faculty of Health, Deakin University, Geelong, Victoria, Australia
- School of Biological Sciences, Faculty of Science, University of Canterbury, Christchurch, New Zealand
| | - Gavin Abbott
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Faculty of Health, Deakin University, Geelong, Victoria, Australia
| | - Victoria Foletta
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Faculty of Health, Deakin University, Geelong, Victoria, Australia
| | - Adam K Walker
- Neurodegeneration Pathobiology Laboratory, Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia, Queensland, Australia
| | - Aaron P Russell
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Faculty of Health, Deakin University, Geelong, Victoria, Australia
| | - Paul A Della Gatta
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Faculty of Health, Deakin University, Geelong, Victoria, Australia
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Zhang R, Farshadyeganeh P, Ohkawara B, Nakajima K, Takeda JI, Ito M, Zhang S, Miyasaka Y, Ohno T, Mori-Yoshimura M, Masuda A, Ohno K. Muscle-specific lack of Gfpt1 triggers ER stress to alleviate misfolded protein accumulation. Dis Model Mech 2024; 17:dmm050768. [PMID: 38903011 PMCID: PMC11554261 DOI: 10.1242/dmm.050768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 06/12/2024] [Indexed: 06/22/2024] Open
Abstract
Pathogenic variants in GFPT1, encoding a key enzyme to synthesize UDP-N-acetylglucosamine (UDP-GlcNAc), cause congenital myasthenic syndrome (CMS). We made a knock-in (KI) mouse model carrying a frameshift variant in Gfpt1 exon 9, simulating that found in a patient with CMS. As Gfpt1 exon 9 is exclusively expressed in striated muscles, Gfpt1-KI mice were deficient for Gfpt1 only in skeletal muscles. In Gfpt1-KI mice, (1) UDP-HexNAc, CMP-NeuAc and protein O-GlcNAcylation were reduced in skeletal muscles; (2) aged Gfpt1-KI mice showed poor exercise performance and abnormal neuromuscular junction structures; and (3) markers of the unfolded protein response (UPR) were elevated in skeletal muscles. Denervation-mediated enhancement of endoplasmic reticulum (ER) stress in Gfpt1-KI mice facilitated protein folding, ubiquitin-proteasome degradation and apoptosis, whereas autophagy was not induced and protein aggregates were markedly increased. Lack of autophagy was accounted for by enhanced degradation of FoxO1 by increased Xbp1-s/u proteins. Similarly, in Gfpt1-silenced C2C12 myotubes, ER stress exacerbated protein aggregates and activated apoptosis, but autophagy was attenuated. In both skeletal muscles in Gfpt1-KI mice and Gfpt1-silenced C2C12 myotubes, maladaptive UPR failed to eliminate protein aggregates and provoked apoptosis.
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Affiliation(s)
- Ruchen Zhang
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Paniz Farshadyeganeh
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Bisei Ohkawara
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Kazuki Nakajima
- Institute for Glyco-core Research (iGCORE), Gifu University, Gifu 501-1193, Japan
| | - Jun-ichi Takeda
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Mikako Ito
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Shaochuan Zhang
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Yuki Miyasaka
- Division of Experimental Animals, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Tamio Ohno
- Division of Experimental Animals, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Madoka Mori-Yoshimura
- Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira 187-8775, Japan
| | - Akio Masuda
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Kinji Ohno
- Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
- Graduate School of Nutritional Sciences, Nagoya University of Arts and Sciences, Nisshin 470-0196, Japan
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Sebastián D, Beltrà M, Irazoki A, Sala D, Aparicio P, Aris C, Alibakhshi E, Rubio-Valera M, Palacín M, Castellanos J, Lores L, Zorzano A. TP53INP2-dependent activation of muscle autophagy ameliorates sarcopenia and promotes healthy aging. Autophagy 2024; 20:1815-1824. [PMID: 38545813 PMCID: PMC11262205 DOI: 10.1080/15548627.2024.2333717] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 03/18/2024] [Indexed: 07/23/2024] Open
Abstract
Sarcopenia is a major contributor to disability in older adults, and thus, it is key to elucidate the mechanisms underlying its development. Increasing evidence suggests that impaired macroautophagy/autophagy contributes to the development of sarcopenia. However, the mechanisms leading to reduced autophagy during aging remain largely unexplored, and whether autophagy activation protects from sarcopenia has not been fully addressed. Here we show that the autophagy regulator TP53INP2/TRP53INP2 is decreased during aging in mouse and human skeletal muscle. Importantly, chronic activation of autophagy by muscle-specific overexpression of TRP53INP2 prevents sarcopenia and the decline of muscle function in mice. Acute re-expression of TRP53INP2 in aged mice also improves muscle atrophy, enhances mitophagy, and reduces ROS production. In humans, high levels of TP53INP2 in muscle are associated with increased muscle strength and healthy aging. Our findings highlight the relevance of an active muscle autophagy in the maintenance of muscle mass and prevention of sarcopenia.Abbreviation: ATG7: autophagy related 7; BMI: body mass index; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ROS: reactive oxygen species; TP53INP2: tumor protein p53 inducible nuclear protein 2; WT: wild type.
