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Yue F, Gu L, Qiu J, Oprescu SN, Beckett LM, Ellis JM, Donkin SS, Kuang S. Mitochondrial fatty acid oxidation regulates adult muscle stem cell function through modulating metabolic flux and protein acetylation. EMBO J 2025; 44:2566-2595. [PMID: 40065099 PMCID: PMC12048568 DOI: 10.1038/s44318-025-00397-1] [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: 09/19/2024] [Revised: 01/31/2025] [Accepted: 02/10/2025] [Indexed: 05/04/2025] Open
Abstract
During homeostasis and regeneration, satellite cells, the resident stem cells of skeletal muscle, have distinct metabolic requirements for fate transitions between quiescence, proliferation and differentiation. However, the contribution of distinct energy sources to satellite cell metabolism and function remains largely unexplored. Here, we uncover a role of mitochondrial fatty acid oxidation (FAO) in satellite cell integrity and function. Single-cell RNA sequencing revealed progressive enrichment of mitochondrial FAO and downstream pathways during activation, proliferation and myogenic commitment of satellite cells. Deletion of Carnitine palmitoyltransferase 2 (Cpt2), the rate-limiting enzyme in FAO, hampered muscle stem cell expansion and differentiation upon acute muscle injury, markedly delaying regeneration. Cpt2 deficiency reduces acetyl-CoA levels in satellite cells, impeding the metabolic flux and acetylation of selective proteins including Pax7, the central transcriptional regulator of satellite cells. Notably, acetate supplementation restored cellular metabolic flux and partially rescued the regenerative defects of Cpt2-null satellite cells. These findings highlight an essential role of fatty acid oxidation in controlling satellite cell function and suggest an integration of lipid metabolism and protein acetylation in adult stem cells.
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Affiliation(s)
- Feng Yue
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA.
- Department of Animal Sciences, University of Florida, Gainesville, FL, 32611, USA.
| | - Lijie Gu
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Jiamin Qiu
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Stephanie N Oprescu
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Linda M Beckett
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Jessica M Ellis
- East Carolina Diabetes and Obesity Institute and Department of Physiology, East Carolina University, Greenville, NC, 27858, USA
| | - Shawn S Donkin
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Shihuan Kuang
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA.
- Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, 27710, USA.
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Hirano K, Nakabayashi C, Sasaki M, Suzuki M, Aoyagi Y, Tanaka K, Murakami A, Tsuchiya M, Umemoto E, Takabayashi S, Kitajima Y, Ono Y, Matsukawa T, Matsushita M, Ohkawa Y, Mori Y, Hara Y. Mg 2+ influx mediated by TRPM7 triggers the initiation of muscle stem cell activation. SCIENCE ADVANCES 2025; 11:eadu0601. [PMID: 40184450 PMCID: PMC11970462 DOI: 10.1126/sciadv.adu0601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 02/28/2025] [Indexed: 04/06/2025]
Abstract
Muscle satellite cells (MuSCs) respond immediately to environmental cues upon skeletal muscle injuries. Despite decades of research into muscle regeneration, the specific molecular factors that trigger the transition of MuSCs from a quiescent to an active state remain largely unidentified. Here, we identify transient receptor potential melastatin 7 (TRPM7), an Mg2+-permeable ion channel, as a critical regulator of MuSC activation. Trpm7 deletion in MuSCs reduced Mg2+ influx, impairing myofiber regeneration and leading to decreased MuSC numbers and cell cycle arrest during regeneration. These changes were linked to disrupted mTOR signaling, which drives the transition of MuSCs from G0 to GAlert phase. In addition, Trpm7-deficient MuSCs exhibited impaired early responses, including quiescent projection retraction and AP-1 induction. Mg2+ supplementation rescued these defects, restoring normal MuSC activation. Our findings reveal a previously unrecognized mechanism where Mg2+ permeation through TRPM7 is essential for MuSC activation and efficient skeletal muscle regeneration, highlighting TRPM7 as a critical regulator of muscle repair.
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Affiliation(s)
- Kotaro Hirano
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Chika Nakabayashi
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Mao Sasaki
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Miki Suzuki
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
- Faculty of Pharmacy, Laboratory of Hygienic Chemistry, Juntendo University, Chiba 279-0013, Japan
| | - Yuta Aoyagi
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Kaori Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Akira Murakami
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Masaki Tsuchiya
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
- PRESTO, JST, Kawaguchi, Saitama 332-0012, Japan
| | - Eiji Umemoto
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Shuji Takabayashi
- Institute of Photonics Medicine, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan
| | - Yasuo Kitajima
- Department of Immunology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Yusuke Ono
- Department of Muscle Development and Regeneration, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
| | - Takehisa Matsukawa
- Faculty of Pharmacy, Laboratory of Hygienic Chemistry, Juntendo University, Chiba 279-0013, Japan
| | - Masayuki Matsushita
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0213, Japan
| | - Yasuyuki Ohkawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yasuo Mori
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
| | - Yuji Hara
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
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Huang X, Xu C, Zhang J, Wu W, Wang Z, Pang Q, Liu Z, Liu B. Endurance exercise remodels skeletal muscle by suppressing Ythdf1-mediated myostatin expression. Cell Death Dis 2025; 16:96. [PMID: 39948064 PMCID: PMC11825732 DOI: 10.1038/s41419-025-07379-5] [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: 08/07/2024] [Revised: 12/20/2024] [Accepted: 01/21/2025] [Indexed: 02/16/2025]
Abstract
Exercise can improve health via skeletal muscle remodeling. Elucidating the underlying mechanism may lead to new therapeutics for aging-related loss of skeletal muscle mass. Here, we show that endurance exercise suppresses expression of YT521-B homology domain family (Ythdf1) in skeletal muscle, which recognizes the N6-methyladenosine (m6A). Ythdf1 deletion phenocopies endurance exercise-induced muscle hypertrophy in mice increases muscle mitochondria content and type I fiber specification. At the molecular level, Ythdf1 recognizes and promotes the translation of m6A-modified Mstn mRNA, which encodes a muscle growth inhibitor, Myostatin. Loss of Ythdf1 leads to hyperactivation of skeletal muscle stem cells (MuSCs), also called satellite cells (SCs), enhancing muscle growth and injury-induced regeneration. Our data reveal Ythdf1 as a key regulator of skeletal muscle homeostasis, provide insights into the mechanism by which endurance exercise promotes skeletal muscle remodeling and highlight potential strategies to prevent aging-related muscle degeneration.
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Affiliation(s)
- Xin Huang
- Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, China
| | - Chenzhong Xu
- Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, China
| | - Jie Zhang
- Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, China
| | - Weiwei Wu
- Anti-aging & Regenerative Medicine Research Institution, School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Zimei Wang
- Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, China
| | - Qiuxiang Pang
- Anti-aging & Regenerative Medicine Research Institution, School of Life Sciences, Shandong University of Technology, Zibo, China
| | - Zuojun Liu
- Hainan Province Key Laboratory of One Health, Collaborative Innovation Center of One Health, School of Life and Health Sciences, Hainan University, Haikou, Hainan, China.
- School of Environmental Science and Engineering, Hainan University, Haikou, Hainan, China.
| | - Baohua Liu
- Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, China.
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Wang Z, Peng Q, Zhang Z, You X, Duan H, Sha R, Yuan N, Li Z, Xie Z, Han J, Feng Y. SRSF1 Is Crucial for Maintaining Satellite Cell Homeostasis During Skeletal Muscle Growth and Regeneration. J Cachexia Sarcopenia Muscle 2024; 15:2629-2641. [PMID: 39381961 PMCID: PMC11634495 DOI: 10.1002/jcsm.13607] [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: 12/13/2023] [Revised: 08/07/2024] [Accepted: 08/29/2024] [Indexed: 10/10/2024] Open
Abstract
BACKGROUND The splicing factor SRSF1 emerges as a mater regulator of cell proliferation, displaying high expression in actively proliferative satellite cells (SCs). In SRSF1 knockout mice (KO) generated via MyoD-Cre, early mortality and muscle atrophy are observed during postnatal muscle growth. Despite these findings, the precise mechanisms through which SRSF1 loss influences SCs' functions and its role in muscle regeneration remain to be elucidated. METHODS To unravel the exact mechanisms underlying the impact of SRSF1 deficiency SC functions, we employed single-cell RNA sequencing (scRNA-seq) on a mononuclear cell suspension isolated from the newborn diaphragm of KO and control mice. Concurrently, we subjected diaphragm muscles to RNA-seq analysis to identify dysregulated splicing events associated with SRSF1 deletion. For the analysis of the effect of SRSF1 deletion on muscle regeneration, we generated mice with inducible SC-specific Srsf1 ablation through Pax7-CreER. SRSF1 ablation was induced by intraperitoneal injection of tamoxifen. Using cardiotoxin-induced muscle injury, we examined the consequences of SRSF1 depletion on SC function through HE staining, immunostaining and EdU incorporation assay. C2C12 myoblasts and isolated myoblasts were employed to assess stem cell function and senescence. RESULTS Utilizing scRNA-seq analysis, we observed a noteworthy increase in activated and proliferating myoblasts when SRSF1 was absent. This increase was substantial, with the proportion rising from 28.68% in the control group to 77.06% in the knockout group. However, these myoblasts experienced mitotic abnormalities in the absence of SRSF1, resulting in cell cycle arrest and the onset of cellular senescence. In the knockout mice, the proportion of Pax7+ cells within improper niche positioning increased significantly to 25% compared to 12% in the control cells (n ≥ 10, p < 0.001). Furthermore, there was an observation of persistent cell cycle exit specifically in the Pax7+ cells deficient in SRSF1 (n = 6, p < 0.001). SRSF1 plays a pivotal role in regulating the splicing of Fgfr1op2, favouring the full-length isoform crucial for mitotic spindle organization. Disrupting SRSF1 in C2C12 and primary myoblasts results in multipolar spindle formation (p < 0.001) and dysregulated splicing of Fgfr1op2 and triggers cellular senescence. Consequently, adult SCs lacking SRSF1 initially activate upon injury but face substantial challenge in proliferation (n = 4, p < 0.001), leading to a failure in muscle regeneration. CONCLUSIONS SRSF1 plays a critical role in SCs by ensuring proper splicing, maintaining mitotic progression and preventing premature senescence. These findings underscore the significant role of SRSF1 in controlling SC proliferation during skeletal muscle growth and regeneration.
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Affiliation(s)
- Zhenzhen Wang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of Sciences, Chinese Academy of SciencesShanghaiChina
| | - Qian Peng
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of Sciences, Chinese Academy of SciencesShanghaiChina
| | - Zhige Zhang
- Department of General Surgery, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Xue You
- Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University, Jining Medical UniversityJiningChina
| | - Huimin Duan
- Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University, Jining Medical UniversityJiningChina
| | - Rula Sha
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of Sciences, Chinese Academy of SciencesShanghaiChina
| | - Ningyang Yuan
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of Sciences, Chinese Academy of SciencesShanghaiChina
| | - Zhigang Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of Sciences, Chinese Academy of SciencesShanghaiChina
| | - Zhiqin Xie
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of Sciences, Chinese Academy of SciencesShanghaiChina
| | - Jun Han
- Department of General Surgery, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Ying Feng
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and HealthUniversity of Chinese Academy of Sciences, Chinese Academy of SciencesShanghaiChina
- Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University, Jining Medical UniversityJiningChina
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Qiu J, Yue F, Kim KH, Chen X, Khedr MA, Chen J, Gu L, Ren J, Ferreira CR, Ellis J, Kuang S. Overexpression of CPT1A disrupts the maintenance and regenerative function of muscle stem cells. FASEB J 2024; 38:e70071. [PMID: 39382025 PMCID: PMC11486317 DOI: 10.1096/fj.202400947r] [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: 04/26/2024] [Revised: 09/02/2024] [Accepted: 09/11/2024] [Indexed: 10/10/2024]
Abstract
The skeletal muscle satellite cells (SCs) mediate regeneration of myofibers upon injury. As they switch from maintenance (quiescence) to regeneration, their relative reliance on glucose and fatty acid metabolism alters. To explore the contribution of mitochondrial fatty acid oxidation (FAO) pathway to SCs and myogenesis, we examined the role of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO. CPT1A is highly expressed in quiescent SCs (QSCs) compared with activated and proliferating SCs, and its expression level decreases during myogenic differentiation. Myod1Cre-driven overexpression (OE) of Cpt1a in embryonic myoblasts (Cpt1aMTG) reduces muscle weight, grip strength, and contractile force without affecting treadmill endurance of adult mice. Adult Cpt1aMTG mice have reduced number of SC, impairing muscle regeneration and promoting lipid infiltration. Similarly, Pax7CreER-driven, tamoxifen-inducible Cpt1a-OE in QSCs of adult muscles (Cpt1aPTG) leads to depletion of SCs and compromises muscle regeneration. The reduced proliferation of Cpt1a-OE SCs is associated with elevated level of acyl-carnitine, and acyl-carnitine treatment impedes proliferation of wildtype SCs. These findings indicate that aberrant level of CPT1A elevates acyl-carnitine to impair the maintenance, proliferation and regenerative function of SCs.
