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Wang YJ, Chen ZH, Shen YT, Wang KX, Han YM, Zhang C, Yang XM, Chen BQ. Stem cell therapy: A promising therapeutic approach for skeletal muscle atrophy. World J Stem Cells 2025; 17:98693. [DOI: 10.4252/wjsc.v17.i2.98693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/09/2024] [Accepted: 01/23/2025] [Indexed: 02/24/2025] Open
Abstract
Skeletal muscle atrophy results from disruptions in the growth and metabolism of striated muscle, leading to a reduction or loss of muscle fibers. This condition not only significantly impacts patients’ quality of life but also imposes substantial socioeconomic burdens. The complex molecular mechanisms driving skeletal muscle atrophy contribute to the absence of effective treatment options. Recent advances in stem cell therapy have positioned it as a promising approach for addressing this condition. This article reviews the molecular mechanisms of muscle atrophy and outlines current therapeutic strategies, focusing on mesenchymal stem cells, induced pluripotent stem cells, and their derivatives. Additionally, the challenges these stem cells face in clinical applications are discussed. A deeper understanding of the regenerative potential of various stem cells could pave the way for breakthroughs in the prevention and treatment of muscle atrophy.
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Affiliation(s)
- Ying-Jie Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Ze-Hao Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Yun-Tian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Ke-Xin Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Yi-Min Han
- Medical College, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Chen Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Xiao-Ming Yang
- Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong 226000, Jiangsu Province, China
- Research and Development Center for E-Learning, Ministry of Education, Beijing 100816, China
| | - Bing-Qian Chen
- Department of Orthopaedics, Changshu Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
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Hou M, Yue M, Han X, Sun T, Zhu Y, Li Z, Han J, Zhao B, Tu M, An Y. Comparative analysis of BAG1 and BAG2: Insights into their structures, functions and implications in disease pathogenesis. Int Immunopharmacol 2024; 143:113369. [PMID: 39405938 DOI: 10.1016/j.intimp.2024.113369] [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: 07/19/2024] [Revised: 09/22/2024] [Accepted: 10/06/2024] [Indexed: 10/30/2024]
Abstract
As BAG family members, Bcl-2 associated athanogene family protein 1 (BAG1) and 2 (BAG2) are implicated in multiple cellular processes, including apoptosis, autophagy, protein folding and homeostasis. Although structurally similar, they considerably differ in many ways. Unlike BAG2, BAG1 has four isoforms (BAG1L, BAG1M, BAG1S and BAG1 p29) displaying different expression features and functional patterns. BAG1 and BAG2 play different cellular functions by interacting with different molecules to participate in the regulation of various diseases, including cancer/tumor and neurodegenerative diseases. Commonly, BAG1 acts as a protective factor to predict a good prognosis of patients with some types of cancer or a risk factor in some other cancers, while BAG2 is regarded as a risk factor to promote cancer/tumor progression. In neurodegenerative diseases, BAG2 commonly acts as a neuroprotective factor. In this review, we summarized the differences in molacular structure and biological function between BAG1 and BAG2, as well as the influences of them on pathogenesis of diseases, and explore the prospects for their clinical therapy application by specifying the activators and inhibitors of BAG1 and BAG2, which might provide a better understanding of the underlying pathogenesis and developing the targeted therapy strategies for diseases.
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Affiliation(s)
- Mengwen Hou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Man Yue
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Xu Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Tiantian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Yonghao Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Zhihao Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng 475004, China
| | - Jiayang Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Binbin Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Mengjie Tu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; School of Stomatology, Henan University, Kaifeng 475004, China
| | - Yang An
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng 475004, China.