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Affiliation(s)
- David Sebastián
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Marc Beltrà
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - Andrea Irazoki
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - David Sala
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - Pilar Aparicio
- Department of Orthopedic Surgery and Traumatology, Hospital de Sant Boi Sant Joan de Déu, Sant Boi de Llobregat, Barcelona, Spain
| | - Cecilia Aris
- Department of Family and Community Medicine, Hospital de Sant Boi Sant Joan de Déu, Sant Boi de Llobregat, Barcelona, Spain
| | - Esmaeil Alibakhshi
- Pneumology Department, Hospital de Sant Boi Sant Joan de Déu, Sant Boi de Llobregat, Barcelona, Spain
- Physical Medicine and Rehabilitation Department, Clinical Research Development Unit, Baqyiatallah Hospital, Faculty of Medicine, Baqyiatallah University of Medical Science, Tehran, Iran
- Quantitative MR Imaging and Spectroscopy Group, Research Center for Molecular and Cellular Imaging, Advanced Medical Technologies and Equipment Institute, Tehran University of Medical Science, Tehran, Iran
| | - Maria Rubio-Valera
- Quality and Patient Safety Unit, Hospital de Sant Boi Sant Joan de Déu, Sant Boi de Llobregat, Barcelona, Spain
- Centro de Investigación Biomédica en Epidemiologia y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Palacín
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Juan Castellanos
- Department of Orthopedic Surgery and Traumatology, Hospital de Sant Boi Sant Joan de Déu, Sant Boi de Llobregat, Barcelona, Spain
| | - Luis Lores
- Pneumology Department, Hospital de Sant Boi Sant Joan de Déu, Sant Boi de Llobregat, Barcelona, Spain
| | - Antonio Zorzano
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
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Kim JW, Nam SA, Koh ES, Kim HW, Kim S, Woo JJ, Kim YK. The Impairment of Endothelial Autophagy Accelerates Renal Senescence by Ferroptosis and NLRP3 Inflammasome Signaling Pathways with the Disruption of Endothelial Barrier. Antioxidants (Basel) 2024; 13:886. [PMID: 39199133 PMCID: PMC11351978 DOI: 10.3390/antiox13080886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 09/01/2024] Open
Abstract
Autophagy is a cellular process that degrades damaged cytoplasmic components and regulates cell death. The homeostasis of endothelial cells (ECs) is crucial for the preservation of glomerular structure and function in aging. Here, we investigated the precise mechanisms of endothelial autophagy in renal aging. The genetic deletion of Atg7 in the ECs of Atg7flox/flox;Tie2-Cre mice accelerated aging-related glomerulopathy and tubulointerstitial fibrosis. The EC-specific Atg7 deletion in aging mice induced the detachment of EC with the disruption of glomerular basement membrane (GBM) assembly and increased podocyte loss resulting in microalbuminuria. A Transwell co-culture system of ECs and kidney organoids showed that the iron and oxidative stress induce the disruption of the endothelial barrier and increase vascular permeability, which was accelerated by the inhibition of autophagy. This resulted in the leakage of iron through the endothelial barrier into kidney organoids and increased oxidative stress, which led to ferroptotic cell death. The ferritin accumulation was increased in the kidneys of the EC-specific Atg7-deficient aging mice and upregulated the NLRP3 inflammasome signaling pathway. The pharmacologic inhibition of ferroptosis with liproxstatin-1 recovered the disrupted endothelial barrier and reversed the decreased expression of GPX4, as well as NLRP3 and IL-1β, in endothelial autophagy-deficient aged mice, which attenuated aging-related renal injury including the apoptosis of renal cells, abnormal structures of GBM, and tubulointerstitial fibrosis. Our data showed that endothelial autophagy is essential for the maintenance of the endothelial barrier during renal aging and the impairment of endothelial autophagy accelerates renal senescence by ferroptosis and NLRP3 inflammasome signaling pathways. These processes may be attractive therapeutic targets to reduce cellular injury from renal aging.
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Affiliation(s)
- Jin Won Kim
- Department of Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Sun Ah Nam
- Department of Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Eun-Sil Koh
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Hyung Wook Kim
- Department of Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, St. Vincent’s Hospital, Suwon 16247, Republic of Korea
| | - Sua Kim
- Department of Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jin Ju Woo
- Department of Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Yong Kyun Kim
- Department of Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, St. Vincent’s Hospital, Suwon 16247, Republic of Korea
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Russo C, Valle MS, D’Angeli F, Surdo S, Malaguarnera L. Resveratrol and Vitamin D: Eclectic Molecules Promoting Mitochondrial Health in Sarcopenia. Int J Mol Sci 2024; 25:7503. [PMID: 39062745 PMCID: PMC11277153 DOI: 10.3390/ijms25147503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/01/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
Sarcopenia refers to the progressive loss and atrophy of skeletal muscle function, often associated with aging or secondary to conditions involving systemic inflammation, oxidative stress, and mitochondrial dysfunction. Recent evidence indicates that skeletal muscle function is not only influenced by physical, environmental, and genetic factors but is also significantly impacted by nutritional deficiencies. Natural compounds with antioxidant properties, such as resveratrol and vitamin D, have shown promise in preventing mitochondrial dysfunction in skeletal muscle cells. These antioxidants can slow down muscle atrophy by regulating mitochondrial functions and neuromuscular junctions. This review provides an overview of the molecular mechanisms leading to skeletal muscle atrophy and summarizes recent advances in using resveratrol and vitamin D supplementation for its prevention and treatment. Understanding these molecular mechanisms and implementing combined interventions can optimize treatment outcomes, ensure muscle function recovery, and improve the quality of life for patients.
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Affiliation(s)
- Cristina Russo
- Section of Pathology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy;
| | - Maria Stella Valle
- Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy;
| | - Floriana D’Angeli
- Department of Human Sciences and Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy;
| | - Sofia Surdo
- Italian Center for the Study of Osteopathy (CSDOI), 95124 Catania, Italy;
| | - Lucia Malaguarnera
- Section of Pathology, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy;
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Al-Kuraishy HM, Sulaiman GM, Jabir MS, Mohammed HA, Al-Gareeb AI, Albukhaty S, Klionsky DJ, Abomughaid MM. Defective autophagy and autophagy activators in myasthenia gravis: a rare entity and unusual scenario. Autophagy 2024; 20:1473-1482. [PMID: 38346408 PMCID: PMC11210922 DOI: 10.1080/15548627.2024.2315893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/19/2024] [Accepted: 02/02/2024] [Indexed: 03/07/2024] Open
Abstract
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ) that results from autoantibodies against nicotinic acetylcholine receptors (nAchRs) at NMJs. These autoantibodies are mainly originated from autoreactive B cells that bind and destroy nAchRs at NMJs preventing nerve impulses from activating the end-plates of skeletal muscle. Indeed, immune dysregulation plays a crucial role in the pathogenesis of MG. Autoreactive B cells are increased in MG due to the defect in the central and peripheral tolerance mechanisms. As well, autoreactive T cells are augmented in MG due to the diversion of regulatory T (Treg) cells or a defect in thymic anergy leading to T cell-mediated autoimmunity. Furthermore, macroautophagy/autophagy, which is a conserved cellular catabolic process, plays a critical role in autoimmune diseases by regulating antigen presentation, survival of immune cells and cytokine-mediated inflammation. Abnormal autophagic flux is associated with different autoimmune disorders. Autophagy regulates the connection between innate and adaptive immune responses by controlling the production of cytokines and survival of Tregs. As autophagy is involved in autoimmune disorders, it may play a major role in the pathogenesis of MG. Therefore, this mini-review demonstrates the potential role of autophagy and autophagy activators in MG.Abbreviations: Ach, acetylcholine; Breg, regulatory B; IgG, immunoglobulin G; MG, myasthenia gravis; NMJ, neuromuscular junction; ROS, reactive oxygen species; Treg, regulatory T; Ubl, ubiquitin-like.