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Affiliation(s)
- Jiamin Qiu
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
- These authors contributed equally to this work
| | - Feng Yue
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
- Department of Animal Sciences, University of Florida, Gainesville, FL 32611, USA
- These authors contributed equally to this work
| | - Kun Ho Kim
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Xiyue Chen
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | | | - Jingjuan Chen
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Lijie Gu
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Junxiao Ren
- Department of Animal Sciences, University of Florida, Gainesville, FL 32611, USA
| | - Christina R. Ferreira
- Purdue Metabolite Profiling Facility, Purdue University, West, Lafayette, IN 47907, USA
| | - Jessica Ellis
- Department of Physiology and East Carolina Diabetes and Obesity Institute, Brody School of Medicine at East Carolina University Greenville, NC 27834, USA
| | - Shihuan Kuang
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
- Purdue University Institute for Cancer Research, West Lafayette, IN 47907, USA
- Departments of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC 27710, USA
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6
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Özgüldez HÖ, Bulut-Karslioğlu A. Dormancy, Quiescence, and Diapause: Savings Accounts for Life. Annu Rev Cell Dev Biol 2024; 40:25-49. [PMID: 38985838 DOI: 10.1146/annurev-cellbio-112122-022528] [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] [Indexed: 07/12/2024]
Abstract
Life on Earth has been through numerous challenges over eons and, one way or another, has always triumphed. From mass extinctions to more daily plights to find food, unpredictability is everywhere. The adaptability of life-forms to ever-changing environments is the key that confers life's robustness. Adaptability has become synonymous with Darwinian evolution mediated by heritable genetic changes. The extreme gene-centric view, while being of central significance, at times has clouded our appreciation of the cell as a self-regulating entity informed of, and informing, the genetic data. An essential element that powers adaptability is the ability to regulate cell growth. In this review, we provide an extensive overview of growth regulation spanning species, tissues, and regulatory mechanisms. We aim to highlight the commonalities, as well as differences, of these phenomena and their molecular regulators. Finally, we curate open questions and areas for further exploration.
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Affiliation(s)
- Hatice Özge Özgüldez
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany;
| | - Aydan Bulut-Karslioğlu
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany;
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Karabag D, Heneka MT, Ising C. The putative contribution of cellular senescence to driving tauopathies. Trends Immunol 2024; 45:837-848. [PMID: 39306559 DOI: 10.1016/j.it.2024.08.006] [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: 07/29/2024] [Revised: 08/24/2024] [Accepted: 08/26/2024] [Indexed: 10/13/2024]
Abstract
During mammalian aging, senescent cells accumulate in the body. Recent evidence suggests that senescent cells potentially contribute to age-related neurodegenerative diseases in the central nervous system (CNS), including tauopathies such as Alzheimer's disease (AD). Senescent cells undergo irreversible cell cycle arrest and release an inflammatory 'senescence-associated secretory profile' (SASP), which can exert devastating effects on surrounding cells. Senescent markers and SASP factors have been detected in multiple brain cells in tauopathies, including microglia, astrocytes, and perhaps even post-mitotic neurons, possibly contributing to the initiation as well as progression of these diseases. Here, we discuss the implications of presenting a senescent phenotype in tauopathies and highlight a potential role for the NOD-like receptor protein 3 (NLRP3) inflammasome as a newfound mechanism implicated in senescence and SASP formation.
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Affiliation(s)
- Deniz Karabag
- Department for Neuroimmunology, Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Cologne, Germany
| | - Michael T Heneka
- Department for Neuroimmunology, Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA.
| | - Christina Ising
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Cluster of Excellence Cellular Stress Response in Aging-associated Diseases (CECAD), Cologne, Germany.
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Madl CM, Wang YX, Holbrook CA, Su S, Shi X, Byfield FJ, Wicki G, Flaig IA, Blau HM. Hydrogel biomaterials that stiffen and soften on demand reveal that skeletal muscle stem cells harbor a mechanical memory. Proc Natl Acad Sci U S A 2024; 121:e2406787121. [PMID: 39163337 PMCID: PMC11363279 DOI: 10.1073/pnas.2406787121] [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: 04/04/2024] [Accepted: 07/21/2024] [Indexed: 08/22/2024] Open
Abstract
Muscle stem cells (MuSCs) are specialized cells that reside in adult skeletal muscle poised to repair muscle tissue. The ability of MuSCs to regenerate damaged tissues declines markedly with aging and in diseases such as Duchenne muscular dystrophy, but the underlying causes of MuSC dysfunction remain poorly understood. Both aging and disease result in dramatic increases in the stiffness of the muscle tissue microenvironment from fibrosis. MuSCs are known to lose their regenerative potential if cultured on stiff plastic substrates. We sought to determine whether MuSCs harbor a memory of their past microenvironment and if it can be overcome. We tested MuSCs in situ using dynamic hydrogel biomaterials that soften or stiffen on demand in response to light and found that freshly isolated MuSCs develop a persistent memory of substrate stiffness characterized by loss of proliferative progenitors within the first three days of culture on stiff substrates. MuSCs cultured on soft hydrogels had altered cytoskeletal organization and activity of Rho and Rac guanosine triphosphate hydrolase (GTPase) and Yes-associated protein mechanotransduction pathways compared to those on stiff hydrogels. Pharmacologic inhibition identified RhoA activation as responsible for the mechanical memory phenotype, and single-cell RNA sequencing revealed a molecular signature of the mechanical memory. These studies highlight that microenvironmental stiffness regulates MuSC fate and leads to MuSC dysfunction that is not readily reversed by changing stiffness. Our results suggest that stiffness can be circumvented by targeting downstream signaling pathways to overcome stem cell dysfunction in aged and disease states with aberrant fibrotic tissue mechanics.
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Affiliation(s)
- Christopher M. Madl
- Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA94305
- Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA19104
| | - Yu Xin Wang
- Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA94305
| | - Colin A. Holbrook
- Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA94305
| | - Shiqi Su
- Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA94305
| | - Xuechen Shi
- Department of Physiology, Perelman School of Medicine and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA19104
| | - Fitzroy J. Byfield
- Department of Physiology, Perelman School of Medicine and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA19104
| | - Gwendoline Wicki
- Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA94305
- Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, LausanneCH-1015, Switzerland
| | - Iris A. Flaig
- Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA94305
- Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne, LausanneCH-1015, Switzerland
| | - Helen M. Blau
- Department of Microbiology and Immunology, Baxter Laboratory for Stem Cell Biology, Stanford University, Stanford, CA94305
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9
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Li Y, Ma R, Hao X. Therapeutic role of PTEN in tissue regeneration for management of neurological disorders: stem cell behaviors to an in-depth review. Cell Death Dis 2024; 15:268. [PMID: 38627382 PMCID: PMC11021430 DOI: 10.1038/s41419-024-06657-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: 09/15/2023] [Revised: 03/29/2024] [Accepted: 04/08/2024] [Indexed: 04/19/2024]
Abstract
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) represents the initial tumor suppressor gene identified to possess phosphatase activity, governing various cellular processes including cell cycle regulation, migration, metabolic pathways, autophagy, oxidative stress response, and cellular senescence. Current evidence suggests that PTEN is critical for stem cell maintenance, self-renewal, migration, lineage commitment, and differentiation. Based on the latest available evidence, we provide a comprehensive overview of the mechanisms by which PTEN regulates activities of different stem cell populations and influences neurological disorders, encompassing autism, stroke, spinal cord injury, traumatic brain injury, Alzheimer's disease and Parkinson's disease. This review aims to elucidate the therapeutic impacts and mechanisms of PTEN in relation to neurogenesis or the stem cell niche across a range of neurological disorders, offering a foundation for innovative therapeutic approaches aimed at tissue repair and regeneration in neurological disorders. This review unravels novel therapeutic strategies for tissue restoration and regeneration in neurological disorders based on the regulatory mechanisms of PTEN on neurogenesis and the stem cell niche.
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Affiliation(s)
- Yue Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, 999078, Macau, China.
- Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, 999078, Macau, China.
| | - Ruishuang Ma
- State Key Laboratory of Component-Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 301617, Tianjin, China
| | - Xia Hao
- State Key Laboratory of Component-Based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 301617, Tianjin, China
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10
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Chrysostomou E, Mourikis P. The extracellular matrix niche of muscle stem cells. Curr Top Dev Biol 2024; 158:123-150. [PMID: 38670702 DOI: 10.1016/bs.ctdb.2024.01.021] [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] [Indexed: 04/28/2024]
Abstract
Preserving the potency of stem cells in adult tissues is very demanding and relies on the concerted action of various cellular and non-cellular elements in a precise stoichiometry. This balanced microenvironment is found in specific anatomical "pockets" within the tissue, known as the stem cell niche. In this review, we explore the interplay between stem cells and their niches, with a primary focus on skeletal muscle stem cells and the extracellular matrix (ECM). Quiescent muscle stem cells, known as satellite cells are active producers of a diverse array of ECM molecules, encompassing major constituents like collagens, laminins, and integrins, some of which are explored in this review. The conventional perception of ECM as merely a structural scaffold is evolving. Collagens can directly interact as ligands with receptors on satellite cells, while other ECM proteins have the capacity to sequester growth factors and regulate their release, especially relevant during satellite cell turnover in homeostasis or activation upon injury. Additionally, we explore an evolutionary perspective on the ECM across a range of multicellular organisms and discuss a model wherein satellite cells are self-sustained by generating their own niche. Considering the prevalence of ECM proteins in the connective tissue of various organs it is not surprising that mutations in ECM genes have pathological implications, including in muscle, where they can lead to myopathies. However, the particular role of certain disease-related ECM proteins in stem cell maintenance highlights the potential contribution of stem cell deregulation to the progression of these disorders.
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Affiliation(s)
- Eleni Chrysostomou
- Université Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale (INSERM), Mondor Institute for Biomedical Research (IMRB), Créteil, France
| | - Philippos Mourikis
- Université Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale (INSERM), Mondor Institute for Biomedical Research (IMRB), Créteil, France.
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11
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Rodriguez-Colman MJ, Dansen TB, Burgering BMT. FOXO transcription factors as mediators of stress adaptation. Nat Rev Mol Cell Biol 2024; 25:46-64. [PMID: 37710009 DOI: 10.1038/s41580-023-00649-0] [Citation(s) in RCA: 51] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2023] [Indexed: 09/16/2023]
Abstract
The forkhead box protein O (FOXO, consisting of FOXO1, FOXO3, FOXO4 and FOXO6) transcription factors are the mammalian orthologues of Caenorhabditis elegans DAF-16, which gained notoriety for its capability to double lifespan in the absence of daf-2 (the gene encoding the worm insulin receptor homologue). Since then, research has provided many mechanistic details on FOXO regulation and FOXO activity. Furthermore, conditional knockout experiments have provided a wealth of data as to how FOXOs control development and homeostasis at the organ and organism levels. The lifespan-extending capabilities of DAF-16/FOXO are highly correlated with their ability to induce stress response pathways. Exogenous and endogenous stress, such as cellular redox stress, are considered the main drivers of the functional decline that characterizes ageing. Functional decline often manifests as disease, and decrease in FOXO activity indeed negatively impacts on major age-related diseases such as cancer and diabetes. In this context, the main function of FOXOs is considered to preserve cellular and organismal homeostasis, through regulation of stress response pathways. Paradoxically, the same FOXO-mediated responses can also aid the survival of dysfunctional cells once these eventually emerge. This general property to control stress responses may underlie the complex and less-evident roles of FOXOs in human lifespan as opposed to model organisms such as C. elegans.
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Affiliation(s)
| | - Tobias B Dansen
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Boudewijn M T Burgering
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.
- Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.
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12
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Kim KH, Oprescu SN, Snyder MM, Kim A, Jia Z, Yue F, Kuang S. PRMT5 mediates FoxO1 methylation and subcellular localization to regulate lipophagy in myogenic progenitors. Cell Rep 2023; 42:113329. [PMID: 37883229 PMCID: PMC10727913 DOI: 10.1016/j.celrep.2023.113329] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 08/29/2023] [Accepted: 10/06/2023] [Indexed: 10/28/2023] Open
Abstract
Development is regulated by various factors, including protein methylation status. While PRMT5 is well known for its roles in oncogenesis by mediating symmetric di-methylation of arginine, its role in normal development remains elusive. Using Myod1Cre to drive Prmt5 knockout in embryonic myoblasts (Prmt5MKO), we dissected the role of PRMT5 in myogenesis. The Prmt5MKO mice are born normally but exhibit progressive muscle atrophy and premature death. Prmt5MKO inhibits proliferation and promotes premature differentiation of embryonic myoblasts, reducing the number and regenerative function of satellite cells in postnatal mice. Mechanistically, PRMT5 methylates and destabilizes FoxO1. Prmt5MKO increases the total FoxO1 level and promotes its cytoplasmic accumulation, leading to activation of autophagy and depletion of lipid droplets (LDs). Systemic inhibition of autophagy in Prmt5MKO mice restores LDs in myoblasts and moderately improves muscle regeneration. Together, PRMT5 is essential for muscle development and regeneration at least partially through mediating FoxO1 methylation and LD turnover.
