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Pinto AP, Sarni ÂAJ, Tavares MEA, da Rocha AL, Carolino ROG, de Sousa Neto IV, Da Silva Ferreira DC, Munoz VR, Teixeira GR, Simabuco FM, Pauli JR, Cintra DE, Ropelle ER, de Freitas EC, da Silva ASR. Combined exercise-induced modulation of Notch pathway and muscle quality in senescence-accelerated mice. Pflugers Arch 2025; 477:393-405. [PMID: 39804464 DOI: 10.1007/s00424-024-03048-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/27/2024] [Accepted: 11/29/2024] [Indexed: 02/02/2025]
Abstract
The Notch signaling pathway is crucial for skeletal muscle development, regeneration, inflammation, and aging. This study investigated the association between interleukin-10 (IL-10) and the Notch pathway in C2C12 cells, as well as explored the effects of combined endurance and resistance exercise on the Notch and autophagy pathways in the skeletal muscle of senescence-accelerated mouse-resistant 1 Sedentary (SAMR1 CT), SAMR1 exercised (SAMR1 EX), senescence-accelerated prone mouse 8 Sedentary (SAMP8 CT), and SAMP8 exercised (SAMP8 EX). C2C12 myoblasts were transfected with siIL-10. Histological analysis, reverse transcription-quantitative polymerase chain reaction, and immunoblotting were performed on the quadriceps and tibialis anterior muscles. A publicly available dataset was analyzed to assess the Notch pathway in older men. In summary, IL-10 knockdown in myoblasts reduced the Notch pathway gene and protein expression. In SAMP8 mice, combined exercise improved muscle fiber organization, enhanced balance and coordination, and increased Notch2 and Hes1 mRNA levels. NOTCH2 mRNA levels were also higher in older men compared to young subjects with similar physical activity levels. These findings suggest that combined physical exercise enhances muscle regeneration via the Notch pathway in aged muscle.
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Affiliation(s)
- Ana P Pinto
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14040-907, Brazil
| | - Ângelo Augusto J Sarni
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14040-907, Brazil
| | - Maria Eduarda A Tavares
- Department of Physical Education, State University of São Paulo (UNESP), Presidente Prudente, São Paulo, Brazil
- Multicentric Program of Postgraduate in Physiological Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
| | - Alisson L da Rocha
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Ruither O Gomes Carolino
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14040-907, Brazil
| | - Ivo V de Sousa Neto
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14040-907, Brazil
| | - Driele C Da Silva Ferreira
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14040-907, Brazil
| | - Vitor R Munoz
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14040-907, Brazil
| | - Giovana R Teixeira
- Department of Physical Education, State University of São Paulo (UNESP), Presidente Prudente, São Paulo, Brazil
- Multicentric Program of Postgraduate in Physiological Sciences, School of Dentistry of Araçatuba, São Paulo State University (UNESP), Araçatuba, São Paulo, Brazil
| | - Fernando M Simabuco
- Department of Biochemistry, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - José R Pauli
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Dennys E Cintra
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Eduardo R Ropelle
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil
| | - Ellen C de Freitas
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14040-907, Brazil
- Department of Health Sciences, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Adelino S R da Silva
- School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Avenida Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, São Paulo, 14040-907, Brazil.
- Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
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Runyan CE, Luo L, Welch LC, Lu Z, Chen F, Schleck MJ, Nafikova RA, Grant RA, Aillon RP, Senkow KJ, Bunyan EG, Plodzeen WT, Abdala-Valencia H, Weiss C, Dada LA, Thorp EB, Sznajder JI, Chandel NS, Misharin AV, Budinger GRS. Tissue-resident skeletal muscle macrophages promote recovery from viral pneumonia-induced sarcopenia in normal aging. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.09.631996. [PMID: 39868236 PMCID: PMC11760773 DOI: 10.1101/2025.01.09.631996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Sarcopenia, which diminishes lifespan and healthspan in the elderly, is commonly exacerbated by viral pneumonia, including influenza and COVID-19. In a study of influenza A pneumonia in mice, young mice fully recovered from sarcopenia, while older mice did not. We identified a population of tissue-resident skeletal muscle macrophages that form a spatial niche with satellite cells and myofibers in young mice but are lost with age. Mice with a gain-of-function mutation in the Mertk receptor maintained this macrophage-myofiber interaction during aging and fully recovered from influenza-induced sarcopenia. In contrast, deletion of Mertk in macrophages or loss of Cx3cr1 disrupted this niche, preventing muscle regeneration. Heterochronic parabiosis did not restore the niche in old mice. These findings suggest that age-related loss of Mertk in muscle tissue-resident macrophages disrupts the cellular signaling necessary for muscle regeneration after viral pneumonia, offering a potential target to mitigate sarcopenia in aging.
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Affiliation(s)
- Constance E Runyan
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Lucy Luo
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Lynn C Welch
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Ziyan Lu
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Fei Chen
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Maxwell J Schleck
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Radmila A Nafikova
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Rogan A Grant
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Raul Piseaux Aillon
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Karolina J Senkow
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Elsie G Bunyan
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - William T Plodzeen
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Hiam Abdala-Valencia
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Craig Weiss
- Department of Neuroscience, Northwestern University Feinberg School of Medicine. Chicago, IL, USA
| | - Laura A Dada
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Edward B Thorp
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jacob I Sznajder
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Navdeep S Chandel
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - Alexander V Misharin
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
| | - G R Scott Budinger
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Simpson Querrey Lung Institute for Translational Sciences. Northwestern University. Chicago, IL, USA
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Lin WH, Tzeng CY, Kao FC, Tsao CW, Li N, Wu CC, Lee SH, Huang KF, Hu WW, Chen SL. The proliferation and differentiation of skeletal muscle stem cells are enhanced in a bioreactor. Biotechnol Bioeng 2025; 122:95-109. [PMID: 39369338 DOI: 10.1002/bit.28857] [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: 04/03/2024] [Revised: 09/18/2024] [Accepted: 09/24/2024] [Indexed: 10/07/2024]
Abstract
Skeletal muscle (SKM) is the largest organ in mammalian body and it can repair damages by using the residential myogenic stem cells (MuSC), but this repairing capacity reduces with age and in some genetic muscular dystrophy. Under these circumstances, artificial amplification of autologous MuSC in vitro might be necessary to repair the damaged SKM. The amplification of MuSC is highly dependent on myogenic signals, such as sonic hedgehog (Shh), Wnt3a, and fibroblast growth factors, so formulating an optimum myogenic kit composed of specific myogenic signals might increase the proliferation and differentiation of MuSC efficiently. In this study, various myogenic signals have been tested on C2C12 myoblasts and primary MuSC, and a myogenic kit consists of insulin, lithium chloride, T3, and retinoic acid has been formulated, and we found it significantly increased the fusion index and MHC expression level of both C2C12 and MuSC myotubes. A novel bioreactor providing cyclic stretching (CS) and electrical stimulation (ES) has been fabricated to enhance the myogenic differentiation of both C2C12 and MuSC. We further found that coating the bioreactor substratum with collagen gave the best effect on proliferation and differentiation of MuSC. Furthermore, combining the collagen coating and physical stimuli (CS + ES) in the bioreactor can generate more proliferative primary MuSC cells. Our results have demonstrated that the combination of myogenic kit and bioreactor can provide environment for efficient MuSC proliferation and differentiation. These MuSC and mature myotubes amplified in the bioreactor might be useful for clinical grafting into damaged SKM in the future.
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Affiliation(s)
- Wei-Hsuan Lin
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Chung-Yuh Tzeng
- Department of Orthopedics, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Rehabilitation, Jen-Teh Junior College of Medicine, Nursing, and Management, Miaoli, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Fan-Che Kao
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Chia-Wen Tsao
- Department of Mechanical Engineering, National Central University, Taoyuan, Taiwan
| | - Ning Li
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Chuan-Che Wu
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Sheng-Huei Lee
- Department of Electric Engineering, Chien Hsin University of Science and Technology, Taoyuan, Taiwan
| | - Kai-Fan Huang
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
| | - Wei-Wen Hu
- Department of Chemical and Materials Engineering, National Central University, Taoyuan, Taiwan
| | - Shen-Liang Chen
- Department of Life Sciences, National Central University, Taoyuan, Taiwan
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Chinvattanachot G, Rivas D, Duque G. Mechanisms of muscle cells alterations and regeneration decline during aging. Ageing Res Rev 2024; 102:102589. [PMID: 39566742 DOI: 10.1016/j.arr.2024.102589] [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: 07/13/2024] [Revised: 10/27/2024] [Accepted: 11/14/2024] [Indexed: 11/22/2024]
Abstract
Skeletal muscles are essential for locomotion and body metabolism regulation. As muscles age, they lose strength, elasticity, and metabolic capability, leading to ineffective motion and metabolic derangement. Both cellular and extracellular alterations significantly influence muscle aging. Satellite cells (SCs), the primary muscle stem cells responsible for muscle regeneration, become exhausted, resulting in diminished population and functionality during aging. This decline in SC function impairs intercellular interactions as well as extracellular matrix production, further hindering muscle regeneration. Other muscle-resident cells, such as fibro-adipogenic progenitors (FAPs), pericytes, and immune cells, also deteriorate with age, reducing local growth factor activities and responsiveness to stress or injury. Systemic signaling, including hormonal changes, contributes to muscle cellular catabolism and disrupts muscle homeostasis. Collectively, these cellular and environmental components interact, disrupting muscle homeostasis and regeneration in advancing age. Understanding these complex interactions offers insights into potential regenerative strategies to mitigate age-related muscle degeneration.