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Cheon YP, Ryou C, Svedružić ŽM. Roles of prion proteins in mammalian development. Anim Cells Syst (Seoul) 2024; 28:551-566. [PMID: 39664939 PMCID: PMC11633422 DOI: 10.1080/19768354.2024.2436860] [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: 09/12/2024] [Revised: 11/02/2024] [Accepted: 11/25/2024] [Indexed: 12/13/2024] Open
Abstract
Prion protein (PrP) is highly conserved and is expressed in most tissues in a developmental stage-specific manner. Glycosylated cellular prion protein (PrPC) is found in most cells and subcellular areas as a physiological regulating molecule. On the other hand, the amyloid form of PrPC, scrapie PrP (PrPSC), causes transmissible pathogenesis in the central nervous system and induces degeneration of the nervous system. Although many amyloids are reversible and critical in determining the fate, differentiation, and physiological functions of cells, thus far, PrPSC originating from PrPC is not. Although many studies have focused on disorders involving PrPC and the deletion mammalian models for PrPC have no severe phenotype, it has been suggested that PrPC has a role in normal development. It is conserved and expressed from gametes to adult somatic cells. In addition, severe developmental phenotypes appear in PrP null zebrafish embryos and in various mammalian cell model systems. In addition, it has been well established that PrPC is strongly involved in the stemness and differentiation of embryonic stem cells and progenitors. Thus far, many studies on PrPC have focused mostly on disease-associated conditions with physiological roles as a complex platform but not on development. The known roles of PrPC depend on the interacting molecules through its flexible tail and domains. PrPC interacts with membrane, and various intracellular and extracellular molecules. In addition, PrPC and amyloid can stimulate signaling pathways differentially. In this review, we summarize the function of prion protein and discuss its role in development.
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Affiliation(s)
- Yong-Pil Cheon
- Division of Developmental Biology and Physiology, Department of Biotechnology, Institute for Basic Sciences, Sungshin University, Seoul, Korea
| | - Chongsuk Ryou
- Department of Pharmacy, College of Pharmacy, Hanyang University, ekcho Ansan, Korea
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Zhao Z, Zhao L, Wei XF, Jia YJ, Zhu B. Skin as outermost immune organ of vertebrates that elicits robust early immune responses after immunization with glycoprotein of spring viraemia of carp virus. PLoS Pathog 2024; 20:e1012744. [PMID: 39652527 PMCID: PMC11627376 DOI: 10.1371/journal.ppat.1012744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024] Open
Abstract
As the outermost immune organ in vertebrates, the skin serves as the primary interface with the external environment and plays a crucial role in initiating the early immune response. The skin contains a variety of immune cells that induce mucosal and systemic immune responses, rendering it a prime target for vaccination strategies. Insight into the mechanisms through which vaccination triggers early immune responses is paramount for advancing animal and human health, yet our current understanding remains limited. Given its significance in vertebrate evolution, teleost fish emerges as an excellent model for investigating the early immune response of skin. In this study, we demonstrate that significant quantities of vaccine can be absorbed by the skin and transported to the body through dermis and muscle metabolism by immerses immune zebrafish with glycoprotein of spring viraemia of carp virus. Immersion immunization can elicit robust and enduring immune protection, with the skin triggering a potent immune response early in the immunization process. Analysis of the skin transcriptome revealed the involvement of numerous immune-related genes in the immersion immune response, with indications that HSP70 and MAPK signals might play pivotal roles in the immune process induced by glycoprotein. Co-immunoprecipitation and cell co-localization studies confirmed the interaction between glycoprotein and HSP70. Subsequent research demonstrated that overexpression or inhibition of HSP70 could respectively enhance or impede the expression of JNK and related proteins. However, the survival rate and immune response of HSP70 inhibited zebrafish with glycoprotein treatment were significantly reduced. These findings propose that the interaction between glycoprotein and HSP70 may activate JNK, thereby modulating mucosal and systemic immune responses induced by glycoprotein. This investigation offers novel insights and a foundational understanding of early skin immune reactions.