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Affiliation(s)
- Kun Ho Kim
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Stephanie N Oprescu
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA; Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Madigan M Snyder
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA; Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Aran Kim
- Department of Pharmacy, Purdue University, West Lafayette, IN 47907, USA
| | - Zhihao Jia
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Feng Yue
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Shihuan Kuang
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
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13
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Koopmans PJ, Ismaeel A, Goljanek-Whysall K, Murach KA. The roles of miRNAs in adult skeletal muscle satellite cells. Free Radic Biol Med 2023; 209:228-238. [PMID: 37879420 PMCID: PMC10911817 DOI: 10.1016/j.freeradbiomed.2023.10.403] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/16/2023] [Accepted: 10/22/2023] [Indexed: 10/27/2023]
Abstract
Satellite cells are bona fide muscle stem cells that are indispensable for successful post-natal muscle growth and regeneration after severe injury. These cells also participate in adult muscle adaptation in several capacities. MicroRNAs (miRNAs) are post-transcriptional regulators of mRNA that are implicated in several aspects of stem cell function. There is evidence to suggest that miRNAs affect satellite cell behavior in vivo during development and myogenic progenitor behavior in vitro, but the role of miRNAs in adult skeletal muscle satellite cells is less studied. In this review, we provide evidence for how miRNAs control satellite cell function with emphasis on satellite cells of adult skeletal muscle in vivo. We first outline how miRNAs are indispensable for satellite cell viability and control the phases of myogenesis. Next, we discuss the interplay between miRNAs and myogenic cell redox status, senescence, and communication to other muscle-resident cells during muscle adaptation. Results from recent satellite cell miRNA profiling studies are also summarized. In vitro experiments in primary myogenic cells and cell lines have been invaluable for exploring the influence of miRNAs, but we identify a need for novel genetic tools to further interrogate how miRNAs control satellite cell behavior in adult skeletal muscle in vivo.
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Affiliation(s)
- Pieter Jan Koopmans
- Exercise Science Research Center, Molecular Muscle Mass Regulation Laboratory, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, AR, 72701, USA; Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, 72701, USA
| | - Ahmed Ismaeel
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, 40506, USA
| | - Katarzyna Goljanek-Whysall
- School of Medicine, College of Medicine, Nursing, and Health Sciences, University of Galway, Galway, Ireland
| | - Kevin A Murach
- Exercise Science Research Center, Molecular Muscle Mass Regulation Laboratory, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, AR, 72701, USA; Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, 72701, USA.
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14
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Qiu J, Yue F, Zhu P, Chen J, Xu F, Zhang L, Kim KH, Snyder MM, Luo N, Xu HW, Huang F, Tao WA, Kuang S. FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes. Nat Commun 2023; 14:6344. [PMID: 37816711 PMCID: PMC10564795 DOI: 10.1038/s41467-023-41988-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 09/26/2023] [Indexed: 10/12/2023] Open
Abstract
Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold revealed FAM210A as a cold-inducible mitochondrial inner membrane protein. An adipocyte-specific constitutive knockout of Fam210a (Fam210aAKO) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210aAKO mice vulnerable to lethal hypothermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes (Fam210aiAKO) does not affect steady-state mitochondrial structure under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold.
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Affiliation(s)
- Jiamin Qiu
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Feng Yue
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA.
- Department of Animal Sciences, University of Florida, Gainesville, FL, 32611, USA.
| | - Peipei Zhu
- Department of Biochemistry, Purdue University, West Lafayette, IN, 47907, USA
| | - Jingjuan Chen
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Fan Xu
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA
| | - Lijia Zhang
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Kun Ho Kim
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Madigan M Snyder
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Nanjian Luo
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Hao-Wei Xu
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Fang Huang
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, 47907, USA
| | - W Andy Tao
- Department of Biochemistry, Purdue University, West Lafayette, IN, 47907, USA
- Purdue University Institute for Cancer Research, West Lafayette, IN, 47907, USA
| | - Shihuan Kuang
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA.
- Purdue University Institute for Cancer Research, West Lafayette, IN, 47907, USA.
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15
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Zhang S, Yang F, Huang Y, He L, Li Y, Wan YCE, Ding Y, Chan KM, Xie T, Sun H, Wang H. ATF3 induction prevents precocious activation of skeletal muscle stem cell by regulating H2B expression. Nat Commun 2023; 14:4978. [PMID: 37591871 PMCID: PMC10435463 DOI: 10.1038/s41467-023-40465-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: 08/21/2022] [Accepted: 07/27/2023] [Indexed: 08/19/2023] Open
Abstract
Skeletal muscle stem cells (also called satellite cells, SCs) are important for maintaining muscle tissue homeostasis and damage-induced regeneration. However, it remains poorly understood how SCs enter cell cycle to become activated upon injury. Here we report that AP-1 family member ATF3 (Activating Transcription Factor 3) prevents SC premature activation. Atf3 is rapidly and transiently induced in SCs upon activation. Short-term deletion of Atf3 in SCs accelerates acute injury-induced regeneration, however, its long-term deletion exhausts the SC pool and thus impairs muscle regeneration. The Atf3 loss also provokes SC activation during voluntary exercise and enhances the activation during endurance exercise. Mechanistically, ATF3 directly activates the transcription of Histone 2B genes, whose reduction accelerates nucleosome displacement and gene transcription required for SC activation. Finally, the ATF3-dependent H2B expression also prevents genome instability and replicative senescence in SCs. Therefore, this study has revealed a previously unknown mechanism for preserving the SC population by actively suppressing precocious activation, in which ATF3 is a key regulator.
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Affiliation(s)
- Suyang Zhang
- Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, New Territories, Hong Kong SAR, China
| | - Feng Yang
- Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yile Huang
- Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Liangqiang He
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, New Territories, Hong Kong SAR, China
- Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yuying Li
- Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yi Ching Esther Wan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518172, China
| | - Yingzhe Ding
- Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Kui Ming Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
- Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute of City University of Hong Kong, Shenzhen, 518172, China
| | - Ting Xie
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong SAR, China
| | - Hao Sun
- Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China.
| | - Huating Wang
- Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China.
- Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, New Territories, Hong Kong SAR, China.
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16
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Wang Y, Yu Y, Yang W, Wu L, Yang Y, Lu Q, Zhou J. SETD4 Confers Cancer Stem Cell Chemoresistance in Nonsmall Cell Lung Cancer Patients via the Epigenetic Regulation of Cellular Quiescence. Stem Cells Int 2023; 2023:7367854. [PMID: 37274024 PMCID: PMC10239305 DOI: 10.1155/2023/7367854] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 04/23/2023] [Accepted: 05/08/2023] [Indexed: 06/06/2023] Open
Abstract
Increasing evidence indicates that quiescent cancer stem cells (CSCs) are a root cause of chemoresistance. SET domain-containing protein 4 (SETD4) epigenetically regulates cell quiescence in breast cancer stem cells (BCSCs), and SETD4-positive BCSCs are chemoradioresistant. However, the role of SETD4 in chemoresistance, tumor progression, and prognosis in nonsmall cell lung cancer (NSCLC) patients is unclear. Here, SETD4-positive cells were identified as quiescent lung cancer stem cells (qLCSCs) since they expressed high levels of ALDH1 and CD133 and low levels of Ki67. SETD4 expression was significantly higher in advanced-stage NSCLC tissues than in early-stage NSCLC tissues and significantly higher in samples from the chemoresistant group than in those from the chemosensitive group. Patients with high SETD4 expression had shorter progression-free survival (PFS) times than those with low SETD4 expression. SETD4 facilitated heterochromatin formation via H4K20me3, thereby leading to cell quiescence. RNA-seq analysis showed upregulation of genes involved in cell proliferation, glucose metabolism, and PI3K-AKT signaling in activated qLCSCs (A-qLCSCs) compared with qLCSCs. In addition, SETD4 overexpression facilitated PTEN-mediated inhibition of the PI3K-mTOR pathway. In summary, SETD4 confers chemoresistance, tumor progression, and a poor prognosis by regulating CSCs in NSCLC patients.
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Affiliation(s)
- Yuehong Wang
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yuman Yu
- Department of Geriatrics, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Weijun Yang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Linying Wu
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yaoshun Yang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qianyun Lu
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jianying Zhou
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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17
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Nanba D, Sakabe JI, Mosig J, Brouard M, Toki F, Shimokawa M, Kamiya M, Braschler T, Azzabi F, Droz-Georget Lathion S, Johnsson K, Roy K, Schmid CD, Bureau JB, Rochat A, Barrandon Y. Low temperature and mTOR inhibition favor stem cell maintenance in human keratinocyte cultures. EMBO Rep 2023:e55439. [PMID: 37139607 DOI: 10.15252/embr.202255439] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 03/26/2023] [Accepted: 04/14/2023] [Indexed: 05/05/2023] Open
Abstract
Adult autologous human epidermal stem cells can be extensively expanded ex vivo for cell and gene therapy. Identifying the mechanisms involved in stem cell maintenance and defining culture conditions to maintain stemness is critical, because an inadequate environment can result in the rapid conversion of stem cells into progenitors/transient amplifying cells (clonal conversion), with deleterious consequences on the quality of the transplants and their ability to engraft. Here, we demonstrate that cultured human epidermal stem cells respond to a small drop in temperature through thermoTRP channels via mTOR signaling. Exposure of cells to rapamycin or a small drop in temperature induces the nuclear translocation of mTOR with an impact on gene expression. We also demonstrate by single-cell analysis that long-term inhibition of mTORC1 reduces clonal conversion and favors the maintenance of stemness. Taken together, our results demonstrate that human keratinocyte stem cells can adapt to environmental changes (e.g., small variations in temperature) through mTOR signaling and constant inhibition of mTORC1 favors stem cell maintenance, a finding of high importance for regenerative medicine applications.
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Affiliation(s)
- Daisuke Nanba
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Division of Aging and Regeneration, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Jun-Ichi Sakabe
- Duke-NUS Medical School, Singapore City, Singapore
- Department of Plastic, Reconstructive and Aesthetic Surgery, Singapore General Hospital and A*STAR Skin Research Labs, Singapore City, Singapore
| | - Johannes Mosig
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Michel Brouard
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Fujio Toki
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Division of Aging and Regeneration, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Mariko Shimokawa
- Division of Aging and Regeneration, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Mako Kamiya
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Thomas Braschler
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Fahd Azzabi
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Stéphanie Droz-Georget Lathion
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Kai Johnsson
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Keya Roy
- Duke-NUS Medical School, Singapore City, Singapore
- Department of Plastic, Reconstructive and Aesthetic Surgery, Singapore General Hospital and A*STAR Skin Research Labs, Singapore City, Singapore
| | - Christoph D Schmid
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | - Jean-Baptiste Bureau
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Ariane Rochat
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Yann Barrandon
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Duke-NUS Medical School, Singapore City, Singapore
- Department of Plastic, Reconstructive and Aesthetic Surgery, Singapore General Hospital and A*STAR Skin Research Labs, Singapore City, Singapore
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18
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Lim S, Lee DE, Morena da Silva F, Koopmans PJ, Vechetti IJ, von Walden F, Greene NP, Murach KA. MicroRNA control of the myogenic cell transcriptome and proteome: the role of miR-16. Am J Physiol Cell Physiol 2023; 324:C1101-C1109. [PMID: 36971422 PMCID: PMC10191132 DOI: 10.1152/ajpcell.00071.2023] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/20/2023] [Accepted: 03/20/2023] [Indexed: 03/29/2023]
Abstract
MicroRNAs (miRs) control stem cell biology and fate. Ubiquitously expressed and conserved miR-16 was the first miR implicated in tumorigenesis. miR-16 is low in muscle during developmental hypertrophy and regeneration. It is enriched in proliferating myogenic progenitor cells but is repressed during differentiation. The induction of miR-16 blocks myoblast differentiation and myotube formation, whereas knockdown enhances these processes. Despite a central role for miR-16 in myogenic cell biology, how it mediates its potent effects is incompletely defined. In this investigation, global transcriptomic and proteomic analyses after miR-16 knockdown in proliferating C2C12 myoblasts revealed how miR-16 influences myogenic cell fate. Eighteen hours after miR-16 inhibition, ribosomal protein gene expression levels were higher relative to control myoblasts and p53 pathway-related gene abundance was lower. At the protein level at this same time point, miR-16 knockdown globally upregulated tricarboxylic acid (TCA) cycle proteins while downregulating RNA metabolism-related proteins. miR-16 inhibition induced specific proteins associated with myogenic differentiation such as ACTA2, EEF1A2, and OPA1. We extend prior work in hypertrophic muscle tissue and show that miR-16 is lower in mechanically overloaded muscle in vivo. Our data collectively point to how miR-16 is implicated in aspects of myogenic cell differentiation. A deeper understanding of the role of miR-16 in myogenic cells has consequences for muscle developmental growth, exercise-induced hypertrophy, and regenerative repair after injury, all of which involve myogenic progenitors.