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Affiliation(s)
- Guntarat Chinvattanachot
- Department of Orthopedics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Bone, Muscle & Geroscience Group, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
| | - Daniel Rivas
- Bone, Muscle & Geroscience Group, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Gustavo Duque
- Bone, Muscle & Geroscience Group, Research Institute of the McGill University Health Centre, Montreal, QC, Canada; Dr. Joseph Kaufmann Chair in Geriatric Medicine, Department of Medicine, McGill University, Montreal, QC, Canada
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Tey SR, Anderson RS, Yu CH, Robertson S, Kletzien H, Connor NP, Tanaka K, Ohkawa Y, Suzuki M. Cellular and transcriptomic changes by the supplementation of aged rat serum in human pluripotent stem cell-derived myogenic progenitors. Front Cell Dev Biol 2024; 12:1481491. [PMID: 39474351 PMCID: PMC11518775 DOI: 10.3389/fcell.2024.1481491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 09/25/2024] [Indexed: 11/06/2024] Open
Abstract
Introduction The changing composition of non-cell autonomous circulating factors in blood as humans age is believed to play a role in muscle mass and strength loss. The mechanisms through which these circulating factors act in age-related skeletal muscle changes is not fully understood. In this study, we used human myogenic progenitors derived from human pluripotent stem cells to study non-cell autonomous roles of circulating factors during the process of myogenic differentiation. Methods Myogenic progenitors from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) were supplemented with serum samples from aged or young Fischer 344 × Brown Norway F1-hybrid rats. The effect of aged or young serum supplementation on myogenic progenitor proliferation, myotube formation capacity, differentiation, and early transcriptomic profiles were analyzed. Results We found that aged rat serum supplementation significantly reduced cell proliferation and increased cell death in both ESC- and iPSC-derived myogenic progenitors. Next, we found that the supplementation of aged rat serum inhibited myotube formation and maturation during terminal differentiation from progenitors to skeletal myocytes when compared to the cells treated with young adult rat serum. Lastly, we identified that gene expression profiles were affected following serum supplementation in culture. Discussion Together, aged serum supplementation caused cellular and transcriptomic changes in human myogenic progenitors. The current data from our in vitro model possibly simulate non-cell autonomous contributions of blood composition to age-related processes in human skeletal muscle.
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Affiliation(s)
- Sin-Ruow Tey
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Ryan S. Anderson
- Department of Surgical Sciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Clara H. Yu
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Samantha Robertson
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Heidi Kletzien
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Nadine P. Connor
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- Department of Communication Sciences and Disorders, University of Wisconsin-Madison, Madison, WI, United States
| | - Kaori Tanaka
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Yasuyuki Ohkawa
- Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Masatoshi Suzuki
- Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, United States
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States
- Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, Madison, WI, United States
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Andries A, Deschrevel J, Maes K, De Beukelaer N, Corvelyn M, Staut L, De Houwer H, Costamagna D, Nijs S, Metsemakers WJ, Nijs E, Hens G, De Wachter E, Prinsen S, Desloovere K, Van Campenhout A, Gayan-Ramirez G. Histological analysis of the medial gastrocnemius muscle in young healthy children. Front Physiol 2024; 15:1336283. [PMID: 38651045 PMCID: PMC11034367 DOI: 10.3389/fphys.2024.1336283] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 03/19/2024] [Indexed: 04/25/2024] Open
Abstract
Introduction: Histological data on muscle fiber size and proportion in (very) young typically developing (TD) children is not well documented and data on capillarization and satellite cell content are also lacking. Aims: This study investigated the microscopic properties of the medial gastrocnemius muscle in growing TD children, grouped according to age and gender to provide normal reference values in healthy children. Methods: Microbiopsies of the medial gastrocnemius (MG) muscle were collected in 46 TD boys and girls aged 2-10 years subdivided into 4 age groups (2-4, 4-6, 6-8 and 8-10 years). Sections were immunostained to assess fiber type cross-sectional area (fCSA) and proportion, the number of satellite cells (SC), capillary to fiber ratio (C/F), capillary density for type I and II fiber (CFD), capillary domain, capillary-to-fiber perimeter exchange index (CFPE) and heterogeneity index. fCSA was normalized to fibula length2 and the coefficient of variation (CV) was calculated to reflect fCSA intrasubject variability. Results: Absolute fCSA of all fibers increased with age (r = 0.72, p < 0.001) but more in boys (+112%, p < 0.05) than in girls (+48%, p > 0.05) Normalized fCSA, CV and fiber proportion did not differ between age groups and gender. C/F was strongly correlated with age in boys (r = 0.83, p < 0.001), and to a lesser extent in girls (r = 0.37, p = 0.115), while other capillary parameters as well as the number of SC remained stable with increasing age in boys and girls. Discussion: This study provides reference values of histological measures in MG according to age in normally growing boys and girls. These data may be used as a reference to determine disease impact and efficacy of therapeutic approach on the muscle.
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Affiliation(s)
- Anke Andries
- Laboratory of Respiratory Diseases and Thoracic Surgery, Department of Chronic Diseases and Metabolism, KU-Leuven, Leuven, Belgium
| | - Jorieke Deschrevel
- Laboratory of Respiratory Diseases and Thoracic Surgery, Department of Chronic Diseases and Metabolism, KU-Leuven, Leuven, Belgium
| | - Karen Maes
- Laboratory of Respiratory Diseases and Thoracic Surgery, Department of Chronic Diseases and Metabolism, KU-Leuven, Leuven, Belgium
| | - Nathalie De Beukelaer
- Neurorehabilitation Group, Department of Rehabilitation Sciences, KU-Leuven, Leuven, Belgium
| | - Marlies Corvelyn
- Stem Cell and Developmental Biology, Department of Development and Regeneration, KU-Leuven, Leuven, Belgium
| | - Lauraine Staut
- Neurorehabilitation Group, Department of Rehabilitation Sciences, KU-Leuven, Leuven, Belgium
| | - Hannah De Houwer
- Pediatric Orthopedics, Department of Development and Regeneration, KU-Leuven, Leuven, Belgium
| | - Domiziana Costamagna
- Neurorehabilitation Group, Department of Rehabilitation Sciences, KU-Leuven, Leuven, Belgium
- Stem Cell and Developmental Biology, Department of Development and Regeneration, KU-Leuven, Leuven, Belgium
- Exercise Physiology Research Group, Department of Movement Sciences, KU-Leuven, Leuven, Belgium
| | - Stefaan Nijs
- Department of Trauma Surgery, University Hospitals Leuven, Leuven, Belgium
| | | | - Elga Nijs
- Department of Trauma Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Greet Hens
- Department of Ear Nose Throat, University Hospitals Leuven, Leuven, Belgium
| | - Eva De Wachter
- Department of Orthopaedic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Sandra Prinsen
- Department of Orthopaedic Surgery, University Hospitals Leuven, Leuven, Belgium
| | - Kaat Desloovere
- Neurorehabilitation Group, Department of Rehabilitation Sciences, KU-Leuven, Leuven, Belgium
| | - Anja Van Campenhout
- Pediatric Orthopedics, Department of Development and Regeneration, KU-Leuven, Leuven, Belgium
| | - Ghislaine Gayan-Ramirez
- Laboratory of Respiratory Diseases and Thoracic Surgery, Department of Chronic Diseases and Metabolism, KU-Leuven, Leuven, Belgium
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Ciuffoli V, Feng X, Jiang K, Acevedo-Luna N, Ko KD, Wang AHJ, Riparini G, Khateb M, Glancy B, Dell'Orso S, Sartorelli V. Psat1-generated α-ketoglutarate and glutamine promote muscle stem cell activation and regeneration. Genes Dev 2024; 38:151-167. [PMID: 38453480 PMCID: PMC10982694 DOI: 10.1101/gad.351428.123] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/21/2024] [Indexed: 03/09/2024]
Abstract
By satisfying bioenergetic demands, generating biomass, and providing metabolites serving as cofactors for chromatin modifiers, metabolism regulates adult stem cell biology. Here, we report that a branch of glycolysis, the serine biosynthesis pathway (SBP), is activated in regenerating muscle stem cells (MuSCs). Gene inactivation and metabolomics revealed that Psat1, one of the three SBP enzymes, controls MuSC activation and expansion of myogenic progenitors through production of the metabolite α-ketoglutarate (α-KG) and α-KG-generated glutamine. Psat1 ablation resulted in defective expansion of MuSCs and impaired regeneration. Psat1, α-KG, and glutamine were reduced in MuSCs of old mice. α-KG or glutamine re-established appropriate muscle regeneration of adult conditional Psat1 -/- mice and of old mice. These findings contribute insights into the metabolic role of Psat1 during muscle regeneration and suggest α-KG and glutamine as potential therapeutic interventions to ameliorate muscle regeneration during aging.