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Affiliation(s)
- Hayder M. Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | | | - Majid S. Jabir
- Department of Applied Sciences, University of Technology, Baghdad, Iraq
| | - Hamdoon A. Mohammed
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim, Saudi Arabia
- Department of Pharmacognosy and Medicinal Plants, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
| | | | - Salim Albukhaty
- Department of Chemistry, College of Science, University of Misan, Maysan, Iraq
| | | | - Mosleh M. Abomughaid
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha, Saudi Arabia
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Couturier N, Hörner SJ, Nürnberg E, Joazeiro C, Hafner M, Rudolf R. Aberrant evoked calcium signaling and nAChR cluster morphology in a SOD1 D90A hiPSC-derived neuromuscular model. Front Cell Dev Biol 2024; 12:1429759. [PMID: 38966427 PMCID: PMC11222430 DOI: 10.3389/fcell.2024.1429759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 06/03/2024] [Indexed: 07/06/2024] Open
Abstract
Familial amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is due to mutations in one of several target genes, including SOD1. So far, clinical records, rodent studies, and in vitro models have yielded arguments for either a primary motor neuron disease, or a pleiotropic pathogenesis of ALS. While mouse models lack the human origin, in vitro models using human induced pluripotent stem cells (hiPSC) have been recently developed for addressing ALS pathogenesis. In spite of improvements regarding the generation of muscle cells from hiPSC, the degree of maturation of muscle cells resulting from these protocols has remained limited. To fill these shortcomings, we here present a new protocol for an enhanced myotube differentiation from hiPSC with the option of further maturation upon coculture with hiPSC-derived motor neurons. The described model is the first to yield a combination of key myogenic maturation features that are consistent sarcomeric organization in association with complex nAChR clusters in myotubes derived from control hiPSC. In this model, myotubes derived from hiPSC carrying the SOD1 D90A mutation had reduced expression of myogenic markers, lack of sarcomeres, morphologically different nAChR clusters, and an altered nAChR-dependent Ca2+ response compared to control myotubes. Notably, trophic support provided by control hiPSC-derived motor neurons reduced nAChR cluster differences between control and SOD1 D90A myotubes. In summary, a novel hiPSC-derived neuromuscular model yields evidence for both muscle-intrinsic and nerve-dependent aspects of neuromuscular dysfunction in SOD1-based ALS.
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Affiliation(s)
- Nathalie Couturier
- CeMOS, Mannheim University of Applied Sciences, Mannheim, Germany
- Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany
| | - Sarah Janice Hörner
- CeMOS, Mannheim University of Applied Sciences, Mannheim, Germany
- Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany
| | - Elina Nürnberg
- CeMOS, Mannheim University of Applied Sciences, Mannheim, Germany
| | - Claudio Joazeiro
- Center for Molecular Biology, Heidelberg University, Heidelberg, Germany
| | - Mathias Hafner
- Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, Mannheim, Germany
- Institute of Medical Technology, Mannheim University of Applied Sciences and Heidelberg University, Mannheim, Germany
| | - Rüdiger Rudolf
- CeMOS, Mannheim University of Applied Sciences, Mannheim, Germany
- Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany
- Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, Mannheim, Germany
- Institute of Medical Technology, Mannheim University of Applied Sciences and Heidelberg University, Mannheim, Germany
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Franco-Romero A, Morbidoni V, Milan G, Sartori R, Wulff J, Romanello V, Armani A, Salviati L, Conte M, Salvioli S, Franceschi C, Buonomo V, Swoboda CO, Grumati P, Pannone L, Martinelli S, Jefferies HB, Dikic I, van der Laan J, Cabreiro F, Millay DP, Tooze SA, Trevisson E, Sandri M. C16ORF70/MYTHO promotes healthy aging in C.elegans and prevents cellular senescence in mammals. J Clin Invest 2024; 134:e165814. [PMID: 38869949 PMCID: PMC11291266 DOI: 10.1172/jci165814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 06/07/2024] [Indexed: 06/15/2024] Open
Abstract
The identification of genes that confer either extension of life span or accelerate age-related decline was a step forward in understanding the mechanisms of aging and revealed that it is partially controlled by genetics and transcriptional programs. Here, we discovered that the human DNA sequence C16ORF70 encodes a protein, named MYTHO (macroautophagy and youth optimizer), which controls life span and health span. MYTHO protein is conserved from Caenorhabditis elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the orthologous myt-1 gene in C. elegans dramatically shortened life span and decreased animal survival upon exposure to oxidative stress. Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy aging.