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Affiliation(s)
- Seongkyun Lim
- Department of Health, Human Performance, and Recreation, Exercise Science Research Center, University of Arkansas, Fayetteville, Arkansas, United States
| | - David E Lee
- Department of Health, Human Performance, and Recreation, Exercise Science Research Center, University of Arkansas, Fayetteville, Arkansas, United States
| | - Francielly Morena da Silva
- Department of Health, Human Performance, and Recreation, Exercise Science Research Center, University of Arkansas, Fayetteville, Arkansas, United States
| | - Pieter J Koopmans
- Department of Health, Human Performance, and Recreation, Exercise Science Research Center, University of Arkansas, Fayetteville, Arkansas, United States
- Cell and Molecular Biology Graduate Program, University of Arkansas, Fayetteville, Arkansas, United States
| | - Ivan J Vechetti
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, United States
| | - Ferdinand von Walden
- Neuropediatrics, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Nicholas P Greene
- Department of Health, Human Performance, and Recreation, Exercise Science Research Center, University of Arkansas, Fayetteville, Arkansas, United States
- Cell and Molecular Biology Graduate Program, University of Arkansas, Fayetteville, Arkansas, United States
| | - Kevin A Murach
- Department of Health, Human Performance, and Recreation, Exercise Science Research Center, University of Arkansas, Fayetteville, Arkansas, United States
- Cell and Molecular Biology Graduate Program, University of Arkansas, Fayetteville, Arkansas, United States
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19
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de Morree A, Rando TA. Regulation of adult stem cell quiescence and its functions in the maintenance of tissue integrity. Nat Rev Mol Cell Biol 2023; 24:334-354. [PMID: 36922629 PMCID: PMC10725182 DOI: 10.1038/s41580-022-00568-6] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2022] [Indexed: 03/18/2023]
Abstract
Adult stem cells are important for mammalian tissues, where they act as a cell reserve that supports normal tissue turnover and can mount a regenerative response following acute injuries. Quiescent stem cells are well established in certain tissues, such as skeletal muscle, brain, and bone marrow. The quiescent state is actively controlled and is essential for long-term maintenance of stem cell pools. In this Review, we discuss the importance of maintaining a functional pool of quiescent adult stem cells, including haematopoietic stem cells, skeletal muscle stem cells, neural stem cells, hair follicle stem cells, and mesenchymal stem cells such as fibro-adipogenic progenitors, to ensure tissue maintenance and repair. We discuss the molecular mechanisms that regulate the entry into, maintenance of, and exit from the quiescent state in mice. Recent studies revealed that quiescent stem cells have a discordance between RNA and protein levels, indicating the importance of post-transcriptional mechanisms, such as alternative polyadenylation, alternative splicing, and translation repression, in the control of stem cell quiescence. Understanding how these mechanisms guide stem cell function during homeostasis and regeneration has important implications for regenerative medicine.
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Affiliation(s)
- Antoine de Morree
- Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, CA, USA.
- Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
| | - Thomas A Rando
- Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, CA, USA.
- Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
- Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
- Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA.
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20
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Su Y, Cao Y, Liu C, Xu Q, Li N, Lan M, Li L, Wang K, Zhang Z, Meng Q. Inactivating IL34 promotes regenerating muscle stem cell expansion and attenuates Duchenne muscular dystrophy in mouse models. Theranostics 2023; 13:2588-2604. [PMID: 37215564 PMCID: PMC10196826 DOI: 10.7150/thno.83817] [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: 03/23/2023] [Accepted: 04/14/2023] [Indexed: 05/24/2023] Open
Abstract
Background: The balance between the differentiation and self-renewal of satellite cells (SCs) is essential for skeletal muscle homeostasis and regeneration. Our knowledge of this regulatory process is incomplete. Methods: Using global and conditional knockout mice as in vivo models and isolated satellite cells as in vitro system, we investigated the regulatory mechanisms of IL34 in the process of skeletal muscle regeneration in vivo and in vitro. Results: Myocytes and regenerating fibers are major source of IL34. Deletion of interleukin 34 (IL34) sustains expansion by sacrificing the differentiation of SCs and leads to significant muscle regeneration defects. We further found that inactivating IL34 in SCs leads to hyperactivation of NFKB1 signaling; NFKB1 translocates to the nucleus and binds to the promoter region of Igfbp5 to synergistically disturb protein kinase B (Akt) activity. Notably, augmented Igfbp5 function in SCs led to deficient differentiation and Akt activity. Furthermore, disrupting Akt activity both in vivo and in vitro mimicked the phenotype of IL34 knockout. Finally, deleting IL34 or interfering Akt in mdx mice ameliorates dystrophic muscles. Conclusion: We comprehensively characterized regenerating myofibers-expressed IL34 plays a pivotal role in controlling myonuclear domain. The results also indicate that impairing IL34 function by promoting SC maintenance can lead to improved muscular performance in mdx mice in which the stem cell pool is compromised.
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Affiliation(s)
- Yang Su
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
- Department of Cell Biology, Third Military Medical University (Army Medical University), Gaotanyan Road No. 30, Shapingba District, Chongqing 400038, China
- State Key Lab of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
| | - Yuxin Cao
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
| | - Chang Liu
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
| | - Qing Xu
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
| | - Na Li
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
| | - Miaomiao Lan
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
| | - Lei Li
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
| | - Kun Wang
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
| | - Zeyu Zhang
- State Key Lab of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
| | - Qingyong Meng
- State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing 100193, China
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21
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Fan T, Fan Y, Yang Y, Qian D, Niu Y, An L, Xiang Y. SEC1A and SEC6 synergistically regulate pollen tube polar growth. JOURNAL OF INTEGRATIVE PLANT BIOLOGY 2023. [PMID: 36951316 DOI: 10.1111/jipb.13486] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 03/21/2023] [Indexed: 06/18/2023]
Abstract
Pollen tube polar growth is a key physiological activity for angiosperms to complete double fertilization, which is highly dependent on the transport of polar substances mediated by secretory vesicles. The exocyst and Sec1/Munc18 (SM) proteins are involved in the regulation of the tethering and fusion of vesicles and plasma membranes, but the molecular mechanism by which they regulate pollen tube polar growth is still unclear. In this study, we found that loss of function of SEC1A, a member of the SM protein family in Arabidopsis thaliana, resulted in reducing pollen tube growth and a significant increase in pollen tube width. SEC1A was diffusely distributed in the pollen tube cytoplasm, and was more concentrated at the tip of the pollen tube. Through co-immunoprecipitation-mass spectrometry screening, protein interaction analysis and in vivo microscopy, we found that SEC1A interacted with the exocyst subunit SEC6, and they mutually affected the distribution and secretion rate at the tip of the pollen tube. Meanwhile, the functional loss of SEC1A and SEC6 significantly affected the distribution of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex member SYP125 at the tip of the pollen tube, and led to the disorder of pollen tube cell wall components. Genetic analysis revealed that the pollen tube-related phenotype of the sec1a sec6 double mutant was significantly enhanced compared with their respective single mutants. Therefore, we speculated that SEC1A and SEC6 cooperatively regulate the fusion of secretory vesicles and plasma membranes in pollen tubes, thereby affecting the length and the width of pollen tubes.
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Affiliation(s)
- Tingting Fan
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Yuemin Fan
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Yang Yang
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Dong Qian
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Yue Niu
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Lizhe An
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Yun Xiang
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China
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22
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Shen J, Wang J, Zhen H, Liu Y, Li L, Luo Y, Hu J, Liu X, Li S, Hao Z, Li M, Zhao Z. MicroRNA-381 Regulates Proliferation and Differentiation of Caprine Skeletal Muscle Satellite Cells by Targeting PTEN and JAG2. Int J Mol Sci 2022; 23:ijms232113587. [PMID: 36362373 PMCID: PMC9656929 DOI: 10.3390/ijms232113587] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 10/29/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
In our previous study, microRNA (miR)-381 was found to be the most down-regulated miRNA in skeletal muscle of Liaoning cashmere goats with higher skeletal muscle mass, but the molecular mechanism involved remains unclear. In this study, primary caprine skeletal muscle satellite cells (SMSCs) were isolated and identified. We investigated the effect of miR-381 on the viability, proliferation and differentiation of caprine SMSCs, and the target relationships of miR-381 with jagged canonical Notch ligand 2 (JAG2) and phosphatase and tensin homolog (PTEN). Cells isolated were positive for SMSC-specific marker protein Pax7. This suggests that purified SMSCs were obtained. The expression level of miR-381 achieved a peak value on day 4 after SMSC differentiation, and miR-381 also significantly increased the expression levels of myogenic differentiation marker genes: myosin heavy chain (MyHC), myogenin (MyoG) and myocyte enhancer factor 2C (MEF2C) in differentiated SMSCs, the area of MyHC-positive myotubes and the myogenic index. These findings suggest that miR-381 promoted myogenic differentiation of caprine SMSCs. The CCK8 assay and EDU staining analysis showed that miR-381 mimic both inhibited the viability of SMSCs and decreased the percentage of EDU-labeled positive SMSCs. In contrast, miR-381 inhibitor had the opposite effect with miR-381 mimic. A dual luciferase reporter assay verified that miR-381 can target JAG2 and PTEN by binding to the 3′-untranslated regions (3′-UTR) of the genes. The transfection of miR-381 mimic into caprine SMSCs resulted in decreases in expression levels of JAG2 and PTEN, while miR-381 inhibitor increased the two target genes in expression. This is the first study to reveal the biological mechanisms by which miR-381 regulates caprine SMSC activities.
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Affiliation(s)
| | - Jiqing Wang
- Correspondence: ; Tel./Fax: +86-931-763-2469
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23
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Immunoglobulin Superfamily Containing Leucine-Rich Repeat (Islr) Participates in IL-6-Mediated Crosstalk between Muscle and Brown Adipose Tissue to Regulate Energy Homeostasis. Int J Mol Sci 2022; 23:ijms231710008. [PMID: 36077405 PMCID: PMC9455994 DOI: 10.3390/ijms231710008] [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: 07/21/2022] [Revised: 08/20/2022] [Accepted: 08/27/2022] [Indexed: 12/01/2022] Open
Abstract
Brown adipose tissue (BAT) is functionally linked to skeletal muscle because both tissues originate from a common progenitor cell, but the precise mechanism controlling muscle-to-brown-fat communication is insufficiently understood. This report demonstrates that the immunoglobulin superfamily containing leucine-rich repeat (Islr), a marker of mesenchymal stromal/stem cells, is critical for the control of BAT mitochondrial function and whole-body energy homeostasis. The mice loss of Islr in BAT after cardiotoxin injury resulted in improved mitochondrial function, increased energy expenditure, and enhanced thermogenesis. Importantly, it was found that interleukin-6 (IL-6), as a myokine, participates in this process. Mechanistically, Islr interacts with NADH: Ubiquinone Oxidoreductase Core Subunit S2 (Ndufs2) to regulate IL-6 signaling; consequently, Islr functions as a brake that prevents IL-6 from promoting BAT activity. Together, these findings reveal a previously unrecognized mechanism for muscle-BAT cross talk driven by Islr, Ndufs2, and IL-6 to regulate energy homeostasis, which may be used as a potential therapeutic target in obesity.
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24
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Salucci S, Bartoletti-Stella A, Bavelloni A, Aramini B, Blalock WL, Fabbri F, Vannini I, Sambri V, Stella F, Faenza I. Extra Virgin Olive Oil (EVOO), a Mediterranean Diet Component, in the Management of Muscle Mass and Function Preservation. Nutrients 2022; 14:nu14173567. [PMID: 36079827 PMCID: PMC9459997 DOI: 10.3390/nu14173567] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/22/2022] [Accepted: 08/26/2022] [Indexed: 12/25/2022] Open
Abstract
Aging results in a progressive decline in skeletal muscle mass, strength and function, a condition known as sarcopenia. This pathological condition is due to multifactorial processes including physical inactivity, inflammation, oxidative stress, hormonal changes, and nutritional intake. Physical therapy remains the standard approach to treat sarcopenia, although some interventions based on dietary supplementation are in clinical development. In this context, thanks to its known anti-inflammatory and antioxidative properties, there is great interest in using extra virgin olive oil (EVOO) supplementation to promote muscle mass and health in sarcopenic patients. To date, the molecular mechanisms responsible for the pathological changes associated with sarcopenia remain undefined; however, a complete understanding of the signaling pathways that regulate skeletal muscle protein synthesis and their behavior during sarcopenia appears vital for defining how EVOO might attenuate muscle wasting during aging. This review highlights the main molecular players that control skeletal muscle mass, with particular regard to sarcopenia, and discusses, based on the more recent findings, the potential of EVOO in delaying/preventing loss of muscle mass and function, with the aim of stimulating further research to assess dietary supplementation with EVOO as an approach to prevent or delay sarcopenia in aging individuals.