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Affiliation(s)
- Veronica Ciuffoli
- Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Xuesong Feng
- Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Kan Jiang
- Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Natalia Acevedo-Luna
- Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Kyung Dae Ko
- Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - A Hong Jun Wang
- Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Giulia Riparini
- Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Mamduh Khateb
- Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Brian Glancy
- Muscle Energetics, National Heart, Lung, and Blood Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Stefania Dell'Orso
- Genomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Vittorio Sartorelli
- Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;
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Mavillard F, Servian-Morilla E, Dofash L, Rojas-Marcos I, Folland C, Monahan G, Gutierrez-Gutierrez G, Rivas E, Hernández-Lain A, Valladares A, Cantero G, Morales JM, Laing NG, Paradas C, Ravenscroft G, Cabrera-Serrano M. Ablation of the carboxy-terminal end of MAMDC2 causes a distinct muscular dystrophy. Brain 2023; 146:5235-5248. [PMID: 37503746 DOI: 10.1093/brain/awad256] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 07/08/2023] [Accepted: 07/16/2023] [Indexed: 07/29/2023] Open
Abstract
The extracellular matrix (ECM) has an important role in the development and maintenance of skeletal muscle, and several muscle diseases are associated with the dysfunction of ECM elements. MAMDC2 is a putative ECM protein and its role in cell proliferation has been investigated in certain cancer types. However, its participation in skeletal muscle physiology has not been previously studied. We describe 17 individuals with an autosomal dominant muscular dystrophy belonging to two unrelated families in which different heterozygous truncating variants in the last exon of MAMDC2 co-segregate correctly with the disease. The radiological aspect of muscle involvement resembles that of COL6 myopathies with fat replacement at the peripheral rim of vastii muscles. In this cohort, a subfascial and peri-tendinous pattern is observed in upper and lower limb muscles. Here we show that MAMDC2 is expressed in adult skeletal muscle and differentiating muscle cells, where it appears to localize to the sarcoplasm and myonuclei. In addition, we show it is secreted by myoblasts and differentiating myotubes into to the extracellular compartment. The last exon encodes a disordered region with a polar residue compositional bias loss of which likely induces a toxic effect of the mutant protein. The precise mechanisms by which the altered MAMDC2 proteins cause disease remains to be determined. MAMDC2 is a skeletal muscle disease-associated protein. Its role in muscle development and ECM-muscle communication remains to be fully elucidated. Screening of the last exon of MAMDC2 should be considered in patients presenting with autosomal dominant muscular dystrophy, particularly in those with a subfascial radiological pattern of muscle involvement.
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Affiliation(s)
- Fabiola Mavillard
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
- Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED). Instituto de Salud Carlos III, 28220 Madrid, Spain
| | - Emilia Servian-Morilla
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
- Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED). Instituto de Salud Carlos III, 28220 Madrid, Spain
| | - Lein Dofash
- Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, WA 6009, Australia
| | - Iñigo Rojas-Marcos
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
- Department of Neurology, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain
| | - Chiara Folland
- Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, WA 6009, Australia
| | - Gavin Monahan
- Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, WA 6009, Australia
| | - Gerardo Gutierrez-Gutierrez
- Department of Neurology, Hospital Universitario Infanta Sofia, Universidad Europea de Madrid, Madrid 28702, Spain
| | - Eloy Rivas
- Department of Neuropathology, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain
| | | | - Amador Valladares
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
| | - Gloria Cantero
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
| | - Jose M Morales
- Department of Neuroradiology, Hospital Universitario Virgen del Rocio, Sevilla 41013, Spain
| | - Nigel G Laing
- Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, WA 6009, Australia
| | - Carmen Paradas
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
- Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED). Instituto de Salud Carlos III, 28220 Madrid, Spain
- Department of Neurology, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain
| | - Gianina Ravenscroft
- Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, WA 6009, Australia
| | - Macarena Cabrera-Serrano
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain
- Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED). Instituto de Salud Carlos III, 28220 Madrid, Spain
- Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, WA 6009, Australia
- Department of Neurology, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain
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9
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Son YH, Kim WJ, Shin YJ, Lee SM, Lee B, Lee KP, Lee SH, Kim KJ, Kwon KS. Human primary myoblasts derived from paraspinal muscle reflect donor age as an experimental model of sarcopenia. Exp Gerontol 2023; 181:112273. [PMID: 37591335 DOI: 10.1016/j.exger.2023.112273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/28/2023] [Accepted: 08/14/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND Low back pain is a general phenomenon of aging, and surgery is an unavoidable choice to relieve severe back pain. The discarded surgical site during surgery is of high value for muscle and muscle-related research. This study investigated the age-dependent properties of patients' paraspinal muscles at the cellular level. METHODS To define an association of paraspinal muscle degeneration with sarcopenia, we analyzed lumbar paraspinal muscle and myoblasts isolated from donors of various ages (25-77 years). Preoperative evaluations were performed by bioimpedance analysis using the InBody 720, magnetic resonance (MR) imaging of the lumbar spine, and lumbar extension strength using a lumbar extension dynamometer. In addition, the growth and differentiation capacity of myoblasts obtained from the donor was determined using proliferation assay and western blotting. RESULTS The cross-sectional area of the lumbar paraspinal muscle decreased with age and was also correlated with the appendicular skeletal muscle index (ASM/height2). Human primary myoblasts isolated from paraspinal muscle preserved their proliferative capacity in vitro, which tended to decrease with donor age. The age-dependent decline in myoblast proliferation was correlated with levels of cell cycle inhibitory proteins (p16INK4a, p21CIP1, and p27KIP1) associated with cellular senescence. Primary myoblasts isolated from younger donors differentiated into multinucleate myotubes earlier and at a higher rate than those from older donors in vitro. Age-dependent decline in myogenic potential of the isolated primary myoblasts was likely correlated with the inactivation of myogenic transcription factors such as MyoD, myogenin, and MEF2c. CONCLUSIONS Myoblasts isolated from human paraspinal muscle preserve myogenic potential that correlates with donor age, providing an in vitro model of sarcopenia.
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Affiliation(s)
- Young Hoon Son
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Biohybrid Systems Group, Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Whoan Jeang Kim
- Department of Orthopedic Surgery, Eulji University College of Medicine, Daejeon 34824, Republic of Korea
| | - Yeo Jin Shin
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
| | - Seung-Min Lee
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
| | - Bora Lee
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
| | - Kwang-Pyo Lee
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Korea University of Science and Technology, KRIBB School, Daejeon, Republic of Korea; Aventi Inc., Daejeon 34141, Republic of Korea
| | - Seung Hoon Lee
- Department of Neurosurgery, Eulji University College of Medicine, Uijeongbu 11759, Republic of Korea
| | - Kap Jung Kim
- Department of Orthopedic Surgery, Eulji University College of Medicine, Daejeon 34824, Republic of Korea.
| | - Ki-Sun Kwon
- Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Korea University of Science and Technology, KRIBB School, Daejeon, Republic of Korea; Aventi Inc., Daejeon 34141, Republic of Korea.
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10
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Messmer T, Dohmen RGJ, Schaeken L, Melzener L, Hueber R, Godec M, Didoss C, Post MJ, Flack JE. Single-cell analysis of bovine muscle-derived cell types for cultured meat production. Front Nutr 2023; 10:1212196. [PMID: 37781115 PMCID: PMC10535090 DOI: 10.3389/fnut.2023.1212196] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/25/2023] [Indexed: 10/03/2023] Open
Abstract
Cultured meat technologies leverage the proliferation and differentiation of animal-derived stem cells ex vivo to produce edible tissues for human consumption in a sustainable fashion. However, skeletal muscle is a dynamic and highly complex tissue, involving the interplay of numerous mono- and multinucleated cells, including muscle fibers, satellite cells (SCs) and fibro-adipogenic progenitors (FAPs), and recreation of the tissue in vitro thus requires the characterization and manipulation of a broad range of cell types. Here, we use a single-cell RNA sequencing approach to characterize cellular heterogeneity within bovine muscle and muscle-derived cell cultures over time. Using this data, we identify numerous distinct cell types, and develop robust protocols for the easy purification and proliferation of several of these populations. We note overgrowth of undesirable cell types within heterogeneous proliferative cultures as a barrier to efficient cultured meat production, and use transcriptomics to identify conditions that favor the growth of SCs in the context of serum-free medium. Combining RNA velocities computed in silico with time-resolved flow cytometric analysis, we characterize dynamic subpopulations and transitions between active, quiescent, and committed states of SCs, and demonstrate methods for modulation of these states during long-term proliferative cultures. This work provides an important reference for advancing our knowledge of bovine skeletal muscle biology, and its application in the development of cultured meat technologies.