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Affiliation(s)
- Zhao Zhao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Liang Zhao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Xue-Feng Wei
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Yi-Jun Jia
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Bin Zhu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
- Engineering Research Center of the Innovation and Development of Green Fishery Drugs, Universities of Shaanxi Province, Northwest A&F University, Yangling, Shaanxi, China
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Maiullari S, Cicirelli A, Picerno A, Giannuzzi F, Gesualdo L, Notarnicola A, Sallustio F, Moretti B. Pulsed Electromagnetic Fields Induce Skeletal Muscle Cell Repair by Sustaining the Expression of Proteins Involved in the Response to Cellular Damage and Oxidative Stress. Int J Mol Sci 2023; 24:16631. [PMID: 38068954 PMCID: PMC10706358 DOI: 10.3390/ijms242316631] [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: 10/14/2023] [Revised: 11/09/2023] [Accepted: 11/17/2023] [Indexed: 12/18/2023] Open
Abstract
Pulsed electromagnetic fields (PEMF) are employed as a non-invasive medicinal therapy, especially in the orthopedic field to stimulate bone regeneration. However, the effect of PEMF on skeletal muscle cells (SkMC) has been understudied. Here, we studied the potentiality of 1.5 mT PEMF to stimulate early regeneration of human SkMC. We showed that human SkMC stimulated with 1.5 mT PEMF for four hours repeated for two days can stimulate cell proliferation without inducing cell apoptosis or significant impairment of the metabolic activity. Interestingly, when we simulated physical damage of the muscle tissue by a scratch, we found that the same PEMF treatment can speed up the regenerative process, inducing a more complete cell migration to close the scratch and wound healing. Moreover, we investigated the molecular pattern induced by PEMF among 26 stress-related cell proteins. We found that the expression of 10 proteins increased after two consecutive days of PEMF stimulation for 4 h, and most of them were involved in response processes to oxidative stress. Among these proteins, we found that heat shock protein 70 (HSP70), which can promote muscle recovery, inhibits apoptosis and decreases inflammation in skeletal muscle, together with thioredoxin, paraoxonase, and superoxide dismutase (SOD2), which can also promote skeletal muscle regeneration following injury. Altogether, these data support the possibility of using PEMF to increase SkMC regeneration and, for the first time, suggest a possible molecular mechanism, which consists of sustaining the expression of antioxidant enzymes to control the important inflammatory and oxidative process occurring following muscle damage.
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Affiliation(s)
- Silvia Maiullari
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (S.M.); (A.C.); (A.P.); (F.G.)
| | - Antonella Cicirelli
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (S.M.); (A.C.); (A.P.); (F.G.)
| | - Angela Picerno
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (S.M.); (A.C.); (A.P.); (F.G.)
| | - Francesca Giannuzzi
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (S.M.); (A.C.); (A.P.); (F.G.)
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Angela Notarnicola
- Orthopaedic and Trauma Unit, Department of Translational Biomedicine and Neuroscience “DiBraiN”, University of Bari “Aldo Moro”, Piazza G. Cesare 11, 70124 Bari, Italy; (A.N.); (B.M.)
| | - Fabio Sallustio
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Biagio Moretti
- Orthopaedic and Trauma Unit, Department of Translational Biomedicine and Neuroscience “DiBraiN”, University of Bari “Aldo Moro”, Piazza G. Cesare 11, 70124 Bari, Italy; (A.N.); (B.M.)
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Zhu A, Liu N, Shang Y, Zhen Y, An Y. Signaling pathways of adipose stem cell-derived exosomes promoting muscle regeneration. Chin Med J (Engl) 2022; 135:2525-2534. [PMID: 36583914 PMCID: PMC9945488 DOI: 10.1097/cm9.0000000000002404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Indexed: 12/31/2022] Open
Abstract
ABSTRACT Severe muscle injury is still a challenging clinical problem. Exosomes derived from adipose stem cells (ASC-exos) may be a potential therapeutic tool, but their mechanism is not completely clear. This review aims to elaborate the possible mechanism of ASC-exos in muscle regeneration from the perspective of signal pathways and provide guidance for further study. Literature cited in this review was acquired through PubMed using keywords or medical subject headings, including adipose stem cells, exosomes, muscle regeneration, myogenic differentiation, myogenesis, wingless/integrated (Wnt), mitogen-activated protein kinases, phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/Akt), Janus kinase/signal transducers and activators of transcription, and their combinations. We obtained the related signal pathways from proteomics analysis of ASC-exos in the literature, and identified that ASC-exos make different contributions to multiple stages of skeletal muscle regeneration by those signal pathways.