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Affiliation(s)
- Sara Salucci
- Cellular Signalling Laboratory, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, 40126 Bologna, Italy
- Correspondence:
| | - Anna Bartoletti-Stella
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy
| | - Alberto Bavelloni
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Beatrice Aramini
- Division of Thoracic Surgery, Department of Experimental, Diagnostic and Specialty Medicine-DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy
| | - William L. Blalock
- “Luigi Luca Cavalli-Sforza” Istituto di Genetica Molecolare-Consiglio Nazionale delle Ricerche (IGM-CNR), 40136 Bologna, Italy
- IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
| | - Francesco Fabbri
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Ivan Vannini
- Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Vittorio Sambri
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy
- Unit of Microbiology, Greater Romagna Hub Laboratory, 47522 Pievesestina, Italy
| | - Franco Stella
- Division of Thoracic Surgery, Department of Experimental, Diagnostic and Specialty Medicine-DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy
| | - Irene Faenza
- Cellular Signalling Laboratory, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, 40126 Bologna, Italy
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25
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Bidirectional roles of skeletal muscle fibro-adipogenic progenitors in homeostasis and disease. Ageing Res Rev 2022; 80:101682. [PMID: 35809776 DOI: 10.1016/j.arr.2022.101682] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 06/09/2022] [Accepted: 07/04/2022] [Indexed: 02/07/2023]
Abstract
Sarcopenia and myopathies cause progressive muscle weakness and degeneration, which are closely associated with fat infiltration and fibrosis in muscle. Recently, experimental research has shed light on fibro-adipogenic progenitors (FAPs), also known as muscle-resident mesenchymal progenitors with multiple differentiation potential for adipogenesis, fibrosis, osteogenesis and chondrogenesis. They are considered key regulators of muscle homeostasis and integrity. They play supportive roles in muscle development and repair by orchestrating the regulatory interplay between muscle stem cells (MuSCs) and immune cells. Interestingly, FAPs also contribute to intramuscular fat infiltration, fibrosis and other pathologies when the functional integrity of the network is compromised. In this review, we summarize recent insights into the roles of FAPs in maintenance of skeletal muscle homeostasis, and discuss the underlying mechanisms regulating FAPs behavior and fate, highlighting their roles in participating in efficient muscle repair and fat infiltrated muscle degeneration as well as during muscle atrophy. We suggest that controlling and predicting FAPs differentiation may become a promising strategy to improve muscle function and prevent irreparable muscle damage.
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26
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Cutler AA, Pawlikowski B, Wheeler JR, Dalla Betta N, Elston T, O’Rourke R, Jones K, Olwin BB. The regenerating skeletal muscle niche drives satellite cell return to quiescence. iScience 2022; 25:104444. [PMID: 35733848 PMCID: PMC9207300 DOI: 10.1016/j.isci.2022.104444] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 04/27/2022] [Accepted: 05/16/2022] [Indexed: 11/27/2022] Open
Abstract
Skeletal muscle stem cells, or satellite cells (SCs), are essential to regenerate and maintain muscle. Quiescent SCs reside in an asymmetric niche between the basal lamina and myofiber membrane. To repair muscle, SCs activate, proliferate, and differentiate, fusing to repair myofibers or reacquiring quiescence to replenish the SC niche. Little is known about when SCs reacquire quiescence during regeneration or the cellular processes that direct SC fate decisions. We find that most SCs reacquire quiescence 5-10 days after muscle injury, following differentiation and fusion of most cells to regenerate myofibers. Single-cell sequencing of myogenic cells in regenerating muscle identifies SCs reacquiring quiescence and reveals that noncell autonomous signaling networks influence SC fate decisions during regeneration. SC transplantation experiments confirm that the regenerating environment influences SC fate. We define a window for SC repopulation of the niche, emphasizing the temporal contribution of the regenerative muscle environment on SC fate.
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Affiliation(s)
- Alicia A. Cutler
- Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA
| | - Bradley Pawlikowski
- Department of Pediatrics, Section of Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80217, USA
| | - Joshua R. Wheeler
- Departments of Pathology and Neuropathology, Stanford University, Palo Alto, CA 94305, USA
| | - Nicole Dalla Betta
- Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA
| | - Tiffany Elston
- Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA
| | - Rebecca O’Rourke
- Department of Pediatrics, Section of Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80217, USA
| | - Kenneth Jones
- Department of Pediatrics, Section of Developmental Biology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80217, USA
| | - Bradley B. Olwin
- Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA
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27
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Benjamin DI, Both P, Benjamin JS, Nutter CW, Tan JH, Kang J, Machado LA, Klein JDD, de Morree A, Kim S, Liu L, Dulay H, Feraboli L, Louie SM, Nomura DK, Rando TA. Fasting induces a highly resilient deep quiescent state in muscle stem cells via ketone body signaling. Cell Metab 2022; 34:902-918.e6. [PMID: 35584694 PMCID: PMC9177797 DOI: 10.1016/j.cmet.2022.04.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 12/15/2021] [Accepted: 04/25/2022] [Indexed: 01/11/2023]
Abstract
Short-term fasting is beneficial for the regeneration of multiple tissue types. However, the effects of fasting on muscle regeneration are largely unknown. Here, we report that fasting slows muscle repair both immediately after the conclusion of fasting as well as after multiple days of refeeding. We show that ketosis, either endogenously produced during fasting or a ketogenic diet or exogenously administered, promotes a deep quiescent state in muscle stem cells (MuSCs). Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Furthermore, we show that ketone bodies, specifically β-hydroxybutyrate, directly promote MuSC deep quiescence via a nonmetabolic mechanism. We show that β-hydroxybutyrate functions as an HDAC inhibitor within MuSCs, leading to acetylation and activation of an HDAC1 target protein p53. Finally, we demonstrate that p53 activation contributes to the deep quiescence and enhanced resilience observed during fasting.
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Affiliation(s)
- Daniel I Benjamin
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Pieter Both
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA; Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Joel S Benjamin
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Christopher W Nutter
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jenna H Tan
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jengmin Kang
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Leo A Machado
- Biology of the Neuromuscular System, INSERM IMRB U955-E10, UPEC, ENVA, EFS, Creteil 94000, France
| | - Julian D D Klein
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Antoine de Morree
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Soochi Kim
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ling Liu
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Hunter Dulay
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ludovica Feraboli
- Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sharon M Louie
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Daniel K Nomura
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Thomas A Rando
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA 94304, USA; Neurology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
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28
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Han L, Wang G, Zhou S, Situ C, He Z, Li Y, Qiu Y, Huang Y, Xu A, Ong MTY, Wang H, Zhang J, Wu Z. Muscle satellite cells are impaired in type 2 diabetic mice by elevated extracellular adenosine. Cell Rep 2022; 39:110884. [PMID: 35649375 DOI: 10.1016/j.celrep.2022.110884] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 04/12/2022] [Accepted: 05/05/2022] [Indexed: 12/25/2022] Open
Abstract
Muscle regeneration is known to be defective under diabetic conditions. However, the underlying mechanisms remain less clear. Adult quiescent muscle satellite cells (MuSCs) from leptin-receptor-deficient (i.e., db/db) diabetic mice are defective in early activation in vivo, but not in culture, suggesting the involvement of pathogenic niche factors. Elevated extracellular adenosine (eAdo) and AMP (eAMP) are detected under diabetic conditions. eAdo and eAMP potently inhibit cell cycle re-entry of quiescent MuSCs and injury-induced muscle regeneration. Mechanistically, eAdo and eAMP engage the equilibrative Ado transporters (ENTs)-Ado kinase (ADK)-AMPK signaling axis in MuSCs to inhibit the mTORC1-dependent cell growth checkpoint. eAdo and eAMP also inhibit early activation of quiescent fibroadipogenic progenitors and human MuSCs by the same mechanism. Treatment of db/db diabetic mice with an ADK inhibitor partially rescues the activation defects of MuSCs in vivo. Thus, both ADK and ENTs represent potential therapeutic targets for restoring the regenerative functions of tissue stem cells in patients with diabetes.
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Affiliation(s)
- Lifang Han
- Division of Life Science, the State Key Laboratory on Molecular Neuroscience, the Hong Kong University of Science & Technology, Hong Kong, China
| | - Gang Wang
- Division of Life Science, the State Key Laboratory on Molecular Neuroscience, the Hong Kong University of Science & Technology, Hong Kong, China
| | - Shaopu Zhou
- Division of Life Science, the State Key Laboratory on Molecular Neuroscience, the Hong Kong University of Science & Technology, Hong Kong, China
| | - Chenghao Situ
- Division of Life Science, the State Key Laboratory on Molecular Neuroscience, the Hong Kong University of Science & Technology, Hong Kong, China
| | - Zhiming He
- Department of Chemical Pathology, the Chinese University of Hong Kong, Hong Kong, China
| | - Yuying Li
- Li Ka Shing Institute of Health Sciences, Department of Orthopaedics and Traumatology, the Chinese University of Hong Kong, Hong Kong, China
| | - Yudan Qiu
- Division of Life Science, the State Key Laboratory on Molecular Neuroscience, the Hong Kong University of Science & Technology, Hong Kong, China
| | - Yu Huang
- Department of Biomedical Sciences, the City University of Hong Kong, Hong Kong, China
| | - Aimin Xu
- Department of Medicine, the University of Hong Kong, Hong Kong, China
| | - Michael Tim Yun Ong
- Department of Orthopaedics and Traumatology, the Chinese University of Hong Kong, the Prince of Wales Hospital, Hong Kong, China
| | - Huating Wang
- Li Ka Shing Institute of Health Sciences, Department of Orthopaedics and Traumatology, the Chinese University of Hong Kong, Hong Kong, China
| | - Jianfa Zhang
- Nanjing University of Science and Technology, Nanjing, 210094, China
| | - Zhenguo Wu
- Division of Life Science, the State Key Laboratory on Molecular Neuroscience, the Hong Kong University of Science & Technology, Hong Kong, China; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen, 518055, China.
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29
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Gioftsidi S, Relaix F, Mourikis P. The Notch signaling network in muscle stem cells during development, homeostasis, and disease. Skelet Muscle 2022; 12:9. [PMID: 35459219 PMCID: PMC9027478 DOI: 10.1186/s13395-022-00293-w] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/16/2022] [Indexed: 01/22/2023] Open
Abstract
Skeletal muscle stem cells have a central role in muscle growth and regeneration. They reside as quiescent cells in resting muscle and in response to damage they transiently amplify and fuse to produce new myofibers or self-renew to replenish the stem cell pool. A signaling pathway that is critical in the regulation of all these processes is Notch. Despite the major differences in the anatomical and cellular niches between the embryonic myotome, the adult sarcolemma/basement-membrane interphase, and the regenerating muscle, Notch signaling has evolved to support the context-specific requirements of the muscle cells. In this review, we discuss the diverse ways by which Notch signaling factors and other modifying partners are operating during the lifetime of muscle stem cells to establish an adaptive dynamic network.
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Affiliation(s)
- Stamatia Gioftsidi
- Université Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale (INSERM), Mondor Institute for Biomedical Research (IMRB), F-94010, Créteil, France
| | - Frederic Relaix
- Université Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale (INSERM), Mondor Institute for Biomedical Research (IMRB), F-94010, Créteil, France
- EnvA, IMRB, F-94700, Maisons-Alfort, France
- Etablissement Français du Sang (EFS), IMRB, F-94010, Creteil, France
- Assistance Publique-Hôpitaux de Paris, Hopital Mondor, Service d'Histologie, F-94010, Creteil, France
| | - Philippos Mourikis
- Université Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale (INSERM), Mondor Institute for Biomedical Research (IMRB), F-94010, Créteil, France.
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30
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Wang S, Zhao X, Liu Q, Wang Y, Li S, Xu S. Selenoprotein K protects skeletal muscle from damage and is required for satellite cells-mediated myogenic differentiation. Redox Biol 2022; 50:102255. [PMID: 35144051 PMCID: PMC8844831 DOI: 10.1016/j.redox.2022.102255] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/23/2022] [Accepted: 01/28/2022] [Indexed: 12/11/2022] Open
Abstract
The regeneration of adult skeletal muscle after injury is primarily initiated by satellite cells (SCs), but the regulatory mechanisms of cells committed to myogenic differentiation remain poorly explored. Small molecular selenoprotein K (SelK) plays crucial roles in the modulation of endoplasmic reticulum (ER) stress and against oxidative stress. Here, we first showed that SelK expression is activated in myogenic cells during differentiation both in vivo and in vitro. Meanwhile, loss of SelK delayed skeletal muscle regeneration, inhibited the development of myoblasts into myotubes, and was accompanied by reduced expression of myogenic regulatory factors (MRFs). Moreover, ER stress, intracellular reactive oxygen species (ROS), autophagy and apoptosis under myogenesis induction were more severe in SelK-deficient mice and cells than in the corresponding control groups. Supplementation with specific inhibitors to alleviate excessive ER stress or oxidative stress partly rescued the differentiation potential and formation of myotubes. Notably, we demonstrated that Self-mediated regulation of cellular redox status was primarily derived from its subsequent effects on ER stress. Together, our results suggest that SelK protects skeletal muscle from damage and is a crucial regulator of myogenesis.