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Affiliation(s)
- Anais Franco-Romero
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Valeria Morbidoni
- Clinical Genetics Unit, Department of Women’s and Children’s Health, University of Padova, Padova, Italy
- Pediatric Research Institute (IRP) - Fondazione Città della Speranza, Padova, Italy
| | - Giulia Milan
- Department of Cardiac Surgery, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Roberta Sartori
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Jesper Wulff
- Institute of Biochemistry II, Goethe University Frankfurt - Medical Faculty, University Hospital, Frankfurt am Main, Germany
| | - Vanina Romanello
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Andrea Armani
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Leonardo Salviati
- Clinical Genetics Unit, Department of Women’s and Children’s Health, University of Padova, Padova, Italy
- Pediatric Research Institute (IRP) - Fondazione Città della Speranza, Padova, Italy
| | - Maria Conte
- Department of Medical and Surgical Science (DIMEC), University of Bologna, Bologna, Italy
| | - Stefano Salvioli
- Department of Medical and Surgical Science (DIMEC), University of Bologna, Bologna, Italy
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Claudio Franceschi
- Institute of Information Technologies, Mathematics and Mechanics, Lobachevsky State University, Nizhny Novgorod, Russia
| | - Viviana Buonomo
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Casey O. Swoboda
- Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Paolo Grumati
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Luca Pannone
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Simone Martinelli
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Harold B.J. Jefferies
- The Francis Crick Institute, Molecular Cell Biology of Autophagy, London, United Kingdom
| | - Ivan Dikic
- Institute of Biochemistry II, Goethe University Frankfurt - Medical Faculty, University Hospital, Frankfurt am Main, Germany
- Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt - Riedberg Campus, Frankfurt am Main, Germany
| | - Jennifer van der Laan
- CECAD Research Cluster, University of Cologne, Cologne, Germany
- Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, London, UK
| | - Filipe Cabreiro
- CECAD Research Cluster, University of Cologne, Cologne, Germany
- Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, London, UK
| | - Douglas P. Millay
- Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Sharon A. Tooze
- The Francis Crick Institute, Molecular Cell Biology of Autophagy, London, United Kingdom
| | - Eva Trevisson
- Clinical Genetics Unit, Department of Women’s and Children’s Health, University of Padova, Padova, Italy
- Pediatric Research Institute (IRP) - Fondazione Città della Speranza, Padova, Italy
| | - Marco Sandri
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
- Myology Center, University of Padova, Padova, Italy
- Department of Medicine, McGill University, Montreal, Canada
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Kerr HL, Krumm K, Anderson B, Christiani A, Strait L, Li T, Irwin B, Jiang S, Rybachok A, Chen A, Dacek E, Caeiro L, Merrihew GE, MacDonald JW, Bammler TK, MacCoss MJ, Garcia JM. Mouse sarcopenia model reveals sex- and age-specific differences in phenotypic and molecular characteristics. J Clin Invest 2024; 134:e172890. [PMID: 39145448 PMCID: PMC11324300 DOI: 10.1172/jci172890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 06/04/2024] [Indexed: 08/16/2024] Open
Abstract
Our study was to characterize sarcopenia in C57BL/6J mice using a clinically relevant definition to investigate the underlying molecular mechanisms. Aged male (23-32 months old) and female (27-28 months old) C57BL/6J mice were classified as non-, probable-, or sarcopenic based on assessments of grip strength, muscle mass, and treadmill running time, using 2 SDs below the mean of their young counterparts as cutoff points. A 9%-22% prevalence of sarcopenia was identified in 23-26 month-old male mice, with more severe age-related declines in muscle function than mass. Females aged 27-28 months showed fewer sarcopenic but more probable cases compared with the males. As sarcopenia progressed, a decrease in muscle contractility and a trend toward lower type IIB fiber size were observed in males. Mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in males, with pathways linked to mitochondrial metabolism positively correlated with muscle mass. No age- or sarcopenia-related changes were observed in mitochondrial biogenesis, OXPHOS complexes, AMPK signaling, mitophagy, or atrogenes in females. Our results highlight the different trajectories of age-related declines in muscle mass and function, providing insights into sex-dependent molecular changes associated with sarcopenia progression, which may inform the future development of novel therapeutic interventions.
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Affiliation(s)
- Haiming L. Kerr
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Kora Krumm
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Barbara Anderson
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Anthony Christiani
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Lena Strait
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Theresa Li
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Brynn Irwin
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Siyi Jiang
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Artur Rybachok
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Amanda Chen
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Elizabeth Dacek
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Lucas Caeiro
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | | | - James W. MacDonald
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA
| | - Theo K. Bammler
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA
| | | | - Jose M. Garcia
- Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
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Rudolf R, Kettelhut IC, Navegantes LCC. Sympathetic innervation in skeletal muscle and its role at the neuromuscular junction. J Muscle Res Cell Motil 2024; 45:79-86. [PMID: 38367152 PMCID: PMC11096211 DOI: 10.1007/s10974-024-09665-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 01/30/2024] [Indexed: 02/19/2024]
Abstract
Neuromuscular junctions are the synapses between motor neurons and skeletal muscle fibers, which mediate voluntary muscle movement. Since neuromuscular junctions are also tightly associated with the capping function of terminal Schwann cells, these synapses have been classically regarded as tripartite chemical synapses. Although evidences from sympathetic innervation of neuromuscular junctions was described approximately a century ago, the essential presence and functional relevance of sympathetic contribution to the maintenance and modulation of neuromuscular junctions was demonstrated only recently. These findings shed light on the pathophysiology of different clinical conditions and can optimize surgical and clinical treatment modalities for skeletal muscle disorders.
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Affiliation(s)
- Rüdiger Rudolf
- Center for Mass Spectrometry and Optical Spectroscopy, Mannheim University of Applied Sciences, 68163, Mannheim, Germany.
- Interdisciplinary Center for Neurosciences, Heidelberg University, 69117, Heidelberg, Germany.