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Affiliation(s)
- Tobias Messmer
- Mosa Meat B.V., Maastricht, Netherlands
- Maastricht University, Maastricht, Netherlands
| | - Richard G. J. Dohmen
- Mosa Meat B.V., Maastricht, Netherlands
- Maastricht University, Maastricht, Netherlands
| | | | - Lea Melzener
- Mosa Meat B.V., Maastricht, Netherlands
- Maastricht University, Maastricht, Netherlands
| | | | | | | | - Mark J. Post
- Mosa Meat B.V., Maastricht, Netherlands
- Maastricht University, Maastricht, Netherlands
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11
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Kubat GB, Bouhamida E, Ulger O, Turkel I, Pedriali G, Ramaccini D, Ekinci O, Ozerklig B, Atalay O, Patergnani S, Nur Sahin B, Morciano G, Tuncer M, Tremoli E, Pinton P. Mitochondrial dysfunction and skeletal muscle atrophy: Causes, mechanisms, and treatment strategies. Mitochondrion 2023; 72:33-58. [PMID: 37451353 DOI: 10.1016/j.mito.2023.07.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 07/02/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023]
Abstract
Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in movement, posture and force production. More than just a component of the locomotor system, skeletal muscle functions as an endocrine organ capable of producing and secreting hundreds of bioactive molecules. Therefore, maintaining healthy skeletal muscles is crucial for supporting overall body health. Various pathological conditions, such as prolonged immobilization, cachexia, aging, drug-induced toxicity, and cardiovascular diseases (CVDs), can disrupt the balance between muscle protein synthesis and degradation, leading to skeletal muscle atrophy. Mitochondrial dysfunction is a major contributing mechanism to skeletal muscle atrophy, as it plays crucial roles in various biological processes, including energy production, metabolic flexibility, maintenance of redox homeostasis, and regulation of apoptosis. In this review, we critically examine recent knowledge regarding the causes of muscle atrophy (disuse, cachexia, aging, etc.) and its contribution to CVDs. Additionally, we highlight the mitochondrial signaling pathways involvement to skeletal muscle atrophy, such as the ubiquitin-proteasome system, autophagy and mitophagy, mitochondrial fission-fusion, and mitochondrial biogenesis. Furthermore, we discuss current strategies, including exercise, mitochondria-targeted antioxidants, in vivo transfection of PGC-1α, and the potential use of mitochondrial transplantation as a possible therapeutic approach.
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Affiliation(s)
- Gokhan Burcin Kubat
- Department of Mitochondria and Cellular Research, Gulhane Health Sciences Institute, University of Health Sciences, 06010 Ankara, Turkey.
| | - Esmaa Bouhamida
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy
| | - Oner Ulger
- Department of Mitochondria and Cellular Research, Gulhane Health Sciences Institute, University of Health Sciences, 06010 Ankara, Turkey
| | - Ibrahim Turkel
- Department of Exercise and Sport Sciences, Faculty of Sport Sciences, Hacettepe University, 06800 Ankara, Turkey
| | - Gaia Pedriali
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy
| | - Daniela Ramaccini
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy
| | - Ozgur Ekinci
- Department of Pathology, Gazi University, 06500 Ankara, Turkey
| | - Berkay Ozerklig
- Department of Exercise and Sport Sciences, Faculty of Sport Sciences, Hacettepe University, 06800 Ankara, Turkey
| | - Ozbeyen Atalay
- Department of Physiology, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey
| | - Simone Patergnani
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy; Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Beyza Nur Sahin
- Department of Physiology, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey
| | - Giampaolo Morciano
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy; Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - Meltem Tuncer
- Department of Physiology, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey
| | - Elena Tremoli
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy
| | - Paolo Pinton
- Translational Research Center, Maria Cecilia Hospital GVM Care & Research, 48033 Cotignola, Italy; Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy.
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12
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Lathe R, St Clair D. Programmed ageing: decline of stem cell renewal, immunosenescence, and Alzheimer's disease. Biol Rev Camb Philos Soc 2023; 98:1424-1458. [PMID: 37068798 DOI: 10.1111/brv.12959] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 03/27/2023] [Accepted: 03/30/2023] [Indexed: 04/19/2023]
Abstract
The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master 'clock of age' (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin-like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial - specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.
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Affiliation(s)
- Richard Lathe
- Division of Infection Medicine, Chancellor's Building, University of Edinburgh Medical School, Little France, Edinburgh, EH16 4SB, UK
| | - David St Clair
- Institute of Medical Sciences, School of Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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13
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Park JYC, King A, Björk V, English BW, Fedintsev A, Ewald CY. Strategic outline of interventions targeting extracellular matrix for promoting healthy longevity. Am J Physiol Cell Physiol 2023; 325:C90-C128. [PMID: 37154490 DOI: 10.1152/ajpcell.00060.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/28/2023] [Accepted: 04/28/2023] [Indexed: 05/10/2023]
Abstract
The extracellular matrix (ECM), composed of interlinked proteins outside of cells, is an important component of the human body that helps maintain tissue architecture and cellular homeostasis. As people age, the ECM undergoes changes that can lead to age-related morbidity and mortality. Despite its importance, ECM aging remains understudied in the field of geroscience. In this review, we discuss the core concepts of ECM integrity, outline the age-related challenges and subsequent pathologies and diseases, summarize diagnostic methods detecting a faulty ECM, and provide strategies targeting ECM homeostasis. To conceptualize this, we built a technology research tree to hierarchically visualize possible research sequences for studying ECM aging. This strategic framework will hopefully facilitate the development of future research on interventions to restore ECM integrity, which could potentially lead to the development of new drugs or therapeutic interventions promoting health during aging.
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Affiliation(s)
- Ji Young Cecilia Park
- Laboratory of Extracellular Matrix Regeneration, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland
| | - Aaron King
- Foresight Institute, San Francisco, California, United States
| | | | - Bradley W English
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | | | - Collin Y Ewald
- Laboratory of Extracellular Matrix Regeneration, Institute of Translational Medicine, Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland
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14
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de Jong JCBC, Caspers MPM, Keijzer N, Worms N, Attema J, de Ruiter C, Lek S, Nieuwenhuizen AG, Keijer J, Menke AL, Kleemann R, Verschuren L, van den Hoek AM. Caloric Restriction Combined with Immobilization as Translational Model for Sarcopenia Expressing Key-Pathways of Human Pathology. Aging Dis 2023; 14:937-957. [PMID: 37191430 DOI: 10.14336/ad.2022.1201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 12/01/2022] [Indexed: 05/17/2023] Open
Abstract
The prevalence of sarcopenia is increasing while it is often challenging, expensive and time-consuming to test the effectiveness of interventions against sarcopenia. Translational mouse models that adequately mimic underlying physiological pathways could accelerate research but are scarce. Here, we investigated the translational value of three potential mouse models for sarcopenia, namely partial immobilized (to mimic sedentary lifestyle), caloric restricted (CR; to mimic malnutrition) and a combination (immobilized & CR) model. C57BL/6J mice were calorically restricted (-40%) and/or one hindleg was immobilized for two weeks to induce loss of muscle mass and function. Muscle parameters were compared to those of young control (4 months) and old reference mice (21 months). Transcriptome analysis of quadriceps muscle was performed to identify underlying pathways and were compared with those being expressed in aged human vastus lateralis muscle-biopsies using a meta-analysis of five different human studies. Caloric restriction induced overall loss of lean body mass (-15%, p<0.001), whereas immobilization decreased muscle strength (-28%, p<0.001) and muscle mass of hindleg muscles specifically (on average -25%, p<0.001). The proportion of slow myofibers increased with aging in mice (+5%, p<0.05), and this was not recapitulated by the CR and/or immobilization models. The diameter of fast myofibers decreased with aging (-7%, p<0.05), and this was mimicked by all models. Transcriptome analysis revealed that the combination of CR and immobilization recapitulated more pathways characteristic for human muscle-aging (73%) than naturally aged (21 months old) mice (45%). In conclusion, the combination model exhibits loss of both muscle mass (due to CR) and function (due to immobilization) and has a remarkable similarity with pathways underlying human sarcopenia. These findings underline that external factors such as sedentary behavior and malnutrition are key elements of a translational mouse model and favor the combination model as a rapid model for testing the treatments against sarcopenia.
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Affiliation(s)
- Jelle C B C de Jong
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
- Human and Animal Physiology, Wageningen University, Wageningen, the Netherlands
| | - Martien P M Caspers
- Department of Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands
| | - Nanda Keijzer
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
| | - Nicole Worms
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
| | - Joline Attema
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
| | - Christa de Ruiter
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
| | - Serene Lek
- Clinnovate Health UK Ltd, Glasgow, United Kingdom
| | | | - Jaap Keijer
- Human and Animal Physiology, Wageningen University, Wageningen, the Netherlands
| | - Aswin L Menke
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
| | - Robert Kleemann
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
| | - Lars Verschuren
- Department of Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), Zeist, The Netherlands
| | - Anita M van den Hoek
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands
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15
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Sahinyan K, Lazure F, Blackburn DM, Soleimani VD. Decline of regenerative potential of old muscle stem cells: contribution to muscle aging. FEBS J 2023; 290:1267-1289. [PMID: 35029021 DOI: 10.1111/febs.16352] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 12/23/2021] [Accepted: 01/11/2022] [Indexed: 01/01/2023]
Abstract
Muscle stem cells (MuSCs) are required for life-long muscle regeneration. In general, aging has been linked to a decline in the numbers and the regenerative potential of MuSCs. Muscle regeneration depends on the proper functioning of MuSCs, which is itself dependent on intricate interactions with its niche components. Aging is associated with both cell-intrinsic and niche-mediated changes, which can be the result of transcriptional, posttranscriptional, or posttranslational alterations in MuSCs or in the components of their niche. The interplay between cell intrinsic alterations in MuSCs and changes in the stem cell niche environment during aging and its impact on the number and the function of MuSCs is an important emerging area of research. In this review, we discuss whether the decline in the regenerative potential of MuSCs with age is the cause or the consequence of aging skeletal muscle. Understanding the effect of aging on MuSCs and the individual components of their niche is critical to develop effective therapeutic approaches to diminish or reverse the age-related defects in muscle regeneration.