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Affiliation(s)
- Aoxuan Zhu
- Department of Plastic Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Na Liu
- Department of Plastic Surgery, Peking University Third Hospital, Beijing 100191, China
- Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Yujia Shang
- Department of Plastic Surgery, Peking University Third Hospital, Beijing 100191, China
- Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
| | - Yonghuan Zhen
- Department of Plastic Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Yang An
- Department of Plastic Surgery, Peking University Third Hospital, Beijing 100191, China
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Wang Y, Lu J, Liu Y. Skeletal Muscle Regeneration in Cardiotoxin-Induced Muscle Injury Models. Int J Mol Sci 2022; 23:ijms232113380. [PMID: 36362166 PMCID: PMC9657523 DOI: 10.3390/ijms232113380] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Skeletal muscle injuries occur frequently in daily life and exercise. Understanding the mechanisms of regeneration is critical for accelerating the repair and regeneration of muscle. Therefore, this article reviews knowledge on the mechanisms of skeletal muscle regeneration after cardiotoxin-induced injury. The process of regeneration is similar in different mouse strains and is inhibited by aging, obesity, and diabetes. Exercise, microcurrent electrical neuromuscular stimulation, and mechanical loading improve regeneration. The mechanisms of regeneration are complex and strain-dependent, and changes in functional proteins involved in the processes of necrotic fiber debris clearance, M1 to M2 macrophage conversion, SC activation, myoblast proliferation, differentiation and fusion, and fibrosis and calcification influence the final outcome of the regenerative activity.
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Lacroux J, Atteia A, Brugière S, Couté Y, Vallon O, Steyer JP, van Lis R. Proteomics unveil a central role for peroxisomes in butyrate assimilation of the heterotrophic Chlorophyte alga Polytomella sp. Front Microbiol 2022; 13:1029828. [PMID: 36353459 PMCID: PMC9637915 DOI: 10.3389/fmicb.2022.1029828] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 10/05/2022] [Indexed: 09/08/2023] Open
Abstract
Volatile fatty acids found in effluents of the dark fermentation of biowastes can be used for mixotrophic growth of microalgae, improving productivity and reducing the cost of the feedstock. Microalgae can use the acetate in the effluents very well, but butyrate is poorly assimilated and can inhibit growth above 1 gC.L-1. The non-photosynthetic chlorophyte alga Polytomella sp. SAG 198.80 was found to be able to assimilate butyrate fast. To decipher the metabolic pathways implicated in butyrate assimilation, quantitative proteomics study was developed comparing Polytomella sp. cells grown on acetate and butyrate at 1 gC.L-1. After statistical analysis, a total of 1772 proteins were retained, of which 119 proteins were found to be overaccumulated on butyrate vs. only 46 on acetate, indicating that butyrate assimilation necessitates additional metabolic steps. The data show that butyrate assimilation occurs in the peroxisome via the β-oxidation pathway to produce acetyl-CoA and further tri/dicarboxylic acids in the glyoxylate cycle. Concomitantly, reactive oxygen species defense enzymes as well as the branched amino acid degradation pathway were strongly induced. Although no clear dedicated butyrate transport mechanism could be inferred, several membrane transporters induced on butyrate are identified as potential condidates. Metabolic responses correspond globally to the increased needs for central cofactors NAD, ATP and CoA, especially in the peroxisome and the cytosol.