- Mannheim Center for Translational Neuroscience, Medical Faculty Mannheim Heidelberg University, 69167, Mannheim, Germany.
| | - Isis C Kettelhut
- Department of Biochemistry & Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto-SP, 14049900, Brazil
| | - Luiz Carlos C Navegantes
- Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto-SP, 14049900, Brazil
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42
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Zhao H, Iyama R, Kurogi E, Hayashi T, Egawa T. Direct and acute effects of advanced glycation end products on proteostasis in isolated mouse skeletal muscle. Physiol Rep 2024; 12:e16121. [PMID: 38898369 PMCID: PMC11186708 DOI: 10.14814/phy2.16121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 06/12/2024] [Accepted: 06/12/2024] [Indexed: 06/21/2024] Open
Abstract
Advanced glycation end products (AGEs) have been implicated in several skeletal muscle dysfunctions. However, whether the adverse effects of AGEs on skeletal muscle are because of their direct action on the skeletal muscle tissue is unclear. Therefore, this study aimed to investigate the direct and acute effects of AGEs on skeletal muscle using an isolated mouse skeletal muscle to eliminate several confounders derived from other organs. The results showed that the incubation of isolated mouse skeletal muscle with AGEs (1 mg/mL) for 2-6 h suppressed protein synthesis and the mechanistic target of rapamycin signaling pathway. Furthermore, AGEs showed potential inhibitory effects on protein degradation pathways, including autophagy and the ubiquitin-proteasome system. Additionally, AGEs stimulated endoplasmic reticulum (ER) stress by modulating the activating transcription factor 6, PKR-like ER kinase, C/EBP homologous protein, and altered inflammatory cytokine expression. AGEs also stimulated receptor for AGEs (RAGE)-associated signaling molecules, including mitogen-activated protein kinases. These findings suggest that AGEs have direct and acute effect on skeletal muscle and disturb proteostasis by modulating intracellular pathways such as RAGE signaling, protein synthesis, proteolysis, ER stress, and inflammatory cytokines.
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Affiliation(s)
- Haiyu Zhao
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
- Laboratory of Molecular Exercise Adaptation Sciences, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
| | - Ryota Iyama
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
- Laboratory of Molecular Exercise Adaptation Sciences, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
| | - Eriko Kurogi
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
| | - Tatsuya Hayashi
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
| | - Tatsuro Egawa
- Laboratory of Molecular Exercise Adaptation Sciences, Graduate School of Human and Environmental StudiesKyoto UniversityKyotoJapan
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43
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Coen PM, Huo Z, Tranah GJ, Barnes HN, Zhang X, Wolff CA, Wu K, Cawthon PM, Hepple RT, Toledo FGS, Evans DS, Santiago‐Fernández O, Cuervo AM, Kritchevsky SB, Newman AB, Cummings SR, Esser KA. Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging (SOMMA). Aging Cell 2024; 23:e14118. [PMID: 38627910 PMCID: PMC11166359 DOI: 10.1111/acel.14118] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 01/14/2024] [Accepted: 02/02/2024] [Indexed: 04/30/2024] Open
Abstract
Autophagy is essential for proteostasis, energetic balance, and cell defense and is a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility, and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy, and mTOR/upstream pathways was determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2 peak, 400 m walking speed, and leg power), and thigh muscle volume, were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB-related genes (RELA, RELB, and NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy, and pexophagy (PPARGC1A, PPARA, and EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion, and fission-related genes (NIPSNAP2, DNM1L, and OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1), and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume, and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence.
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Affiliation(s)
- Paul M. Coen
- Translational Research Institute, AdventHealthOrlandoFloridaUSA
| | - Zhiguang Huo
- Department of Biostatistics, College of Public Health & Health ProfessionsCollege of Medicine University of FloridaGainesvilleFloridaUSA
| | - Gregory J. Tranah
- California Pacific Medical Center Research InstituteSan FranciscoCaliforniaUSA
| | - Haley N. Barnes
- California Pacific Medical Center Research InstituteSan FranciscoCaliforniaUSA
| | - Xiping Zhang
- Department of Physiology and Aging, College of MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Christopher A. Wolff
- Department of Physiology and Aging, College of MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Kevin Wu
- Department of Physiology and Aging, College of MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Peggy M. Cawthon
- California Pacific Medical Center Research InstituteSan FranciscoCaliforniaUSA
- Department of Epidemiology and BiostatisticsUniversity of California San FranciscoSan FranciscoCaliforniaUSA
| | - Russell T. Hepple
- Department of Physical TherapyUniversity of FloridaGainesvilleFloridaUSA
| | - Frederico G. S. Toledo
- Department of Medicine, Division of Endocrinology and MetabolismUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
| | - Daniel S. Evans
- California Pacific Medical Center Research InstituteSan FranciscoCaliforniaUSA
- Department of Epidemiology and BiostatisticsUniversity of California San FranciscoSan FranciscoCaliforniaUSA
| | - Olaya Santiago‐Fernández
- Department of Developmental & Molecular BiologyAlbert Einstein College of MedicineNew YorkNew YorkUSA
| | - Ana Maria Cuervo
- Department of Developmental & Molecular BiologyAlbert Einstein College of MedicineNew YorkNew YorkUSA
| | - Stephen B. Kritchevsky
- Department of Internal MedicineWake Forest University School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Anne B. Newman
- Department of Epidemiology, School of Public HealthUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Steven R. Cummings
- California Pacific Medical Center Research InstituteSan FranciscoCaliforniaUSA
- Department of Epidemiology and BiostatisticsUniversity of California San FranciscoSan FranciscoCaliforniaUSA
| | - Karyn A. Esser
- Department of Physiology and Aging, College of MedicineUniversity of FloridaGainesvilleFloridaUSA
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44
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Cefis M, Dargegen M, Marcangeli V, Taherkhani S, Dulac M, Leduc-Gaudet JP, Mayaki D, Hussain SNA, Gouspillou G. MFN2 overexpression in skeletal muscles of young and old mice causes a mild hypertrophy without altering mitochondrial respiration and H 2O 2 emission. Acta Physiol (Oxf) 2024; 240:e14119. [PMID: 38400630 DOI: 10.1111/apha.14119] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 02/06/2024] [Accepted: 02/11/2024] [Indexed: 02/25/2024]
Abstract
AIM Sarcopenia, the aging-related loss of muscle mass and function, is a debilitating process negatively impacting the quality of life of affected individuals. Although the mechanisms underlying sarcopenia are incompletely understood, impairments in mitochondrial dynamics, including mitochondrial fusion, have been proposed as a contributing factor. However, the potential of upregulating mitochondrial fusion proteins to alleviate the effects of aging on skeletal muscles remains unexplored. We therefore hypothesized that overexpressing Mitofusin 2 (MFN2) in skeletal muscle in vivo would mitigate the effects of aging on muscle mass and improve mitochondrial function. METHODS MFN2 was overexpressed in young (7 mo) and old (24 mo) male mice for 4 months through intramuscular injections of an adeno-associated viruses. The impacts of MFN2 overexpression on muscle mass and fiber size (histology), mitochondrial respiration, and H2O2 emission (Oroboros fluororespirometry), and various signaling pathways (qPCR and western blotting) were investigated. RESULTS MFN2 overexpression increased muscle mass and fiber size in both young and old mice. No sign of fibrosis, necrosis, or inflammation was found upon MFN2 overexpression, indicating that the hypertrophy triggered by MFN2 overexpression was not pathological. MFN2 overexpression even reduced the proportion of fibers with central nuclei in old muscles. Importantly, MFN2 overexpression had no impact on muscle mitochondrial respiration and H2O2 emission in both young and old mice. MFN2 overexpression attenuated the increase in markers of impaired autophagy in old muscles. CONCLUSION MFN2 overexpression may be a viable approach to mitigate aging-related muscle atrophy and may have applications for other muscle disorders.