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Affiliation(s)
- Korin Sahinyan
- Department of Human Genetics, McGill University, Montréal, QC, Canada.,Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada
| | - Felicia Lazure
- Department of Human Genetics, McGill University, Montréal, QC, Canada.,Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada
| | - Darren M Blackburn
- Department of Human Genetics, McGill University, Montréal, QC, Canada.,Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada
| | - Vahab D Soleimani
- Department of Human Genetics, McGill University, Montréal, QC, Canada.,Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada
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16
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Zamfirescu AM, Yatsenko AS, Shcherbata HR. Notch signaling sculpts the stem cell niche. Front Cell Dev Biol 2022; 10:1027222. [PMID: 36605720 PMCID: PMC9810114 DOI: 10.3389/fcell.2022.1027222] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022] Open
Abstract
Adult stem cells depend on their niches for regulatory signaling that controls their maintenance, division, and their progeny differentiation. While communication between various types of stem cells and their niches is becoming clearer, the process of stem cell niche establishment is still not very well understood. Model genetic organisms provide simplified systems to address various complex questions, for example, how is a stem cell niche formed? What signaling cascades induce the stem cell niche formation? Are the mechanisms of stem cell niche formation conserved? Notch signaling is an evolutionarily conserved pathway first identified in fruit flies, crucial in fate acquisition and spatiotemporal patterning. While the core logic behind its activity is fairly simple and requires direct cell-cell interaction, it reaches an astonishing complexity and versatility by combining its different modes of action. Subtleties such as equivalency between communicating cells, their physical distance, receptor and ligand processing, and endocytosis can have an effect on the way the events unfold, and this review explores some important general mechanisms of action, later on focusing on its involvement in stem cell niche formation. First, looking at invertebrates, we will examine how Notch signaling induces the formation of germline stem cell niche in male and female Drosophila. In the developing testis, a group of somatic gonadal precursor cells receive Delta signals from the gut, activating Notch signaling and sealing their fate as niche cells even before larval hatching. Meanwhile, the ovarian germline stem cell niche is built later during late larval stages and requires a two-step process that involves terminal filament formation and cap cell specification. Intriguingly, double security mechanisms of Notch signaling activation coordinated by the soma or the germline control both steps to ensure the robustness of niche assembly. Second, in the vast domains of mammalian cellular signaling, there is an emerging picture of Notch being an active player in a variety of tissues in health and disease. Notch involvement has been shown in stem cell niche establishment in multiple organs, including the brain, muscle, and intestine, where the stem cell niches are essential for the maintenance of adult stem cells. But adult stem cells are not the only cells looking for a home. Cancer stem cells use Notch signaling at specific stages to gain an advantage over endogenous tissue and overpower it, at the same time acquiring migratory and invasive abilities to claim new tissues (e.g., bone) as their territory. Moreover, in vitro models such as organoids reveal similar Notch employment when it comes to the developing stem cell niches. Therefore, a better understanding of the processes regulating stem cell niche assembly is key for the fields of stem cell biology and regenerative medicines.
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Affiliation(s)
| | | | - Halyna R. Shcherbata
- Mount Desert Island Biological Laboratory, Bar Harbor, ME, United States,*Correspondence: Halyna R. Shcherbata,
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17
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Sun H, Shen L, Zhang P, Lin F, Ma J, Wu Y, Yu H, Sun L. Inhibition of High-Temperature Requirement Protein A2 Protease Activity Represses Myogenic Differentiation via UPRmt. Int J Mol Sci 2022; 23:ijms231911761. [PMID: 36233059 PMCID: PMC9569504 DOI: 10.3390/ijms231911761] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/09/2022] [Accepted: 09/14/2022] [Indexed: 12/02/2022] Open
Abstract
Skeletal muscles require muscle satellite cell (MuSC) differentiation to facilitate the replenishment and repair of muscle fibers. A key step in this process is called myogenic differentiation. The differentiation ability of MuSCs decreases with age and can result in sarcopenia. Although mitochondria have been reported to be involved in myogenic differentiation by promoting a bioenergetic remodeling, little is known about the interplay of mitochondrial proteostasis and myogenic differentiation. High-temperature-requirement protein A2 (HtrA2/Omi) is a protease that regulates proteostasis in the mitochondrial intermembrane space (IMS). Mice deficient in HtrA2 protease activity show a distinct phenotype of sarcopenia. To investigate the role of IMS proteostasis during myogenic differentiation, we treated C2C12 myoblasts with UCF101, a specific inhibitor of HtrA2 during differentiation process. A key step in this process is called myogenic differentiation. The differentiation ability of MuSCs decreases with age and can result in sarcopenia. Further, CHOP, p-eIF2α, and other mitochondrial unfolded protein response (UPRmt)-related proteins are upregulated. Therefore, we suggest that imbalance of mitochondrial IMS proteostasis acts via a retrograde signaling pathway to inhibit myogenic differentiation via the UPRmt pathway. These novel mechanistic insights may have implications for the development of new strategies for the treatment of sarcopenia.
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Affiliation(s)
| | | | | | | | | | | | - Huimei Yu
- Correspondence: (H.Y.); (L.S.); Tel.: +86-0431-8561-9495 (H.Y. & L.S.)
| | - Liankun Sun
- Correspondence: (H.Y.); (L.S.); Tel.: +86-0431-8561-9495 (H.Y. & L.S.)
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18
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Rahmati M, McCarthy JJ, Malakoutinia F. Myonuclear permanence in skeletal muscle memory: a systematic review and meta-analysis of human and animal studies. J Cachexia Sarcopenia Muscle 2022; 13:2276-2297. [PMID: 35961635 PMCID: PMC9530508 DOI: 10.1002/jcsm.13043] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 05/24/2022] [Accepted: 06/13/2022] [Indexed: 12/09/2022] Open
Abstract
One aspect of skeletal muscle memory is the ability of a previously trained muscle to hypertrophy more rapidly following a period of detraining. Although the molecular basis of muscle memory remains to be fully elucidated, one potential mechanism thought to mediate muscle memory is the permanent retention of myonuclei acquired during the initial phase of hypertrophic growth. However, myonuclear permanence is debated and would benefit from a meta-analysis to clarify the current state of the field for this important aspect of skeletal muscle plasticity. The objective of this study was to perform a meta-analysis to assess the permanence of myonuclei associated with changes in physical activity and ageing. When available, the abundance of satellite cells (SCs) was also considered given their potential influence on changes in myonuclear abundance. One hundred forty-seven peer-reviewed articles were identified for inclusion across five separate meta-analyses; (1-2) human and rodent studies assessed muscle response to hypertrophy; (3-4) human and rodent studies assessed muscle response to atrophy; and (5) human studies assessed muscle response with ageing. Skeletal muscle hypertrophy was associated with higher myonuclear content that was retained in rodents, but not humans, with atrophy (SMD = -0.60, 95% CI -1.71 to 0.51, P = 0.29, and MD = 83.46, 95% CI -649.41 to 816.32, P = 0.82; respectively). Myonuclear and SC content were both lower following atrophy in humans (MD = -11, 95% CI -0.19 to -0.03, P = 0.005, and SMD = -0.49, 95% CI -0.77 to -0.22, P = 0.0005; respectively), although the response in rodents was affected by the type of muscle under consideration and the mode of atrophy. Whereas rodent myonuclei were found to be more permanent regardless of the mode of atrophy, atrophy of ≥30% was associated with a reduction in myonuclear content (SMD = -1.02, 95% CI -1.53 to -0.51, P = 0.0001). In humans, sarcopenia was accompanied by a lower myonuclear and SC content (MD = 0.47, 95% CI 0.09 to 0.85, P = 0.02, and SMD = 0.78, 95% CI 0.37-1.19, P = 0.0002; respectively). The major finding from the present meta-analysis is that myonuclei are not permanent but are lost during periods of atrophy and with ageing. These findings do not support the concept of skeletal muscle memory based on the permanence of myonuclei and suggest other mechanisms, such as epigenetics, may have a more important role in mediating this aspect of skeletal muscle plasticity.