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Affiliation(s)
| | - Ariane Atteia
- MARBEC, Univ Montpellier, CNRS, Ifremer, IRD, Sète, France
| | - Sabine Brugière
- Univ Grenoble Alpes, CEA, INSERM, UMR BioSanté U1292, CNRS, CEA, Grenoble, France
| | - Yohann Couté
- Univ Grenoble Alpes, CEA, INSERM, UMR BioSanté U1292, CNRS, CEA, Grenoble, France
| | - Olivier Vallon
- Institut de Biologie Physico-Chimique, UMR7141 CNRS-Sorbonne Université, Paris, France
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Bernard C, Zavoriti A, Pucelle Q, Chazaud B, Gondin J. Role of macrophages during skeletal muscle regeneration and hypertrophy-Implications for immunomodulatory strategies. Physiol Rep 2022; 10:e15480. [PMID: 36200266 PMCID: PMC9535344 DOI: 10.14814/phy2.15480] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 09/12/2022] [Indexed: 06/16/2023] Open
Abstract
Skeletal muscle is a plastic tissue that regenerates ad integrum after injury and adapts to raise mechanical loading/contractile activity by increasing its mass and/or myofiber size, a phenomenon commonly refers to as skeletal muscle hypertrophy. Both muscle regeneration and hypertrophy rely on the interactions between muscle stem cells and their neighborhood, which include inflammatory cells, and particularly macrophages. This review first summarizes the role of macrophages in muscle regeneration in various animal models of injury and in response to exercise-induced muscle damage in humans. Then, the potential contribution of macrophages to skeletal muscle hypertrophy is discussed on the basis of both animal and human experiments. We also present a brief comparative analysis of the role of macrophages during muscle regeneration versus hypertrophy. Finally, we summarize the current knowledge on the impact of different immunomodulatory strategies, such as heat therapy, cooling, massage, nonsteroidal anti-inflammatory drugs and resolvins, on skeletal muscle regeneration and their potential impact on muscle hypertrophy.
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Affiliation(s)
- Clara Bernard
- Institut NeuroMyoGène, Unité Physiopathologie et Génétique du Neurone et du MuscleUniversité Claude Bernard Lyon 1, CNRS UMR 5261, INSERM U1315, Université LyonLyonFrance
| | - Aliki Zavoriti
- Institut NeuroMyoGène, Unité Physiopathologie et Génétique du Neurone et du MuscleUniversité Claude Bernard Lyon 1, CNRS UMR 5261, INSERM U1315, Université LyonLyonFrance
| | - Quentin Pucelle
- Université de Versailles Saint‐Quentin‐En‐YvelinesVersaillesFrance
| | - Bénédicte Chazaud
- Institut NeuroMyoGène, Unité Physiopathologie et Génétique du Neurone et du MuscleUniversité Claude Bernard Lyon 1, CNRS UMR 5261, INSERM U1315, Université LyonLyonFrance
| | - Julien Gondin
- Institut NeuroMyoGène, Unité Physiopathologie et Génétique du Neurone et du MuscleUniversité Claude Bernard Lyon 1, CNRS UMR 5261, INSERM U1315, Université LyonLyonFrance
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Bao Z, Wang J, He M, Zhang P, Shan L, Yao Y, Wang Q, Zheng L, Ge H, Zhou J. Benzo[a]pyrene inhibits myoblast differentiation through downregulating the Hsp70-K2-p38MAPK complex. Toxicol In Vitro 2022; 82:105356. [PMID: 35427736 DOI: 10.1016/j.tiv.2022.105356] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 03/11/2022] [Accepted: 04/07/2022] [Indexed: 10/18/2022]
Abstract
Cigarette smoking causes skeletal muscle dysfunction and worse prognosis for patients with diverse systemic diseases. Benzo[a]pyrene (BaP), one major constituent that is inhaled during smoking, is particularly known for its ability to impair neurodevelopment, impede reproductivity, or reduce birth weight. Here, we found that BaP exposure led to the inhibition of C2C12 myoblasts differentiation in a dose-dependent manner and reduced the expression of both early and late myogenic differentiation markers. BaP exposure significantly decreased the expression of p38 mitogen-activated protein kinase (p38MAPK), but not AKT, which are both critical during myogenic differentiation. Mechanistically, BaP deregulated the expression levels of MAPK-activated protein kinase 2 (MK2) and heat shock protein 70 (Hsp70), both of which stabilize p38MAPK. Interestingly, treatment of proteasome inhibitor MG132 was able to reverse BaP-induced degradation of Hsp70/ MK2 and p38MAPK in myoblasts, implying BaP-mediated p38MAPK degradation is proteasome-dependent. Overexpression of p38MAPK also rescued the defective differentiation phenotype of C2C12 induced by BaP. Taken together, we suggest that BaP exposure induces MK2/Hsp70/p38MAPK complex degradation in C2C12 myoblasts and impairs myogenic differentiation by proteasomal-dependent mechanisms. As application of the proteasome inhibitor MG132 or overexpression of p38MAPK could reverse impaired differentiation of myoblasts induced by BaP, this may suggest potential related strategies for preventing tobacco-related skeletal muscle diseases or for respiratory rehabilitation.