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Affiliation(s)
- Shengchen Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Xia Zhao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Qingqing Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Yue Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China
| | - Shu Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
| | - Shiwen Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.
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31
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Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther 2022; 7:95. [PMID: 35332121 PMCID: PMC8948217 DOI: 10.1038/s41392-022-00934-y] [Citation(s) in RCA: 518] [Impact Index Per Article: 172.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/16/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.
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Abstract
Metabolism has been studied mainly in cultured cells or at the level of whole tissues or whole organisms in vivo. Consequently, our understanding of metabolic heterogeneity among cells within tissues is limited, particularly when it comes to rare cells with biologically distinct properties, such as stem cells. Stem cell function, tissue regeneration and cancer suppression are all metabolically regulated, although it is not yet clear whether there are metabolic mechanisms unique to stem cells that regulate their activity and function. Recent work has, however, provided evidence that stem cells do have a metabolic signature that is distinct from that of restricted progenitors and that metabolic changes influence tissue homeostasis and regeneration. Stem cell maintenance throughout life in many tissues depends upon minimizing anabolic pathway activation and cell division. Consequently, stem cell activation by tissue injury is associated with changes in mitochondrial function, lysosome activity and lipid metabolism, potentially at the cost of eroding self-renewal potential. Stem cell metabolism is also regulated by the environment: stem cells metabolically interact with other cells in their niches and are able to sense and adapt to dietary changes. The accelerating understanding of stem cell metabolism is revealing new aspects of tissue homeostasis with the potential to promote tissue regeneration and cancer suppression.
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A Long Journey before Cycling: Regulation of Quiescence Exit in Adult Muscle Satellite Cells. Int J Mol Sci 2022; 23:ijms23031748. [PMID: 35163665 PMCID: PMC8836154 DOI: 10.3390/ijms23031748] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/28/2022] [Accepted: 01/30/2022] [Indexed: 02/04/2023] Open
Abstract
Skeletal muscle harbors a pool of stem cells called muscle satellite cells (MuSCs) that are mainly responsible for its robust regenerative capacities. Adult satellite cells are mitotically quiescent in uninjured muscles under homeostasis, but they exit quiescence upon injury to re-enter the cell cycle to proliferate. While most of the expanded satellites cells differentiate and fuse to form new myofibers, some undergo self-renewal to replenish the stem cell pool. Specifically, quiescence exit describes the initial transition of MuSCs from quiescence to the first cell cycle, which takes much longer than the time required for subsequent cell cycles and involves drastic changes in cell size, epigenetic and transcriptomic profiles, and metabolic status. It is, therefore, an essential period indispensable for the success of muscle regeneration. Diverse mechanisms exist in MuSCs to regulate quiescence exit. In this review, we summarize key events that occur during quiescence exit in MuSCs and discuss the molecular regulation of this process with an emphasis on multiple levels of intrinsic regulatory mechanisms. A comprehensive understanding of how quiescence exit is regulated will facilitate satellite cell-based muscle regenerative therapies and advance their applications in various disease and aging conditions.
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34
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Jia Z, Chen X, Chen J, Zhang L, Oprescu SN, Luo N, Xiong Y, Yue F, Kuang S. ACSS3 in brown fat drives propionate catabolism and its deficiency leads to autophagy and systemic metabolic dysfunction. Clin Transl Med 2022; 12:e665. [PMID: 35184387 PMCID: PMC8858619 DOI: 10.1002/ctm2.665] [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: 05/24/2021] [Revised: 11/11/2021] [Accepted: 11/17/2021] [Indexed: 11/22/2022] Open
Abstract
Propionate is a gut microbial metabolite that has been reported to have controversial effects on metabolic health. Here we show that propionate is activated by acyl-CoA synthetase short-chain family member 3 (ACSS3), located on the mitochondrial inner membrane in brown adipocytes. Knockout of Acss3 gene (Acss3-/- ) in mice reduces brown adipose tissue (BAT) mass but increases white adipose tissue (WAT) mass, leading to glucose intolerance and insulin resistance that are exacerbated by high-fat diet (HFD). Intriguingly, Acss3-/- or HFD feeding significantly elevates propionate levels in BAT and serum, and propionate supplementation induces autophagy in cultured brown and white adipocytes. The elevated levels of propionate in Acss3-/- mice similarly drive adipocyte autophagy, and pharmacological inhibition of autophagy using hydroxychloroquine ameliorates obesity, hepatic steatosis and insulin resistance of the Acss3-/- mice. These results establish ACSS3 as the key enzyme for propionate metabolism and demonstrate that accumulation of propionate promotes obesity and Type 2 diabetes through triggering adipocyte autophagy.
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Affiliation(s)
- Zhihao Jia
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Xiyue Chen
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Jingjuan Chen
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Lijia Zhang
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Stephanie N. Oprescu
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
- Department of Biological SciencesPurdue UniversityWest LafayetteIndiana
| | - Nanjian Luo
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Yan Xiong
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Feng Yue
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
| | - Shihuan Kuang
- Department of Animal SciencesPurdue UniversityWest LafayetteIndiana
- Center for Cancer ResearchPurdue UniversityWest LafayetteIndiana
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35
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Hao D, Wang X, Yang Y, Thomsen B, Holm LE, Qu K, Huang B, Chen H. Integrated Analysis of mRNA and MicroRNA Co-expressed Network for the Differentiation of Bovine Skeletal Muscle Cells After Polyphenol Resveratrol Treatment. Front Vet Sci 2022; 8:777477. [PMID: 35036414 PMCID: PMC8759604 DOI: 10.3389/fvets.2021.777477] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/15/2021] [Indexed: 01/01/2023] Open
Abstract
Resveratrol (RSV) has been confirmed to benefit human health. Resveratrol supplemented in the feeds of animals improved pork, chicken, and duck meat qualities. In this study, we identified differentially expressed (DE) messenger RNAs (mRNAs) (n = 3,856) and microRNAs (miRNAs) (n = 93) for the weighted gene co-expression network analysis (WGCNA) to investigate the co-expressed DE mRNAs and DE miRNAs in the primary bovine myoblasts after RSV treatment. The mRNA results indicated that RSV treatments had high correlations with turquoise module (0.91, P-value = 0.01) and blue module (0.93, P-value < 0.01), while only the turquoise module (0.96, P-value < 0.01) was highly correlated with the treatment status using miRNA data. After biological enrichment analysis, the 2,579 DE genes in the turquoise module were significantly enriched in the Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The top two GO terms were actin filament-based process (GO:0030029) and actin cytoskeleton organization (GO:0030036). The top two KEGG pathways were regulation of actin cytoskeleton (bta04810) and tight junction (bta04530). Then, we constructed the DE mRNA co-expression and DE miRNA co-expression networks in the turquoise module and the mRNA–miRNA targeting networks based on their co-expressions in the key module. In summary, the RSV-induced miRNAs participated in the co-expression networks that could affect mRNA expressions to regulate the primary myoblast differentiation. Our study provided a better understanding of the roles of RSV in inducing miRNA and of the characteristics of DE miRNAs in the key co-expressed module in regulation of mRNAs and revealed new candidate regulatory miRNAs and genes for the beef quality traits.
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Affiliation(s)
- Dan Hao
- College of Animal Science and Technology, Northwest A&F University, Shaanxi Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Yangling, China.,Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Xiao Wang
- Konge Larsen ApS, Kongens Lyngby, Denmark
| | - Yu Yang
- College of Animal Science and Technology, Northwest A&F University, Shaanxi Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Yangling, China
| | - Bo Thomsen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Lars-Erik Holm
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Kaixing Qu
- Academy of Science and Technology, Chuxiong Normal University, Chuxiong, China
| | - Bizhi Huang
- Yunnan Academy of Grassland and Animal Science, Kunming, China
| | - Hong Chen
- College of Animal Science and Technology, Northwest A&F University, Shaanxi Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Yangling, China.,College of Animal Science, Xinjiang Agricultural University, Urumqi, China
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36
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Yue F, Oprescu SN, Qiu J, Gu L, Zhang L, Chen J, Narayanan N, Deng M, Kuang S. Lipid droplet dynamics regulate adult muscle stem cell fate. Cell Rep 2022; 38:110267. [PMID: 35045287 PMCID: PMC9127130 DOI: 10.1016/j.celrep.2021.110267] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 08/31/2021] [Accepted: 12/21/2021] [Indexed: 11/03/2022] Open
Abstract
The lipid droplet (LD) is a central hub for fatty acid metabolism in cells. Here we define the dynamics and explore the role of LDs in skeletal muscle satellite cells (SCs), a stem cell population responsible for muscle regeneration. In newly divided SCs, LDs are unequally distributed in sister cells exhibiting asymmetric cell fates, as the LDLow cell self-renews while the LDHigh cell commits to differentiation. When transplanted into regenerating muscles, LDLow cells outperform LDHigh cells in self-renewal and regeneration in vivo. Pharmacological inhibition of LD biogenesis or genetic inhibition of LD catabolism through knockout of Pnpla2 (encoding ATGL, the rate-limiting enzyme for lipolysis) disrupts cell fate homeostasis and impairs the regenerative capacity of SCs. Dysfunction of Pnpla2-null SCs is associated with energy insufficiency and oxidative stress that can be partially rescued by antioxidant (N-acetylcysteine) treatment. These results establish a direct link between LD dynamics and stem cell fate determination.
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Affiliation(s)
- Feng Yue
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
| | - Stephanie N Oprescu
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA; Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Jiamin Qiu
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Lijie Gu
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Lijia Zhang
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Jingjuan Chen
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Naagarajan Narayanan
- Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Meng Deng
- Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Shihuan Kuang
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
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Mao Y, Han CY, Hao L, Bang IH, Bae EJ, Park BH. p21-activated kinase 4 phosphorylates peroxisome proliferator-activated receptor Υ and suppresses skeletal muscle regeneration. J Cachexia Sarcopenia Muscle 2021; 12:1776-1788. [PMID: 34431242 PMCID: PMC8718036 DOI: 10.1002/jcsm.12774] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/28/2021] [Accepted: 07/10/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Skeletal muscle regeneration is an adaptive response to injury that is crucial to the maintenance of muscle mass and function. A p21-activated kinase 4 (PAK4) serine/threonine kinase is critical to the regulation of cytoskeletal changes, cell proliferation, and growth. However, PAK4's role in myoblast differentiation and regenerative myogenesis remains to be determined. METHODS We used a mouse model of myotoxin (notexin)-induced muscle regeneration. In vitro myogenesis was performed in the C2C12 myoblast cell line, primary myoblasts, and primary satellite cells. In vivo overexpression of PAK4 or kinase-inactive mutant PAK4S474A was conducted in skeletal muscle to examine PAK4's kinase-dependent effect on muscle regeneration. The regeneration process was evaluated by determining the number and size of multinucleated myofibres and expression patterns of myogenin and eMyHC. To explore whether PAK4 inhibition improves muscle regeneration, mice were injected intramuscularly with siRNA that targeted PAK4 or orally administered with a chemical inhibitor of PAK4. RESULTS p21-activated kinase 4 was highly expressed during the myoblast stage, but expression gradually and substantially decreased as myoblasts differentiated into myotubes. PAK4 overexpression, but not kinase-inactive mutant PAK4S474A overexpression, significantly impeded myoblast fusion and MyHC-positive myotube formation in C2C12 cells, primary myoblasts, and satellite cells (P < 0.01). Conversely, PAK4 silencing led to an 8.7% and a 20.3% increase in the number of multinucleated larger myotubes in C2C12 cells and primary myoblasts. Further, in vivo overexpression of PAK4 by adenovirus injection to mice prior to and after myotoxin-induced injury led to a 52.6% decrease in the number of eMyHC-positive myofibres on Day 5 in tibialis anterior muscles as compared with those injected with control adenoviruses (P < 0.01), while Ad-PAK4S474A showed comparable muscle regeneration parameters. PAK4-induced repression of muscle regeneration coincided with an increase in phosphatase and tensin homologue (PTEN) expression and a decrease in phosphoinositide 3-kinase-Akt signalling. In contrast, PAK4 silencing reduced PTEN expression in mice. Consistent with these findings, prodrug of PAK4 inhibitor CZh-226 (30 mg/kg) orally administered to mice repressed PTEN expression and accelerated myotube formation. Subsequent mechanistic studies revealed that PAK4 directly phosphorylates PPARγ at S273 to increase its transcription activity, thereby up-regulating PTEN expression. Importantly, an analysis of the Genotype-Tissue Expression database showed a positive correlation between PAK4 and PTEN in human skeletal muscle tissues (P < 0.01). CONCLUSIONS p1-activated kinase 4 is a new member of PPARγ kinase, and PAK4 inhibition may have a therapeutic role as an accelerant of muscle regeneration.