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Affiliation(s)
- Masoud Rahmati
- Department of Physical Education and Sport Sciences, Faculty of Literature and Human SciencesLorestan UniversityKhorramabadIran
| | - John J. McCarthy
- Department of PhysiologyUniversity of KentuckyLexingtonKYUSA
- Center for Muscle BiologyUniversity of KentuckyLexingtonKYUSA
| | - Fatemeh Malakoutinia
- Department of Physical Education and Sport Sciences, Faculty of Literature and Human SciencesLorestan UniversityKhorramabadIran
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19
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Effect of Massage Therapy in Regulating Wnt/β-Catenin Pathway on Retarding Denervated Muscle Atrophy in Rabbits. J Manipulative Physiol Ther 2022. [DOI: 10.1016/j.jmpt.2022.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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20
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Torcinaro A, Cappetta D, De Santa F, Telesca M, Leigheb M, Berrino L, Urbanek K, De Angelis A, Ferraro E. Ranolazine Counteracts Strength Impairment and Oxidative Stress in Aged Sarcopenic Mice. Metabolites 2022; 12:663. [PMID: 35888787 PMCID: PMC9316887 DOI: 10.3390/metabo12070663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/04/2022] [Accepted: 07/11/2022] [Indexed: 12/02/2022] Open
Abstract
Sarcopenia is defined as the loss of muscle mass associated with reduced strength leading to poor quality of life in elderly people. The decline of skeletal muscle performance is characterized by bioenergetic impairment and severe oxidative stress, and does not always strictly correlate with muscle mass loss. We chose to investigate the ability of the metabolic modulator Ranolazine to counteract skeletal muscle dysfunctions that occur with aging. For this purpose, we treated aged C57BL/6 mice with Ranolazine/vehicle for 14 days and collected the tibialis anterior and gastrocnemius muscles for histological and gene expression analyses, respectively. We found that Ranolazine treatment significantly increased the muscle strength of aged mice. At the histological level, we found an increase in centrally nucleated fibers associated with an up-regulation of genes encoding MyoD, Periostin and Osteopontin, thus suggesting a remodeling of the muscle even in the absence of physical exercise. Notably, these beneficial effects of Ranolazine were also accompanied by an up-regulation of antioxidant and mitochondrial genes as well as of NADH-dehydrogenase activity, together with a more efficient protection from oxidative damage in the skeletal muscle. These data indicate that the protection of muscle from oxidative stress by Ranolazine might represent a valuable approach to increase skeletal muscle strength in elderly populations.
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Affiliation(s)
- Alessio Torcinaro
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council of Italy (CNR), Via Ercole Ramarini, 32, Monterotondo, 00015 Rome, Italy; (A.T.); (F.D.S.)
- Istituto Dermopatico dell’Immacolata (IDI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Immunology Laboratory, Via Monti di Creta, 104, 00167 Rome, Italy
| | - Donato Cappetta
- Department of Experimental Medicine, Division of Pharmacology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.C.); (M.T.); (L.B.); (A.D.A.)
| | - Francesca De Santa
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council of Italy (CNR), Via Ercole Ramarini, 32, Monterotondo, 00015 Rome, Italy; (A.T.); (F.D.S.)
| | - Marialucia Telesca
- Department of Experimental Medicine, Division of Pharmacology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.C.); (M.T.); (L.B.); (A.D.A.)
| | - Massimiliano Leigheb
- Orthopaedics and Traumatology Unit, “Maggiore della Carità” Hospital, Department of Health Sciences, University of Piemonte Orientale (UPO), 28100 Novara, Italy;
| | - Liberato Berrino
- Department of Experimental Medicine, Division of Pharmacology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.C.); (M.T.); (L.B.); (A.D.A.)
| | - Konrad Urbanek
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80138 Naples, Italy;
- CEINGE-Advanced Biotechnologies, 80138 Naples, Italy
| | - Antonella De Angelis
- Department of Experimental Medicine, Division of Pharmacology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.C.); (M.T.); (L.B.); (A.D.A.)
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21
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Nunan E, Wright CL, Semola OA, Subramanian M, Balasubramanian P, Lovern PC, Fancher IS, Butcher JT. Obesity as a premature aging phenotype - implications for sarcopenic obesity. GeroScience 2022; 44:1393-1405. [PMID: 35471692 PMCID: PMC9213608 DOI: 10.1007/s11357-022-00567-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 04/10/2022] [Indexed: 12/15/2022] Open
Abstract
Obesity and aging have both seen dramatic increases in prevalence throughout society. This review seeks to highlight common pathologies that present with obesity, along with the underlying risk factors, that have remarkable similarity to what is observed in the aged. These include skeletal muscle dysfunction (loss of quantity and quality), significant increases in adiposity, systemic alterations to autonomic dysfunction, reduction in nitric oxide bioavailability, increases in oxidant stress and inflammation, dysregulation of glucose homeostasis, and mitochondrial dysfunction. This review is organized by the aforementioned indices and succinctly highlights literature that demonstrates similarities between the aged and obese phenotypes in both human and animal models. As aging is an inevitability and obesity prevalence is unlikely to significantly decrease in the near future, these two phenotypes will ultimately combine as a multidimensional syndrome (a pathology termed sarcopenic obesity). Whether the pre-mature aging indices accompanying obesity are additive or synergistic upon entering aging is not yet well defined, but the goal of this review is to illustrate the potential consequences of a double aged phenotype in sarcopenic obesity. Clinically, the modifiable risk factors could be targeted specifically in obesity to allow for increased health span in the aged and sarcopenic obese populations.
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Affiliation(s)
- Emily Nunan
- College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
| | - Carson L Wright
- College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
| | - Oluwayemisi A Semola
- College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, USA
| | - Madhan Subramanian
- College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, USA
| | - Priya Balasubramanian
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Pamela C Lovern
- College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, USA
| | - Ibra S Fancher
- Department of Kinesiology and Applied Physiology, College of Health Sciences, University of Delaware, Newark, DE, USA
| | - Joshua T Butcher
- College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA.
- Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, USA.
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22
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Williams K, Yokomori K, Mortazavi A. Heterogeneous Skeletal Muscle Cell and Nucleus Populations Identified by Single-Cell and Single-Nucleus Resolution Transcriptome Assays. Front Genet 2022; 13:835099. [PMID: 35646075 PMCID: PMC9136090 DOI: 10.3389/fgene.2022.835099] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/25/2022] [Indexed: 11/13/2022] Open
Abstract
Single-cell RNA-seq (scRNA-seq) has revolutionized modern genomics, but the large size of myotubes and myofibers has restricted use of scRNA-seq in skeletal muscle. For the study of muscle, single-nucleus RNA-seq (snRNA-seq) has emerged not only as an alternative to scRNA-seq, but as a novel method providing valuable insights into multinucleated cells such as myofibers. Nuclei within myofibers specialize at junctions with other cell types such as motor neurons. Nuclear heterogeneity plays important roles in certain diseases such as muscular dystrophies. We survey current methods of high-throughput single cell and subcellular resolution transcriptomics, including single-cell and single-nucleus RNA-seq and spatial transcriptomics, applied to satellite cells, myoblasts, myotubes and myofibers. We summarize the major myonuclei subtypes identified in homeostatic and regenerating tissue including those specific to fiber type or at junctions with other cell types. Disease-specific nucleus populations were found in two muscular dystrophies, FSHD and Duchenne muscular dystrophy, demonstrating the importance of performing transcriptome studies at the single nucleus level in muscle.
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Affiliation(s)
- Katherine Williams
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, United States
- Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, United States
| | - Kyoko Yokomori
- Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, United States
| | - Ali Mortazavi
- Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, United States
- Center for Complex Biological Systems, University of California, Irvine, Irvine, CA, United States
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23
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Hsu WB, Lin SJ, Hung JS, Chen MH, Lin CY, Hsu WH, Hsu WWR. Effect of resistance training on satellite cells in old mice - a transcriptome study : implications for sarcopenia. Bone Joint Res 2022; 11:121-133. [PMID: 35188421 PMCID: PMC8882320 DOI: 10.1302/2046-3758.112.bjr-2021-0079.r2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Aims The decrease in the number of satellite cells (SCs), contributing to myofibre formation and reconstitution, and their proliferative capacity, leads to muscle loss, a condition known as sarcopenia. Resistance training can prevent muscle loss; however, the underlying mechanisms of resistance training effects on SCs are not well understood. We therefore conducted a comprehensive transcriptome analysis of SCs in a mouse model. Methods We compared the differentially expressed genes of SCs in young mice (eight weeks old), middle-aged (48-week-old) mice with resistance training intervention (MID+ T), and mice without exercise (MID) using next-generation sequencing and bioinformatics. Results After the bioinformatic analysis, the PI3K-Akt signalling pathway and the regulation of actin cytoskeleton in particular were highlighted among the top ten pathways with the most differentially expressed genes involved in the young/MID and MID+ T/MID groups. The expression of Gng5, Atf2, and Rtor in the PI3K-Akt signalling pathway was higher in the young and MID+ T groups compared with the MID group. Similarly, Limk1, Arhgef12, and Araf in the regulation of the actin cytoskeleton pathway had a similar bias. Moreover, the protein expression profiles of Atf2, Rptor, and Ccnd3 in each group were paralleled with the results of NGS. Conclusion Our results revealed that age-induced muscle loss might result from age-influenced genes that contribute to muscle development in SCs. After resistance training, age-impaired genes were reactivated, and age-induced genes were depressed. The change fold in these genes in the young/MID mice resembled those in the MID + T/MID group, suggesting that resistance training can rejuvenate the self-renewing ability of SCs by recovering age-influenced genes to prevent sarcopenia. Cite this article: Bone Joint Res 2022;11(2):121–133.