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Affiliation(s)
- Marina Cefis
- Département des sciences de l'activité physique, Faculté des Sciences, UQÀM, Montréal, Québec, Canada
| | - Manon Dargegen
- Département des sciences de l'activité physique, Faculté des Sciences, UQÀM, Montréal, Québec, Canada
| | - Vincent Marcangeli
- Département des sciences de l'activité physique, Faculté des Sciences, UQÀM, Montréal, Québec, Canada
- Département des sciences biologiques, Faculté des Sciences, UQÀM, Montréal, Québec, Canada
| | - Shima Taherkhani
- Département des sciences de l'activité physique, Faculté des Sciences, UQÀM, Montréal, Québec, Canada
- Département des sciences biologiques, Faculté des Sciences, UQÀM, Montréal, Québec, Canada
| | - Maude Dulac
- Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Québec, Canada
| | - Jean-Philippe Leduc-Gaudet
- Research Group in Cellular Signaling, Department of Medical Biology, Université du Québec À Trois-Rivières, Trois-Rivières, Québec, Canada
| | - Dominique Mayaki
- Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Québec, Canada
- Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program, Department of Critical Care, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
| | - Sabah N A Hussain
- Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Québec, Canada
- Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program, Department of Critical Care, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
| | - Gilles Gouspillou
- Département des sciences de l'activité physique, Faculté des Sciences, UQÀM, Montréal, Québec, Canada
- Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program, Department of Critical Care, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
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45
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Chen H, Zhang Z, Wang Y, Ma A, Li L, Zhao G. Iron status and sarcopenia-related traits: a bi-directional Mendelian randomization study. Sci Rep 2024; 14:9179. [PMID: 38649459 PMCID: PMC11035655 DOI: 10.1038/s41598-024-60059-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 04/18/2024] [Indexed: 04/25/2024] Open
Abstract
Although serum iron status and sarcopenia are closely linked, the presence of comprehensive evidence to establish a causal relationship between them remains insufficient. The objective of this study is to employ Mendelian randomization techniques to clarify the association between serum iron status and sarcopenia. We conducted a bi-directional Mendelian randomization (MR) analysis to investigate the potential causal relationship between iron status and sarcopenia. MR analyses were performed using inverse variance weighted (IVW), MR-Egger, and weighted median methods. Additionally, sensitivity analyses were conducted to verify the reliability of the causal association results. Then, we harvested a combination of SNPs as an integrated proxy for iron status to perform a MVMR analysis based on IVW MVMR model. UVMR analyses based on IVW method identified causal effect of ferritin on appendicular lean mass (ALM, β = - 0.051, 95% CI - 0.072, - 0.031, p = 7.325 × 10-07). Sensitivity analyses did not detect pleiotropic effects or result fluctuation by outlying SNPs in the effect estimates of four iron status on sarcopenia-related traits. After adjusting for PA, the analysis still revealed that each standard deviation higher genetically predicted ferritin was associated with lower ALM (β = - 0.054, 95% CI - 0.092, - 0.015, p = 0.006). Further, MVMR analyses determined a predominant role of ferritin (β = - 0.068, 95% CI - 0.12, - 0.017, p = 9.658 × 10-03) in the associations of iron status with ALM. Our study revealed a causal association between serum iron status and sarcopenia, with ferritin playing a key role in this relationship. These findings contribute to our understanding of the complex interplay between iron metabolism and muscle health.
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Affiliation(s)
- Honggu Chen
- Department of Orthopedics, the Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu Province, People's Republic of China
| | - Ziyi Zhang
- Department of Orthopedics, the Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu Province, People's Republic of China
| | - Yizhe Wang
- School of Medicine of Jiangsu University, Zhenjiang, 212000, Jiangsu, China
| | - Anpei Ma
- Department of Orthopedics, Yancheng First People's Hospital, Yancheng, 224000, Jiangsu Province, People's Republic of China
| | - Lingbo Li
- Department of Internal Medicine, Peking Union Medical College Hospital, Beijing, 100730, Beijing, People's Republic of China
| | - Guoyang Zhao
- Department of Orthopedics, the Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu Province, People's Republic of China.
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46
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Jagaraj CJ, Shadfar S, Kashani SA, Saravanabavan S, Farzana F, Atkin JD. Molecular hallmarks of ageing in amyotrophic lateral sclerosis. Cell Mol Life Sci 2024; 81:111. [PMID: 38430277 PMCID: PMC10908642 DOI: 10.1007/s00018-024-05164-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/21/2024] [Accepted: 02/06/2024] [Indexed: 03/03/2024]
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal, severely debilitating and rapidly progressing disorder affecting motor neurons in the brain, brainstem, and spinal cord. Unfortunately, there are few effective treatments, thus there remains a critical need to find novel interventions that can mitigate against its effects. Whilst the aetiology of ALS remains unclear, ageing is the major risk factor. Ageing is a slowly progressive process marked by functional decline of an organism over its lifespan. However, it remains unclear how ageing promotes the risk of ALS. At the molecular and cellular level there are specific hallmarks characteristic of normal ageing. These hallmarks are highly inter-related and overlap significantly with each other. Moreover, whilst ageing is a normal process, there are striking similarities at the molecular level between these factors and neurodegeneration in ALS. Nine ageing hallmarks were originally proposed: genomic instability, loss of telomeres, senescence, epigenetic modifications, dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and altered inter-cellular communication. However, these were recently (2023) expanded to include dysregulation of autophagy, inflammation and dysbiosis. Hence, given the latest updates to these hallmarks, and their close association to disease processes in ALS, a new examination of their relationship to pathophysiology is warranted. In this review, we describe possible mechanisms by which normal ageing impacts on neurodegenerative mechanisms implicated in ALS, and new therapeutic interventions that may arise from this.