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Affiliation(s)
- Zhang Bao
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jianfeng Wang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Mingjie He
- Department of Biochemistry and Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Laboratory for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Pei Zhang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lu Shan
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yinan Yao
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qing Wang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Liling Zheng
- Department of Biochemistry and Department of General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Laboratory for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Huiqing Ge
- Department of Respiratory Care, Regional Medical Center for the National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
| | - Jianying Zhou
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Novel approach to unravel the Heat shock proteins (HSPs) with anti-ischemic stroke and human infections. J Infect Public Health 2022; 15:379-388. [DOI: 10.1016/j.jiph.2022.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/17/2022] [Accepted: 03/01/2022] [Indexed: 11/18/2022] Open
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12
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Sasaki S, Negishi T, Tsuzuki T, Yukawa K. Diphenylarsinic acid induced activation of MAP kinases, transcription factors, and oxidative stress-responsive factors and hypersecretion of cytokines in cultured normal human cerebellar astrocytes. Neurotoxicology 2021; 88:196-207. [PMID: 34883095 DOI: 10.1016/j.neuro.2021.12.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 09/24/2021] [Accepted: 12/02/2021] [Indexed: 01/09/2023]
Abstract
Diphenylarsinic acid (DPAA) is a non-natural pentavalent organic arsenic and was detected in well water in Kamisu, Ibaraki, Japan in 2003. Individuals that had consumed this arsenic-contaminated water developed cerebellar symptoms such as myoclonus. We previously revealed that DPAA exposure in rats in vitro and in vivo specifically affected astrocytes rather than neurons among cerebellar cells. Here, we evaluated adverse effects of DPAA in cultured normal human cerebellar astrocytes (NHA), which were compared with those in normal rat cerebellar astrocytes (NRA) exposed to DPAA at 10 μM for 96 h, focusing on aberrant activation of astrocytes; increase in cell viability, activation of MAP kinases (ERK1/2, p38MAPK, and SAPK/JNK) and transcription factors (CREB, c-Jun, and c-Fos), upregulation of oxidative stress-responsive factors (Nrf2, HO-1, and Hsp70), and also hypersecretion of brain cytokines (MCP-1, adrenomedullin, FGF-2, CXCL1, and IL-6) as reported in NRA. While DPAA exposure at 10 μM for 96 h had little effect on NHA, a higher concentration (50 μM for 96 h) and longer exposure (10 μM for 288 h) induced similar aberrant activation. Moreover, exposure to DPAA at 50 μM for 96 h or 10 μM for 288 h in NHA induced hypersecretion of cytokines induced in DPAA-exposed NRA (MCP-1, adrenomedullin, FGF-2, CXCL1, and IL-6), and IL-8 besides into culture medium. These results suggested that aberrantly activated human astrocytes by DPAA exposure might play a pivotal role in the pathogenesis of cerebellar symptoms, affecting adjacent neurons, microglia, brain blood vessels, or astrocyte itself through these brain cytokines in human.