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Affiliation(s)
- Wei-Bin Hsu
- Sports Medicine Center, Chang Gung Memorial Hospital Chiayi Branch, Puzi, Taiwan
| | - Shih-Jie Lin
- Department of Orthopaedic Surgery, New Taipei City Municipal Tucheng Hospital, New Taipei City, Taiwan.,Bone and Joint Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Ji-Shiuan Hung
- Department of Orthopaedic Surgery, Chang Gung Memorial Hospital Chiayi Branch, Chiayi, Taiwan
| | - Mei-Hsin Chen
- Department of Orthopaedic Surgery, Chang Gung Memorial Hospital Chiayi Branch, Chiayi, Taiwan.,Chang Gung University, Taoyuan, Taiwan
| | - Che-Yi Lin
- Institute of Cellular and Organismic Biology Academia Sinica, Taipei, Taiwan
| | - Wei-Hsiu Hsu
- Department of Orthopaedic Surgery, Chang Gung Memorial Hospital Chiayi Branch, Chiayi, Taiwan.,Chang Gung University, Taoyuan, Taiwan
| | - Wen-Wei Robert Hsu
- Sports Medicine Center, Chang Gung Memorial Hospital Chiayi Branch, Puzi, Taiwan.,Department of Orthopaedic Surgery, Chang Gung Memorial Hospital Chiayi Branch, Chiayi, Taiwan.,Chang Gung University, Taoyuan, Taiwan
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24
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Sasaki KI, Fukumoto Y. Sarcopenia as a comorbidity of cardiovascular disease. J Cardiol 2021; 79:596-604. [PMID: 34906433 DOI: 10.1016/j.jjcc.2021.10.013] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 12/27/2022]
Abstract
Sarcopenia, the lowered skeletal muscle mass, weakened skeletal muscle strength, and reduced physical performance with aging, is a component of frailty and high-risk factor for falls, resulting in an increase in mortality. In cardiovascular disease (CVD) patients, systemic inflammation, oxidative stress, overactivation of ubiquitin-proteasome system, endothelial dysfunction, lowering muscle blood flow, impaired glucose tolerance, hormonal changes, and physical inactivity possibly contribute to CVD-related sarcopenia. Prevalence of sarcopenia and osteosarcopenia, which is osteopenia and sarcopenia coexisting together, seems to be higher in CVD patients than in community-dwelling adults, suggesting the necessity of early diagnosis and prevention of CVD-related sarcopenia. Atrial stiffness, coronary artery calcification score, and serum vitamin D levels may be of help as the biomarkers to suspect sarcopenia, and renin-angiotensin-aldosterone system inhibitors may play a role in the medical prevention and treatment of CVD-related sarcopenia. There are few reports to convince the efficacies of dietary and antioxidant supplementation on sarcopenia at present, whereas aerobic and resistance training exercises have been recognized as an effective strategy to prevent and treat sarcopenia.
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Affiliation(s)
- Ken-Ichiro Sasaki
- Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
| | - Yoshihiro Fukumoto
- Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
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Englund DA, Zhang X, Aversa Z, LeBrasseur NK. Skeletal muscle aging, cellular senescence, and senotherapeutics: Current knowledge and future directions. Mech Ageing Dev 2021; 200:111595. [PMID: 34742751 PMCID: PMC8627455 DOI: 10.1016/j.mad.2021.111595] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 12/16/2022]
Abstract
Cellular senescence is a state of cell cycle arrest induced by several forms of metabolic stress. Senescent cells accumulate with advancing age and have a distinctive phenotype, characterized by profound chromatin alterations and a robust senescence-associated secretory phenotype (SASP) that exerts negative effects on tissue health, both locally and systemically. In preclinical models, pharmacological agents that eliminate senescent cells (senotherapeutics) restore health and youthful properties in multiple tissues. To date, however, very little is understood about the vulnerability of terminally-differentiated skeletal muscle fibers and the resident mononuclear cells that populate the interstitial microenvironment of skeletal muscle to senescence, and their contribution to the onset and progression of skeletal muscle loss and dysfunction with aging. Scientific advances in these areas have the potential to highlight new therapeutic approaches to optimize late-life muscle health. To this end, this review highlights the current evidence and the key questions that need to be addressed to advance the field's understanding of cellular senescence as a mediator of skeletal muscle aging and the potential for emerging senescent cell-targeting therapies to counter age-related deficits in muscle mass, strength, and function. This article is part of the Special Issue - Senolytics - Edited by Joao Passos and Diana Jurk.
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Affiliation(s)
- Davis A Englund
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA; Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA
| | - Xu Zhang
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA; Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA
| | - Zaira Aversa
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA; Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA
| | - Nathan K LeBrasseur
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA; Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
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26
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Gerrard JC, Hay JP, Adams RN, Williams JC, Huot JR, Weathers KM, Marino JS, Arthur ST. Current Thoughts of Notch's Role in Myoblast Regulation and Muscle-Associated Disease. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph182312558. [PMID: 34886282 PMCID: PMC8657396 DOI: 10.3390/ijerph182312558] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/17/2021] [Accepted: 11/23/2021] [Indexed: 12/25/2022]
Abstract
The evolutionarily conserved signaling pathway Notch is unequivocally essential for embryogenesis. Notch’s contribution to the muscle repair process in adult tissue is complex and obscure but necessary. Notch integrates with other signals in a functional antagonist manner to direct myoblast activity and ultimately complete muscle repair. There is profound recent evidence describing plausible mechanisms of Notch in muscle repair. However, the story is not definitive as evidence is slowly emerging that negates Notch’s importance in myoblast proliferation. The purpose of this review article is to examine the prominent evidence and associated mechanisms of Notch’s contribution to the myogenic repair phases. In addition, we discuss the emerging roles of Notch in diseases associated with muscle atrophy. Understanding the mechanisms of Notch’s orchestration is useful for developing therapeutic targets for disease.
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Affiliation(s)
- Jeffrey C. Gerrard
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - Jamison P. Hay
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - Ryan N. Adams
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - James C. Williams
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - Joshua R. Huot
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Kaitlin M. Weathers
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - Joseph S. Marino
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
| | - Susan T. Arthur
- Department of Applied Physiology, Health and Clinical Sciences, University of North Carolina-Charlotte, Charlotte, NC 28223, USA; (J.C.G.); (J.P.H.); (R.N.A.); (J.C.W.III); (K.M.W.); (J.S.M.)
- Correspondence:
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Opportunities and Challenges in Stem Cell Aging. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1341:143-175. [PMID: 33748933 DOI: 10.1007/5584_2021_624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Studying aging, as a physiological process that can cause various pathological phenotypes, has attracted lots of attention due to its increasing burden and prevalence. Therefore, understanding its mechanism to find novel therapeutic alternatives for age-related disorders such as neurodegenerative and cardiovascular diseases is essential. Stem cell senescence plays an important role in aging. In the context of the underlying pathways, mitochondrial dysfunction, epigenetic and genetic alterations, and other mechanisms have been studied and as a consequence, several rejuvenation strategies targeting these mechanisms like pharmaceutical interventions, genetic modification, and cellular reprogramming have been proposed. On the other hand, since stem cells have great potential for disease modeling, they have been useful for representing aging and its associated disorders. Accordingly, the main mechanisms of senescence in stem cells and promising ways of rejuvenation, along with some examples of stem cell models for aging are introduced and discussed. This review aims to prepare a comprehensive summary of the findings by focusing on the most recent ones to shine a light on this area of research.
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28
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Jayawardena TU, Kim SY, Jeon YJ. Sarcopenia; functional concerns, molecular mechanisms involved, and seafood as a nutritional intervention - review article. Crit Rev Food Sci Nutr 2021; 63:1983-2003. [PMID: 34459311 DOI: 10.1080/10408398.2021.1969889] [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: 12/13/2022]
Abstract
The fundamental basis for the human function is provided by skeletal muscle. Advancing age causes selective fiber atrophy, motor unit loss, and hybrid fiber formation resulting in hampered mass and strength, thus referred to as sarcopenia. Influence on the loss of independence of aged adults, contribute toward inclined healthcare costs conveys the injurious impact. The current understating of age-related skeletal muscle changes are addressed in this review, and further discusses mechanisms regulating protein turnover, although they do not completely define the process yet. Moreover, the reduced capacity of muscle regeneration due to impairment of satellite cell activation and proliferation with neuronal, immunological, hormonal factors were brought into the light of attention. Nevertheless, complete understating of sarcopenia requires disentangling it from disuse and disease. Nutritional intervention is considered a potentially preventable factor contributing to sarcopenia. Seafood is a crucial player in the fight against hunger and malnutrition, where it consists of macro and micronutrients. Hence, the review shed light on seafood as a nutritional intrusion in the treatment and prevention of sarcopenia. Understanding multiple factors will provide therapeutic targets in the prevention, treatment, and overcoming adverse effects of sarcopenia.