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Affiliation(s)
- Cyril Jones Jagaraj
- MND Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, 75 Talavera Road, Sydney, NSW, 2109, Australia
| | - Sina Shadfar
- MND Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, 75 Talavera Road, Sydney, NSW, 2109, Australia
| | - Sara Assar Kashani
- MND Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, 75 Talavera Road, Sydney, NSW, 2109, Australia
| | - Sayanthooran Saravanabavan
- MND Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, 75 Talavera Road, Sydney, NSW, 2109, Australia
| | - Fabiha Farzana
- MND Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, 75 Talavera Road, Sydney, NSW, 2109, Australia
| | - Julie D Atkin
- MND Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, 75 Talavera Road, Sydney, NSW, 2109, Australia.
- La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, VIC, 3086, Australia.
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47
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Okubo M, Morishita M, Odani T, Sakaguchi H, Kikutani T, Kokabu S. The importance of taste on swallowing function. Front Nutr 2024; 11:1356165. [PMID: 38385009 PMCID: PMC10879290 DOI: 10.3389/fnut.2024.1356165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 01/26/2024] [Indexed: 02/23/2024] Open
Abstract
The world's population is aging. Pneumonia is the leading cause of death among the older adults, with aspiration pneumonia being particularly common. Aspiration pneumonia is caused by a decline in swallowing function. Causes can include age-related sarcopenia of swallowing muscles, cognitive decline, cerebrovascular and other diseases or even changes in individual taste preference. Currently, the main treatment approach for dysphagia is resistance training of swallowing-related muscles. This approach has not been effective and establishment of novel methods are required. In this review, we introduce and discuss the relationship between taste, taste preference, carbonation and swallowing function. Taste and preference improve swallowing function. Recently, it has been shown that a carbonated beverage that combines the functionality of a thickening agent, the appeal of taste, and the stimulation of carbonation improves swallowing function. This may be very useful in the recovery of swallowing function. It is important to note that deliciousness is based not only on taste and preference, but also on visual information such as food form. Umami taste receptors are expressed not only in taste buds but also in skeletal muscle and small intestine. These receptors may be involved in homeostasis of the amino acid metabolic network, i.e., the process of amino acid ingestion, intestine absorption, and storage in skeletal muscle. Proper stimulation of umami receptors in organs other than taste buds may help maintain nutritional status and muscle mass. Umami receptors are therefore a potential therapeutic target for dysphagia.
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Affiliation(s)
- Masahiko Okubo
- Department of Dentistry and Oral Surgery, Ongata Hospital, Hachioji, Tokyo, Japan
| | - Motoyoshi Morishita
- Department of Physical Therapy, Faculty of Rehabilitation, Reiwa Health Sciences University, Fukuoka, Japan
| | - Tomoko Odani
- Department of Dentistry, Kawaguchi Cupola Rehabilitation Hospital, Kawaguchi, Saitama, Japan
| | - Hideo Sakaguchi
- Department of Dentistry, Ryohoku Hospital, Hachioji, Tokyo, Japan
| | - Takeshi Kikutani
- Division of Clinical Oral Rehabilitation, Nippon Dental University Graduate School of Life Dentistry, Iidabashi, Tokyo, Japan
| | - Shoichiro Kokabu
- Division of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu, Japan
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48
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Iannuzzo F, Cicatiello AG, Sagliocchi S, Schiano E, Nappi A, Miro C, Stornaiuolo M, Mollica A, Tenore GC, Dentice M, Novellino E. Therapeutic Effect of an Ursolic Acid-Based Nutraceutical on Neuronal Regeneration after Sciatic Nerve Injury. Int J Mol Sci 2024; 25:902. [PMID: 38255977 PMCID: PMC10815361 DOI: 10.3390/ijms25020902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/08/2024] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
Peripheral nerve injuries lead to severe functional impairments and long recovery times, with limited effectiveness and accessibility of current treatments. This has increased interest in natural bioactive compounds, such as ursolic acid (UA). Our study evaluated the effect of an oleolyte rich in UA from white grape pomace (WGPO) on neuronal regeneration in mice with induced sciatic nerve resection, administered concurrently with the induced damage (the WGPO group) and 10 days prior (the PRE-WGPO group). The experiment was monitored at two-time points (4 and 10 days) after injury. After 10 days, the WGPO group demonstrated a reduction in muscle atrophy, evidenced by an increased number and diameter of muscle fibers and a decreased Atrogin-1 and Murf-1 expression relative to the denervated control. It was also observed that 85.7% of neuromuscular junctions (NMJs) were fully innervated, as indicated by the colocalization of α-bungarotoxin and synaptophysin, along with the significant modulation of Oct-6 and S-100. The PRE-WGPO group showed a more beneficial effect on nerve fiber reformation, with a significant increase in myelin protein zero and 95.2% fully innervated NMJs, and a pro-hypertrophic effect in resting non-denervated muscles. Our findings suggest WGPO as a potential treatment for various conditions that require the repair of nerve and muscle injuries.