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Affiliation(s)
- Shoto Sasaki
- Department of Physiology, Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi, 468-8503, Japan
| | - Takayuki Negishi
- Department of Physiology, Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi, 468-8503, Japan; Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi, 468-8503, Japan.
| | - Takamasa Tsuzuki
- Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi, 468-8503, Japan
| | - Kazunori Yukawa
- Department of Physiology, Graduate School of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi, 468-8503, Japan; Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi, 468-8503, Japan
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Zhang Y, Ding H, Wang X, Wang X, Wan S, Xu A, Gan R, Ye SD. MK2 promotes Tfcp2l1 degradation via β-TrCP ubiquitin ligase to regulate mouse embryonic stem cell self-renewal. Cell Rep 2021; 37:109949. [PMID: 34731635 DOI: 10.1016/j.celrep.2021.109949] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 08/31/2021] [Accepted: 10/14/2021] [Indexed: 10/19/2022] Open
Abstract
Tfcp2l1 can maintain mouse embryonic stem cell (mESC) self-renewal. However, it remains unknown how Tfcp2l1 protein stability is regulated. Here, we demonstrate that β-transducin repeat-containing protein (β-TrCP) targets Tfcp2l1 for ubiquitination and degradation in a mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2)-dependent manner. Specifically, β-TrCP1 and β-TrCP2 recognize and ubiquitylate Tfcp2l1 through the canonical β-TrCP-binding motif DSGDNS, in which the serine residues have been phosphorylated by MK2. Point mutation of serine-to-alanine residues reduces β-TrCP-mediated ubiquitylation and enhances the ability of Tfcp2l1 to promote mESC self-renewal while repressing the speciation of the endoderm, mesoderm, and trophectoderm. Similarly, inhibition of MK2 reduces the association of Tfcp2l1 with β-TrCP1 and increases the self-renewal-promoting effects of Tfcp2l1, whereas overexpression of MK2 or β-TrCP genes decreases Tfcp2l1 protein levels and induces mESC differentiation. Collectively, our study reveals a posttranslational modification of Tfcp2l1 that will expand our understanding of the regulatory network of stem cell pluripotency.
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Affiliation(s)
- Yan Zhang
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei, Anhui 230601, China
| | - Huiwen Ding
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei, Anhui 230601, China
| | - Xiaoxiao Wang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China
| | - Xin Wang
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei, Anhui 230601, China
| | - Shengpeng Wan
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei, Anhui 230601, China
| | - Anchun Xu
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei, Anhui 230601, China
| | - Ruoyi Gan
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei, Anhui 230601, China
| | - Shou-Dong Ye
- Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei, Anhui 230601, China; Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui 230601, China.
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MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate. Proc Natl Acad Sci U S A 2021; 118:2024562118. [PMID: 34272277 DOI: 10.1073/pnas.2024562118] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Cell survival in response to stress is determined by the coordination of various signaling pathways. The kinase p38α is activated by many stresses, but the intensity and duration of the signal depends on the stimuli. How different p38α-activation dynamics may impact cell life/death decisions is unclear. Here, we show that the p38α-signaling output in response to stress is modulated by the expression levels of the downstream kinase MK2. We demonstrate that p38α forms a complex with MK2 in nonstimulated mammalian cells. Upon pathway activation, p38α phosphorylates MK2, the complex dissociates, and MK2 is degraded. Interestingly, transient p38α activation allows MK2 reexpression, reassembly of the p38α-MK2 complex, and cell survival. In contrast, sustained p38α activation induced by severe stress interferes with p38α-MK2 interaction, resulting in irreversible MK2 loss and cell death. MK2 degradation is mediated by the E3 ubiquitin ligase MDM2, and we identify four lysine residues in MK2 that are directly ubiquitinated by MDM2. Expression of an MK2 mutant that cannot be ubiquitinated by MDM2 enhances the survival of stressed cells. Our results indicate that MK2 reexpression and binding to p38α is critical for cell viability in response to stress and illustrate how particular p38α-activation patterns induced by different signals shape the stress-induced cell fate.