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Affiliation(s)
- Yuancheng Mao
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Korea
| | - Chang Yeob Han
- School of Pharmacy, Jeonbuk National University, Jeonju, Korea
| | - Lihua Hao
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Korea
| | - In Hyuk Bang
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Korea
| | - Eun Ju Bae
- School of Pharmacy, Jeonbuk National University, Jeonju, Korea
| | - Byung-Hyun Park
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Korea
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38
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Safitri E, Purnobasuki H. Effectiveness of mesenchymal stem cells cultured under hypoxia to increase the fertility rate in rats ( Rattus norvegicus). Vet World 2021; 14:3056-3064. [PMID: 35017856 PMCID: PMC8743767 DOI: 10.14202/vetworld.2021.3056-3064] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 10/20/2021] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND AND AIM Mesenchymal stem cells (MSCs) transplanted into the testes of rats with testicular failure can help rescue fertility. However, the low viability of transplanted MSCs limits the success of this treatment. This study aimed to determine the effectiveness of MSCs cultured under hypoxia to increase the fertility rate in rats (Rattus norvegicus). MATERIALS AND METHODS Bone marrow-derived MSCs (200 million cells/rat) were transplanted into male rat models with induced infertility (10 rats/treatment group) after 4 days of culture in 21% O2 (normoxia) and 1% O2 (hypoxia). Ten fertile and 10 untreated infertile rats served as controls. In the infertile male rats that had been fasted from food for 5 days, the fasting condition induced malnutrition and then resulted in testicular failure. RESULTS The results indicated that the MSCs cultured under hypoxic conditions were more effective than those cultured in normoxic conditions as a treatment for testicular failure in infertile male rats based on the increased number of cells expressing p63 as a quiescent cell marker and ETV5 as a transcription factor expressed in Sertoli and germ cells. Furthermore, the structure of the seminiferous tubules, which contain spermatogonia, primary and secondary spermatocytes, and spermatid, Sertoli, and Leydig cells, was improved in infertile male rats treated with the MSCs cultured under hypoxic conditions. CONCLUSION The testicular transplantation of MSCs cultured under hypoxic conditions was an effective treatment for testicular failure in rats.
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Affiliation(s)
- Erma Safitri
- Department of Veterinary Science, Division of Veterinary Reproduction, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Hery Purnobasuki
- Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya 60115, Indonesia
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Rivas DA, Peng F, Benard T, Ramos da Silva AS, Fielding RA, Margolis LM. miR-19b-3p is associated with a diametric response to resistance exercise in older adults and regulates skeletal muscle anabolism via PTEN inhibition. Am J Physiol Cell Physiol 2021; 321:C977-C991. [PMID: 34705586 PMCID: PMC8714992 DOI: 10.1152/ajpcell.00190.2021] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Understanding paradoxical responses to anabolic stimulation and identifying the mechanisms for this inconsistency in mobility-limited older adults may provide new targets for the treatment of sarcopenia. Our laboratory has discovered that dysregulation in microRNA (miRNA) that target anabolic pathways is a potential mechanism resulting in age-associated decreases in skeletal muscle mass and function (sarcopenia). The objective of the current study was to assess circulating miRNA expression profiles in diametric response of leg lean mass in mobility-limited older individuals after a 6-mo progressive resistance exercise training intervention (PRET) and determine the influence of differentially expressing miRNA on regulation of skeletal muscle mass. Participants were dichotomized by gain (Gainers; mean +561.4 g, n = 33) or loss (Losers; mean −589.8 g, n = 40) of leg lean mass after PRET. Gainers significantly increased fat-free mass 2.4% vs. −0.4% for Losers. Six miRNA (miR-1-3p, miR-19b-3p, miR-92a, miR-126, miR-133a-3p, and miR-133b) were significantly identified to be differentially expressed between Gainers and Losers, with miR-19b-3p being the miRNA most highly associated with increases in fat-free mass. Using an aging mouse model, we then assessed if miR-19b-3p expression was different in young mice with larger muscle mass compared with older mice. Circulating and skeletal muscle miR-19b-3p expression was higher in young compared with old mice and was positively associated with muscle mass and grip strength. We then used a novel integrative approach to determine if differences in circulating miR-19b-3p potentially translate to augmented anabolic response in human skeletal muscle cells in vitro. Results from this analysis identified that overexpression of miR-19b-3p targeted and downregulated PTEN by 64% to facilitate significant ∼50% increase in muscle protein synthetic rate as measured with SUnSET. The combine results of these three models identify miR-19b-3p as a potent regulator of muscle anabolism that may contribute to an inter-individual response to PRET in mobility-limited older adults.
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Affiliation(s)
- Donato A Rivas
- Nutrition, Exercise Physiology and Sarcopenia Laboratory; Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States
| | - Fei Peng
- Nutrition, Exercise Physiology and Sarcopenia Laboratory; Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States
| | - Townsend Benard
- Nutrition, Exercise Physiology and Sarcopenia Laboratory; Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States
| | - Adelino Sanchez Ramos da Silva
- Nutrition, Exercise Physiology and Sarcopenia Laboratory; Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States.,School of Physical Education and Sport of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
| | - Roger A Fielding
- Nutrition, Exercise Physiology and Sarcopenia Laboratory; Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States
| | - Lee M Margolis
- Nutrition, Exercise Physiology and Sarcopenia Laboratory; Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States.,Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA, United States
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40
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Wang W, Lu G, Liu H, Xiong Z, Leung H, Cao R, Pang AL, Su X, Law PWN, Zhao Z, Chen Z, Chan W. Pten Regulates Cardiomyocyte Differentiation by Modulating Non-CG Methylation via Dnmt3. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2100849. [PMID: 34247447 PMCID: PMC8425920 DOI: 10.1002/advs.202100849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/04/2021] [Indexed: 06/13/2023]
Abstract
The regulation of cardiomyocyte differentiation is a fundamental aspect of cardiac development and regenerative medicine. PTEN plays important roles during embryonic development. However, its role in cardiomyocyte differentiation remains unknown. In this study, a low-cost protocol for cardiomyocyte differentiation from mouse embryonic stem cells (ESCs) is presented and it is shown that Pten deletion potently suppresses cardiomyocyte differentiation. Transcriptome analysis shows that the expression of a series of cardiomyocyte marker genes is downregulated in Pten-/- cardiomyocytes. Pten ablation induces Dnmt3b expression via the AKT/FoxO3a pathway and regulates the expression of a series of imprinted genes, including Igf2. Double knockout of Dnmt3l and Dnmt3b rescues the deficiency of cardiomyocyte differentiation of Pten-/- ESCs. The DNA methylomes from wild-type and Pten-/- embryoid bodies and cardiomyocytes are analyzed by whole-genome bisulfite sequencing. Pten deletion significantly promotes the non-CG (CHG and CHH) methylation levels of genomic DNA during cardiomyocyte differentiation, and the non-CG methylation levels of cardiomyocyte genes and Igf2 are increased in Pten-/- cardiomyocytes. Igf2 or Igf1r deletion also suppresses cardiomyocyte differentiation through the MAPK/ERK signaling pathway, and IGF2 supplementation partially rescues the cardiomyocyte differentiation. Finally, Pten conditional knockout mice are generated and the role of PTEN in cardiomyocyte differentiation is verified in vivo.
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Affiliation(s)
- Wuming Wang
- CUHK‐SDU Joint Laboratory on Reproductive GeneticsSchool of Biomedical SciencesThe Chinese University of Hong KongHong KongChina
- National Research Center for Assisted Reproductive Technology and Reproductive GeneticsJinan250001China
| | - Gang Lu
- CUHK‐SDU Joint Laboratory on Reproductive GeneticsSchool of Biomedical SciencesThe Chinese University of Hong KongHong KongChina
- National Research Center for Assisted Reproductive Technology and Reproductive GeneticsJinan250001China
| | - Hong‐Bin Liu
- CUHK‐SDU Joint Laboratory on Reproductive GeneticsSchool of Biomedical SciencesThe Chinese University of Hong KongHong KongChina
- National Research Center for Assisted Reproductive Technology and Reproductive GeneticsJinan250001China
| | - Zhiqiang Xiong
- National Research Center for Assisted Reproductive Technology and Reproductive GeneticsJinan250001China
- SDIVF R&D Centre12W, Hong Kong Science ParkShatinHong KongChina
| | - Ho‐Duen Leung
- SDIVF R&D Centre12W, Hong Kong Science ParkShatinHong KongChina
| | - Ruican Cao
- CUHK‐SDU Joint Laboratory on Reproductive GeneticsSchool of Biomedical SciencesThe Chinese University of Hong KongHong KongChina
- National Research Center for Assisted Reproductive Technology and Reproductive GeneticsJinan250001China
| | - Alan Lap‐Yin Pang
- R&D DivisionTGD Life Company Limited15W, Hong Kong Science ParkShatinHong KongChina
| | - Xianwei Su
- CUHK‐SDU Joint Laboratory on Reproductive GeneticsSchool of Biomedical SciencesThe Chinese University of Hong KongHong KongChina
- National Research Center for Assisted Reproductive Technology and Reproductive GeneticsJinan250001China
- SDIVF R&D Centre12W, Hong Kong Science ParkShatinHong KongChina
| | - Patrick Wai Nok Law
- CUHK‐SDU Joint Laboratory on Reproductive GeneticsSchool of Biomedical SciencesThe Chinese University of Hong KongHong KongChina
| | - Zhiju Zhao
- CUHK‐SDU Joint Laboratory on Reproductive GeneticsSchool of Biomedical SciencesThe Chinese University of Hong KongHong KongChina
| | - Zi‐Jiang Chen
- CUHK‐SDU Joint Laboratory on Reproductive GeneticsSchool of Biomedical SciencesThe Chinese University of Hong KongHong KongChina
- National Research Center for Assisted Reproductive Technology and Reproductive GeneticsJinan250001China
| | - Wai‐Yee Chan
- CUHK‐SDU Joint Laboratory on Reproductive GeneticsSchool of Biomedical SciencesThe Chinese University of Hong KongHong KongChina
- National Research Center for Assisted Reproductive Technology and Reproductive GeneticsJinan250001China
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Liang T, Gao F, Chen J. Role of PTEN-less in cardiac injury, hypertrophy and regeneration. CELL REGENERATION (LONDON, ENGLAND) 2021; 10:25. [PMID: 34337686 PMCID: PMC8326232 DOI: 10.1186/s13619-021-00087-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 06/18/2021] [Indexed: 12/20/2022]
Abstract
Cardiovascular diseases are the leading cause of death worldwide. Cardiomyocytes are capable of coordinated contractions, which are mainly responsible for pumping blood. When cardiac stress occurs, cardiomyocytes undergo transition from physiological homeostasis to hypertrophic growth, proliferation, or apoptosis. During these processes, many cellular factors and signaling pathways participate. PTEN is a ubiquitous dual-specificity phosphatase and functions by dephosphorylating target proteins or lipids, such as PIP3, a second messenger in the PI3K/AKT signaling pathway. Downregulation of PTEN expression or inhibiting its biologic activity improves heart function, promotes cardiomyocytes proliferation, reduces cardiac fibrosis as well as dilation, and inhibits apoptosis following ischemic stress such as myocardial infarction. Inactivation of PTEN exhibits a potentially beneficial therapeutic effects against cardiac diseases. In this review, we summarize various strategies for PTEN inactivation and highlight the roles of PTEN-less in regulating cardiomyocytes during cardiac development and stress responses.
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Affiliation(s)
- Tian Liang
- Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Feng Gao
- Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Jinghai Chen
- Department of Cardiology, Provincial Key Lab of Cardiovascular Research, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China. .,Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
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42
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Luo N, Yue F, Jia Z, Chen J, Deng Q, Zhao Y, Kuang S. Reduced electron transport chain complex I protein abundance and function in Mfn2-deficient myogenic progenitors lead to oxidative stress and mitochondria swelling. FASEB J 2021; 35:e21426. [PMID: 33749882 DOI: 10.1096/fj.202002464r] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 11/11/2022]
Abstract
Mitochondrial remodeling through fusion and fission is crucial for progenitor cell differentiation but its role in myogenesis is poorly understood. Here, we characterized the function of mitofusin 2 (Mfn2), a mitochondrial outer membrane protein critical for mitochondrial fusion, in muscle progenitor cells (myoblasts). Mfn2 expression is upregulated during myoblast differentiation in vitro and muscle regeneration in vivo. Targeted deletion of Mfn2 gene in myoblasts (Mfn2MKO ) increases oxygen-consumption rates (OCR) associated with the maximal respiration and spare respiratory capacity, and increased levels of reactive oxygen species (ROS). Skeletal muscles of Mfn2MKO mice exhibit robust mitochondrial swelling with normal mitochondrial DNA content. Additionally, mitochondria isolated from Mfn2MKO muscles have reduced OCR at basal state and for complex I respiration, associated with decreased levels of complex I proteins NDUFB8 (NADH ubiquinone oxidoreductase subunit B8) and NDUFS3 (NADH ubiquinone oxidoreductase subunit S3). However, Mfn2MKO has no obvious effects on myoblast differentiation, muscle development and function, and muscle regeneration. These results demonstrate a novel role of Mfn2 in regulating mitochondrial complex I protein abundance and respiratory functions in myogenic progenitors and myofibers.