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Affiliation(s)
- Fortuna Iannuzzo
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (F.I.); (A.M.)
| | - Annunziata Gaetana Cicatiello
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (A.G.C.); (S.S.); (A.N.); (C.M.)
| | - Serena Sagliocchi
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (A.G.C.); (S.S.); (A.N.); (C.M.)
| | - Elisabetta Schiano
- Healthcare Food Research Center, Inventia Biotech s.r.l., S. S. Sannitica, 81020 Caserta, Italy; (E.S.); (E.N.)
| | - Annarita Nappi
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (A.G.C.); (S.S.); (A.N.); (C.M.)
| | - Caterina Miro
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (A.G.C.); (S.S.); (A.N.); (C.M.)
| | - Mariano Stornaiuolo
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 59, 80131 Napoli, Italy; (M.S.); (G.C.T.)
| | - Adriano Mollica
- Department of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; (F.I.); (A.M.)
| | - Gian Carlo Tenore
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 59, 80131 Napoli, Italy; (M.S.); (G.C.T.)
| | - Monica Dentice
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (A.G.C.); (S.S.); (A.N.); (C.M.)
| | - Ettore Novellino
- Healthcare Food Research Center, Inventia Biotech s.r.l., S. S. Sannitica, 81020 Caserta, Italy; (E.S.); (E.N.)
- Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Roma, Italy
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49
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Miao Y, Xie L, Song J, Cai X, Yang J, Ma X, Chen S, Xie P. Unraveling the causes of sarcopenia: Roles of neuromuscular junction impairment and mitochondrial dysfunction. Physiol Rep 2024; 12:e15917. [PMID: 38225199 PMCID: PMC10789655 DOI: 10.14814/phy2.15917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 12/11/2023] [Accepted: 12/22/2023] [Indexed: 01/17/2024] Open
Abstract
Sarcopenia is a systemic skeletal muscle disease characterized by a decline in skeletal muscle mass and function. Originally defined as an age-associated condition, sarcopenia presently also encompasses muscular atrophy due to various pathological factors, such as intensive care unit-acquired weakness, inactivity, and malnutrition. The exact pathogenesis of sarcopenia is still unknown; herein, we review the pathological roles of the neuromuscular junction and mitochondria in this condition. Sarcopenia is caused by complex and interdependent pathophysiological mechanisms, including aging, neuromuscular junction impairment, mitochondrial dysfunction, insulin resistance, lipotoxicity, endocrine factors, oxidative stress, and inflammation. Among these, neuromuscular junction instability and mitochondrial dysfunction are particularly significant. Dysfunction in neuromuscular junction can lead to muscle weakness or paralysis. Mitochondria, which are plentiful in neurons and muscle fibers, play an important role in neuromuscular junction transmission. Therefore, impairments in both mitochondria and neuromuscular junction may be one of the key pathophysiological mechanisms leading to sarcopenia. Moreover, this article explores the structural and functional alterations in the neuromuscular junction and mitochondria in sarcopenia, suggesting that a deeper understanding of these changes could provide valuable insights for the prevention or treatment of sarcopenia.
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Affiliation(s)
- Yanmei Miao
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
| | - Leiyu Xie
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
| | - Jiamei Song
- Department of Nursing of Affiliated HospitalZunyi Medical UniversityZunyiChina
| | - Xing Cai
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
| | - Jinghe Yang
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
- Department of The First Clinical CollegeZunyi Medical UniversityZunyiChina
| | - Xinglong Ma
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
| | - Shaolin Chen
- Department of Nursing of Affiliated HospitalZunyi Medical UniversityZunyiChina
| | - Peng Xie
- Department of Critical Care Medicine of the Third Affiliated Hospital (The First People's Hospital of Zunyi)Zunyi Medical UniversityZunyiChina
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50
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Xu X, Wen Z. The mediating role of inflammaging between mitochondrial dysfunction and sarcopenia in aging: a review. AMERICAN JOURNAL OF CLINICAL AND EXPERIMENTAL IMMUNOLOGY 2023; 12:109-126. [PMID: 38187366 PMCID: PMC10767199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 11/26/2023] [Indexed: 01/09/2024]
Abstract
Sarcopenia, characterized by the insidious reduction of skeletal muscle mass and strength, detrimentally affects the quality of life in elderly cohorts. Present therapeutic strategies are confined to physiotherapeutic interventions, signaling a critical need for elucidation of the etiological underpinnings to facilitate the development of innovative pharmacotherapies. Recent scientific inquiries have associated mitochondrial dysfunction and inflammation with the etiology of sarcopenia. Mitochondria are integral to numerous fundamental cellular processes within muscle tissue, including but not limited to apoptosis, autophagy, signaling via reactive oxygen species, and the maintenance of protein equilibrium. Deviations in mitochondrial dynamics, coupled with compromised oxidative capabilities, autophagic processes, and protein equilibrium, result in disturbances to muscular architecture and functionality. Mitochondrial dysfunction is particularly detrimental as it diminishes oxidative phosphorylation, escalates apoptotic activity, and hinders calcium homeostasis within muscle cells. Additionally, deleterious feedback loops of deteriorated respiration, exacerbated oxidative injury, and diminished quality control mechanisms precipitate the acceleration of muscular senescence. Notably, mitochondria exhibiting deficient energetic metabolism are pivotal in precipitating the shift from normative muscle aging to a pathogenic state. This analytical review meticulously examines the complex interplay between mitochondrial dysfunction, persistent inflammation, and the pathogenesis of sarcopenia. It underscores the imperative to alleviate inflammation and amend mitochondrial anomalies within geriatric populations as a strategy to forestall and manage sarcopenia. An initial overview provides a succinct exposition of sarcopenia and its clinical repercussions. The discourse then progresses to an examination of the direct correlation between mitochondrial dysfunction and the genesis of sarcopenia. Concomitantly, it accentuates potential synergistic effects between inflammatory responses and mitochondrial insufficiencies during the aging of skeletal muscle, thereby casting light upon emergent therapeutic objectives. In culmination, this review distills the prevailing comprehension of the mitochondrial and inflammatory pathways implicated in sarcopenia and delineates extant lacunae in knowledge to orient subsequent scientific inquiry.
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Affiliation(s)
- Xin Xu
- Department of Rehabilitation Therapy, School of Health, Shanghai Normal University Tianhua CollegeShanghai, China
| | - Zixing Wen
- Department of Rehabilitation, School of International Medical Technology, Shanghai Sanda UniversityShanghai, China
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