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Shen J, Hao Z, Wang J, Hu J, Liu X, Li S, Ke N, Song Y, Lu Y, Hu L, Qiao L, Wu X, Luo Y. Comparative Transcriptome Profile Analysis of Longissimus dorsi Muscle Tissues From Two Goat Breeds With Different Meat Production Performance Using RNA-Seq. Front Genet 2021; 11:619399. [PMID: 33519920 PMCID: PMC7838615 DOI: 10.3389/fgene.2020.619399] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022] Open
Abstract
Carcass weight, meat quality and muscle components are important traits economically and they underpin most of the commercial return to goat producers. In this study, the Longissimus dorsi muscle tissues were collected from five Liaoning cashmere (LC) goats and five Ziwuling black (ZB) goats with phenotypic difference in carcass weight, some meat quality traits and muscle components. The histological quantitative of collagen fibers and the transcriptome profiles in the Longissimus dorsi muscle tissues were investigated using Masson-trichrome staining and RNA-Seq, respectively. The percentage of total collagen fibers in the Longissimus dorsi muscle tissues from ZB goats was less than those from LC goats, suggesting that these ZB goats had more tender meat. An average of 15,919 and 15,582 genes were found to be expressed in Longissimus dorsi muscle tissues from LC and ZB goats, respectively. Compared to LC goats, the expression levels of 78 genes were up-regulated in ZB goats, while 133 genes were down-regulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the differentially expressed genes (DEGs) were significantly enriched in GO terms related to the muscle growth and development and the deposition of intramuscular fat and lipid metabolism, hippo signaling pathway and Jak-STAT signaling pathway. The results provide an improved understanding of the genetic mechanisms regulating meat production performance in goats, and will help us improve the accuracy of selection for meat traits in goats using marker-assisted selection based on these differentially expressed genes obtained.
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Affiliation(s)
- Jiyuan Shen
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Zhiyun Hao
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Jiqing Wang
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Jiang Hu
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Xiu Liu
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Shaobin Li
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Na Ke
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Yize Song
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Yujie Lu
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Liyan Hu
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Lirong Qiao
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Xinmiao Wu
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Yuzhu Luo
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
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Yeung CYC, Schoof EM, Tamáš M, Mackey AL, Kjaer M. Proteomics identifies differences in fibrotic potential of extracellular vesicles from human tendon and muscle fibroblasts. Cell Commun Signal 2020; 18:177. [PMID: 33148271 PMCID: PMC7641822 DOI: 10.1186/s12964-020-00669-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 09/29/2020] [Indexed: 12/21/2022] Open
Abstract
Background Fibroblasts are the powerhouses responsible for the production and assembly of extracellular matrix (ECM). Their activity needs to be tightly controlled especially within the musculoskeletal system, where changes to ECM composition affect force transmission and mechanical loading that are required for effective movement of the body. Extracellular vesicles (EVs) are a mode of cell-cell communication within and between tissues, which has been largely characterised in cancer. However, it is unclear what the role of healthy fibroblast-derived EVs is during tissue homeostasis. Methods Here, we performed proteomic analysis of small EVs derived from primary human muscle and tendon cells to identify the potential functions of healthy fibroblast-derived EVs. Results Mass spectrometry-based proteomics revealed comprehensive profiles for small EVs released from healthy human fibroblasts from different tissues. We found that fibroblast-derived EVs were more similar than EVs from differentiating myoblasts, but there were significant differences between tendon fibroblast and muscle fibroblast EVs. Small EVs from tendon fibroblasts contained higher levels of proteins that support ECM synthesis, including TGFβ1, and muscle fibroblast EVs contained proteins that support myofiber function and components of the skeletal muscle matrix. Conclusions Our data demonstrates a marked heterogeneity among healthy fibroblast-derived EVs, indicating shared tasks between EVs of skeletal muscle myoblasts and fibroblasts, whereas tendon fibroblast EVs could play a fibrotic role in human tendon tissue. These findings suggest an important role for EVs in tissue homeostasis of both tendon and skeletal muscle in humans.
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