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Affiliation(s)
- Nanjian Luo
- Department of Animal Sciences, Purdue University, West Lafayette, IN, USA.,College of Animal Science and Technology, Southwest University, Chongqing, China
| | - Feng Yue
- Department of Animal Sciences, Purdue University, West Lafayette, IN, USA
| | - Zhihao Jia
- Department of Animal Sciences, Purdue University, West Lafayette, IN, USA
| | - Jingjuan Chen
- Department of Animal Sciences, Purdue University, West Lafayette, IN, USA
| | - Qing Deng
- Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.,Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA.,Purdue Institute of Inflammation, Immunology and Infectious Disease, West Lafayette, IN, USA
| | - Yongju Zhao
- College of Animal Science and Technology, Southwest University, Chongqing, China
| | - Shihuan Kuang
- Department of Animal Sciences, Purdue University, West Lafayette, IN, USA.,Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA.,Purdue Institute of Inflammation, Immunology and Infectious Disease, West Lafayette, IN, USA
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In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. Nat Commun 2021; 12:3094. [PMID: 34035273 PMCID: PMC8149870 DOI: 10.1038/s41467-021-23353-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 04/22/2021] [Indexed: 01/09/2023] Open
Abstract
Short-term, systemic expression of the Yamanaka reprogramming factors (Oct-3/4, Sox2, Klf4 and c-Myc [OSKM]) has been shown to rejuvenate aging cells and promote tissue regeneration in vivo. However, the mechanisms by which OSKM promotes tissue regeneration are unknown. In this work, we focus on a specific tissue and demonstrate that local expression of OSKM, specifically in myofibers, induces the activation of muscle stem cells or satellite cells (SCs), which accelerates muscle regeneration in young mice. In contrast, expressing OSKM directly in SCs does not improve muscle regeneration. Mechanistically, expressing OSKM in myofibers regulates the expression of genes important for the SC microenvironment, including upregulation of p21, which in turn downregulates Wnt4. This is critical because Wnt4 is secreted by myofibers to maintain SC quiescence. Thus, short-term induction of the Yamanaka factors in myofibers may promote tissue regeneration by modifying the stem cell niche. Short term systemic expression of the reprogramming factors Oct-3/4, Sox2, Klf4, c-Myc (OSKM) rejuvenates aging cells and promotes tissue regeneration. Here the authors show that myofiber-specific expression of OSKM accelerates muscle regeneration by reducing secretion of muscle stem cell quiescence promoting Wnt4.
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Kok HJ, Barton ER. Actions and interactions of IGF-I and MMPs during muscle regeneration. Semin Cell Dev Biol 2021; 119:11-22. [PMID: 33962867 DOI: 10.1016/j.semcdb.2021.04.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/04/2021] [Accepted: 04/19/2021] [Indexed: 12/11/2022]
Abstract
Muscle regeneration requires the coordination of several factors to mobilize satellite cells and macrophages, remodel the extracellular matrix surrounding muscle fibers, and repair existing and/or form new muscle fibers. In this review, we focus on insulin-like growth factor I and the matrix metalloproteinases, which are secreted proteins that act on cells and the matrix to resolve damage. While their actions appear independent, their interactions occur at the transcriptional and post-translational levels to promote feed-forward activation of each other. Together, these proteins assist at virtually every step of the repair process, and contribute significantly to muscle regenerative capacity.
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Affiliation(s)
- Hui Jean Kok
- Applied Physiology & Kinesiology, College of Health and Human Performance, University of Florida, 1864 Stadium Road, Gainesville, FL 32611, USA
| | - Elisabeth R Barton
- Applied Physiology & Kinesiology, College of Health and Human Performance, University of Florida, 1864 Stadium Road, Gainesville, FL 32611, USA.
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45
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Ran H, Lu Y, Zhang Q, Hu Q, Zhao J, Wang K, Tong X, Su Q. MondoA Is Required for Normal Myogenesis and Regulation of the Skeletal Muscle Glycogen Content in Mice. Diabetes Metab J 2021; 45:439-451. [PMID: 32431117 PMCID: PMC8164950 DOI: 10.4093/dmj.2019.0212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 02/12/2020] [Indexed: 12/28/2022] Open
Abstract
Background Skeletal muscle is the largest tissue in the human body, and it plays a major role in exerting force and maintaining metabolism homeostasis. The role of muscle transcription factors in the regulation of metabolism is not fully understood. MondoA is a glucose-sensing transcription factor that is highly expressed in skeletal muscle. Previous studies suggest that MondoA can influence systemic metabolism homeostasis. However, the function of MondoA in the skeletal muscle remains unclear. Methods We generated muscle-specific MondoA knockout (MAKO) mice and analyzed the skeletal muscle morphology and glycogen content. Along with skeletal muscle from MAKO mice, C2C12 myocytes transfected with small interfering RNA against MondoA were also used to investigate the role and potential mechanism of MondoA in the development and glycogen metabolism of skeletal muscle. Results MAKO caused muscle fiber atrophy, reduced the proportion of type II fibers compared to type I fibers, and increased the muscle glycogen level. MondoA knockdown inhibited myoblast proliferation, migration, and differentiation by inhibiting the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/Akt pathway. Further mechanistic experiments revealed that the increased muscle glycogen in MAKO mice was caused by thioredoxin-interacting protein (TXNIP) downregulation, which led to upregulation of glucose transporter 4 (GLUT4), potentially increasing glucose uptake. Conclusion MondoA appears to mediate mouse myofiber development, and MondoA decreases the muscle glycogen level. The findings indicate the potential function of MondoA in skeletal muscle, linking the glucose-related transcription factor to myogenesis and skeletal myofiber glycogen metabolism.
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Affiliation(s)
- Hui Ran
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yao Lu
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Zhang
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiuyue Hu
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junmei Zhao
- Department of Hematology, Renmin Hospital, Wuhan University, Wuhan, China
| | - Kai Wang
- Department of Pediatrics, 1st Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Xuemei Tong
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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46
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Understanding the biology of volumetric muscle loss for an individualized exercise rehabilitation approach in breast cancer patients. Curr Opin Pharmacol 2021; 58:27-34. [PMID: 33848933 DOI: 10.1016/j.coph.2021.03.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/11/2021] [Accepted: 03/14/2021] [Indexed: 12/11/2022]
Abstract
Muscle maintenance relies on a multidimensional biologic balance that is extremely delicate in breast cancer patients, particularly those with advanced-stage disease. The biology that underpins breast cancer tumorigenesis, tumor progression and response to pharmacotherapies can modify muscle homeostasis, resulting in volumetric muscle loss. This condition dramatically increases the overall patients' frailty, leading to reduced survival and impaired quality of life. Physical activity may potentially improve muscle health in these patients, providing that an optimal patients selection is performed. The understanding of volumetric muscle loss biology in breast cancer survivors, coupled with focused clinical studies, would allow for the implementation of individualized rehabilitation protocols.
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Kumagai H, Coelho AR, Wan J, Mehta HH, Yen K, Huang A, Zempo H, Fuku N, Maeda S, Oliveira PJ, Cohen P, Kim SJ. MOTS-c reduces myostatin and muscle atrophy signaling. Am J Physiol Endocrinol Metab 2021; 320:E680-E690. [PMID: 33554779 PMCID: PMC8238132 DOI: 10.1152/ajpendo.00275.2020] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Obesity and type 2 diabetes are metabolic diseases, often associated with sarcopenia and muscle dysfunction. MOTS-c, a mitochondrial-derived peptide, acts as a systemic hormone and has been implicated in metabolic homeostasis. Although MOTS-c improves insulin sensitivity in skeletal muscle, whether MOTS-c impacts muscle atrophy is not known. Myostatin is a negative regulator of skeletal muscle mass and also one of the possible mediators of insulin resistance-induced skeletal muscle wasting. Interestingly, we found that plasma MOTS-c levels are inversely correlated with myostatin levels in human subjects. We further demonstrated that MOTS-c prevents palmitic acid-induced atrophy in differentiated C2C12 myotubes, whereas MOTS-c administration decreased myostatin levels in plasma in diet-induced obese mice. By elevating AKT phosphorylation, MOTS-c inhibits the activity of an upstream transcription factor for myostatin and other muscle wasting genes, FOXO1. MOTS-c increases mTORC2 and inhibits PTEN activity, which modulates AKT phosphorylation. Further upstream, MOTS-c increases CK2 activity, which leads to PTEN inhibition. These results suggest that through inhibition of myostatin, MOTS-c could be a potential therapy for insulin resistance-induced skeletal muscle atrophy as well as other muscle wasting phenotypes including sarcopenia.NEW & NOTEWORTHY MOTS-c, a mitochondrial-derived peptide reduces high-fat-diet-induced muscle atrophy signaling by reducing myostatin expression. The CK2-PTEN-mTORC2-AKT-FOXO1 pathways play key roles in MOTS-c action on myostatin expression.
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Affiliation(s)
- Hiroshi Kumagai
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
| | - Ana Raquel Coelho
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Cantanhede, Portugal
| | - Junxiang Wan
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California
| | - Hemal H Mehta
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California
| | - Kelvin Yen
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California
| | - Amy Huang
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California
| | - Hirofumi Zempo
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
- Department of Administrative Nutrition, Faculty of Health and Nutrition, Tokyo Seiei College, Tokyo, Japan
| | - Noriyuki Fuku
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
| | - Seiji Maeda
- Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Paulo J Oliveira
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Cantanhede, Portugal
| | - Pinchas Cohen
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California
| | - Su-Jeong Kim
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California
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48
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Paxbp1 controls a key checkpoint for cell growth and survival during early activation of quiescent muscle satellite cells. Proc Natl Acad Sci U S A 2021; 118:2021093118. [PMID: 33753492 DOI: 10.1073/pnas.2021093118] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Adult mouse muscle satellite cells (MuSCs) are quiescent in uninjured muscles. Upon muscle injury, MuSCs exit quiescence, reenter the cell cycle to proliferate and self-renew, and then differentiate and fuse to drive muscle regeneration. However, it remains poorly understood how MuSCs transition from quiescence to the cycling state. Here, we report that Pax3 and Pax7 binding protein 1 (Paxbp1) controls a key checkpoint during this critical transition. Deletion of Paxbp1 in adult MuSCs prevented them from reentering the cell cycle upon injury, resulting in a total regeneration failure. Mechanistically, we found an abnormal elevation of reactive oxygen species (ROS) in Paxbp1-null MuSCs, which induced p53 activation and impaired mTORC1 signaling, leading to defective cell growth, apoptosis, and failure in S-phase reentry. Deliberate ROS reduction partially rescued the cell-cycle reentry defect in mutant MuSCs. Our study reveals that Paxbp1 regulates a late cell-growth checkpoint essential for quiescent MuSCs to reenter the cell cycle upon activation.
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49
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Marescal O, Cheeseman IM. Cellular Mechanisms and Regulation of Quiescence. Dev Cell 2021; 55:259-271. [PMID: 33171109 DOI: 10.1016/j.devcel.2020.09.029] [Citation(s) in RCA: 133] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/25/2020] [Accepted: 09/29/2020] [Indexed: 02/06/2023]
Abstract
Quiescence is a state of reversible proliferative arrest in which cells are not actively dividing and yet retain the capacity to reenter the cell cycle upon receiving an appropriate stimulus. Quiescent cells are remarkably diverse-they reside in different locations throughout the body, serve distinct roles, and are activated by a variety of signals. Despite this diversity, all quiescent cells must be able to persist in a nondividing state without compromising their proliferative potential, which requires changes to core cellular programs. How drastically different cell types are able to implement extensive changes to their gene-expression programs, metabolism, and cellular structures to induce a common cellular state is a fascinating question in cell and developmental biology. In this review, we explore the diversity of quiescent cells and highlight the unifying characteristics that define the quiescent state.
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Affiliation(s)
- Océane Marescal
- Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Iain M Cheeseman
- Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
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50
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Ancel S, Stuelsatz P, Feige JN. Muscle Stem Cell Quiescence: Controlling Stemness by Staying Asleep. Trends Cell Biol 2021; 31:556-568. [PMID: 33674167 DOI: 10.1016/j.tcb.2021.02.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 12/22/2022]
Abstract
Muscle stem cells (MuSCs) are tissue-resident stem cells required for growth and repair of skeletal muscle, that are otherwise maintained in a cell-cycle-arrested state called quiescence. While quiescence was originally believed to be a state of cellular inactivity, increasing evidence suggests that quiescence is dynamically regulated and contributes to stemness, the long-term capacity to maintain regenerative functions. Here, we review the current understanding of MuSC quiescence and highlight recently discovered molecular markers, which differentiate depth of quiescence and influence self-renewal capacity. We also discuss how quiescent MuSCs integrate paracrine factors from their niche and dynamically regulate cell signaling, metabolism and proteostasis as they anticipate physiological needs, and how perturbing these cues during aging impairs muscle regeneration.
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Affiliation(s)
- Sara Ancel
- Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, 1015 Lausanne, Switzerland; School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
| | - Pascal Stuelsatz
- Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, 1015 Lausanne, Switzerland
| | - Jerome N Feige
- Nestlé Institute of Health Sciences, Nestlé Research, EPFL Innovation Park, 1015 Lausanne, Switzerland; School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
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