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Affiliation(s)
- Thilina U Jayawardena
- Department of Marine Life Sciences, Jeju National University, Jeju, Republic of Korea
| | - Seo-Young Kim
- Division of Practical Application, Honam National Institute of Biological Resources, Mokpo-si, Korea
| | - You-Jin Jeon
- Department of Marine Life Sciences, Jeju National University, Jeju, Republic of Korea.,Marine Science Institute, Jeju National University, Jeju, Jeju Self-Governing Province, Republic of Korea
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29
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Fernandez C, Burgos A, Morales D, Rosales-Rojas R, Canelo J, Vergara-Jaque A, Vieira GV, da Silva RAA, Sales KU, Conboy MJ, Bae EJ, Park KS, Torres VA, Garrido M, Cerda O, Conboy IM, Cáceres M. TMPRSS11a is a novel age-altered, tissue specific regulator of migration and wound healing. FASEB J 2021; 35:e21597. [PMID: 33908663 DOI: 10.1096/fj.202002253rrr] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 03/23/2021] [Accepted: 03/31/2021] [Indexed: 01/11/2023]
Abstract
Aging is a gradual biological process characterized by a decrease in cellular and organism functions. Aging-related processes involve changes in the expression and activity of several proteins. Here, we identified the transmembrane protease serine 11a (TMPRSS11a) as a new age-specific protein that plays an important role in skin wound healing. TMPRSS11a levels increased with age in rodent and human skin and gingival samples. Strikingly, overexpression of TMPRSS11a decreased cell migration and spreading, and inducing cellular senescence. Mass spectrometry, bioinformatics, and functional analyses revealed that TMPRSS11a interacts with integrin β1 through an RGD sequence contained within the C-terminal domain and that this motif was relevant for cell migration. Moreover, TMPRSS11a was associated with cellular senescence, as shown by overexpression and downregulation experiments. In agreement with tissue-specific expression of TMPRSS11a, shRNA-mediated downregulation of this protein improved wound healing in the skin, but not in the skeletal muscle of old mice, where TMPRSS11a is undetectable. Collectively, these findings indicate that TMPRSS11a is a tissue-specific factor relevant for wound healing, which becomes elevated with aging, promoting cellular senescence and inhibiting cell migration and skin repair.
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Affiliation(s)
- Christian Fernandez
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Andres Burgos
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Diego Morales
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Roberto Rosales-Rojas
- Center for Bioinformatics, Simulation and Modeling (CBSM), Faculty of Engineering, Universidad de Talca, Talca, Chile
| | - Javiera Canelo
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Ariela Vergara-Jaque
- Center for Bioinformatics, Simulation and Modeling (CBSM), Faculty of Engineering, Universidad de Talca, Talca, Chile.,Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile
| | - Gabriel Viliod Vieira
- Departament of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | | | - Katiuchia Uzzun Sales
- Departament of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Michael J Conboy
- Department of Bioengineering and QB3 Institute, University of California, Berkeley, CA, USA
| | - Eun Ji Bae
- Department of Physiology, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Kang-Sik Park
- Department of Physiology, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Vicente A Torres
- Institute for Research in Dental Sciences, Faculty of Dentistry, Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago, Chile
| | - Mauricio Garrido
- Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago, Chile
| | - Oscar Cerda
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile.,The Wound Repair, Treatment and Health (WoRTH) Initiative, Santiago, Chile
| | - Irina M Conboy
- Department of Bioengineering and QB3 Institute, University of California, Berkeley, CA, USA
| | - Mónica Cáceres
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile.,The Wound Repair, Treatment and Health (WoRTH) Initiative, Santiago, Chile
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30
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Gustafsson T, Ulfhake B. Sarcopenia: What Is the Origin of This Aging-Induced Disorder? Front Genet 2021; 12:688526. [PMID: 34276788 PMCID: PMC8285098 DOI: 10.3389/fgene.2021.688526] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 05/10/2021] [Indexed: 01/03/2023] Open
Abstract
We here review the loss of muscle function and mass (sarcopenia) in the framework of human healthspan and lifespan, and mechanisms involved in aging. The rapidly changing composition of the human population will impact the incidence and the prevalence of aging-induced disorders such as sarcopenia and, henceforth, efforts to narrow the gap between healthspan and lifespan should have top priority. There are substantial knowledge gaps in our understanding of aging. Heritability is estimated to account for only 25% of lifespan length. However, as we push the expected lifespan at birth toward those that we consider long-lived, the genetics of aging may become increasingly important. Linkage studies of genetic polymorphisms to both the susceptibility and aggressiveness of sarcopenia are still missing. Such information is needed to shed light on the large variability in clinical outcomes between individuals and why some respond to interventions while others do not. We here make a case for the concept that sarcopenia has a neurogenic origin and that in manifest sarcopenia, nerve and myofibers enter into a vicious cycle that will escalate the disease progression. We point to gaps in knowledge, for example the crosstalk between the motor axon, terminal Schwann cell, and myofiber in the denervation processes that leads to a loss of motor units and muscle weakness. Further, we argue that the operational definition of sarcopenia should be complemented with dynamic metrics that, along with validated biomarkers, may facilitate early preclinical diagnosis of individuals vulnerable to develop advanced sarcopenia. We argue that preventive measures are likely to be more effective to counter act aging-induced disorders than efforts to treat manifest clinical conditions. To achieve compliance with a prescription of preventive measures that may be life-long, we need to identify reliable predictors to design rational and convincing interventions.
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Affiliation(s)
- Thomas Gustafsson
- Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Brun Ulfhake
- Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
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31
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Strasser B, Wolters M, Weyh C, Krüger K, Ticinesi A. The Effects of Lifestyle and Diet on Gut Microbiota Composition, Inflammation and Muscle Performance in Our Aging Society. Nutrients 2021; 13:nu13062045. [PMID: 34203776 PMCID: PMC8232643 DOI: 10.3390/nu13062045] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/09/2021] [Accepted: 06/11/2021] [Indexed: 01/10/2023] Open
Abstract
Living longer is associated with an increased risk of chronic diseases, including impairments of the musculoskeletal and immune system as well as metabolic disorders and certain cancers, each of which can negatively affect the relationship between host and microbiota up to the occurrence of dysbiosis. On the other hand, lifestyle factors, including regular physical exercise and a healthy diet, can affect skeletal muscle and immune aging positively at all ages. Accordingly, health benefits could partly depend on the effect of such interventions that influence the biodiversity and functionality of intestinal microbiota. In the present review, we first discuss the physiological effects of aging on the gut microbiota, immune system, and skeletal muscle. Secondly, we describe human epidemiological evidence about the associations between physical activity and fitness and the gut microbiota composition in older adults. The third part highlights the relevance and restorative mechanisms of immune protection through physical activity and specific exercise interventions during aging. Fourth, we present important research findings on the effects of exercise and protein as well as other nutrients on skeletal muscle performance in older adults. Finally, we provide nutritional recommendations to prevent malnutrition and support healthy active aging with a focus on gut microbiota. Key nutrition-related concerns include the need for adequate energy and protein intake for preventing low muscle mass and a higher demand for specific nutrients (e.g., dietary fiber, polyphenols and polyunsaturated fatty acids) that can modify the composition, diversity, and metabolic capacity of the gut microbiota, and may thus provide a practical means of enhancing gut and systemic immune function.
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Affiliation(s)
- Barbara Strasser
- Medical Faculty, Sigmund Freud Private University, 1020 Vienna, Austria
- Correspondence:
| | - Maike Wolters
- Leibniz Institute for Prevention Research and Epidemiology–BIPS, 28359 Bremen, Germany;
| | - Christopher Weyh
- Department of Exercise Physiology and Sports Therapy, University of Giessen, 35394 Giessen, Germany; (C.W.); (K.K.)
| | - Karsten Krüger
- Department of Exercise Physiology and Sports Therapy, University of Giessen, 35394 Giessen, Germany; (C.W.); (K.K.)
| | - Andrea Ticinesi
- Geriatric-Rehabilitation Department, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy;
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
- Microbiome Research Hub, University of Parma, 43124 Parma, Italy
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32
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Zhang N, Ji J, Zhou D, Liu X, Zhang X, Liu Y, Xiang W, Wang M, Zhang L, Wang G, Huang B, Lu J, Zhang Y. The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling. Int J Mol Sci 2021; 22:E849. [PMID: 33467780 PMCID: PMC7830992 DOI: 10.3390/ijms22020849] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/06/2021] [Accepted: 01/12/2021] [Indexed: 01/07/2023] Open
Abstract
Chemotherapy is one of the most common strategies for tumor treatment but often associated with post-therapy tumor recurrence. While chemotherapeutic drugs are known to induce tumor cell senescence, the roles and mechanisms of senescence in tumor recurrence remain unclear. In this study, we used doxorubicin to induce senescence in breast cancer cells, followed by culture of breast cancer cells with conditional media of senescent breast cancer cells (indirect co-culture) or directly with senescent breast cancer cells (direct co-culture). We showed that breast cancer cells underwent the epithelial-mesenchymal transition (EMT) to a greater extent and had stronger migration and invasion ability in the direct co-culture compared with that in the indirect co-culture model. Moreover, in the direct co-culture model, non-senescent breast cancer cells facilitated senescent breast cancer cells to escape and re-enter into the cell cycle. Meanwhile, senescent breast cancer cells regained tumor cell characteristics and underwent EMT after direct co-culture. We found that the Notch signaling was activated in both senescent and non-senescent breast cancer cells in the direct co-culture group. Notably, the EMT process of senescent and adjacent breast cancer cells was blocked upon inhibition of Notch signaling with N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester (DAPT) in the direct co-cultures. In addition, DAPT inhibited the lung metastasis of the co-cultured breast cancer cells in vivo. Collectively, data arising from this study suggest that both senescent and adjacent non-senescent breast cancer cells developed EMT through activating Notch signaling under conditions of intratumoral heterogeneity caused by chemotherapy, which infer the possibility that Notch inhibitors used in combination with chemotherapeutic agents may become an effective treatment strategy.
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Affiliation(s)
- Na Zhang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
| | - Jiafei Ji
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Dandan Zhou
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
| | - Xuan Liu
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Xinglin Zhang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
| | - Yingqi Liu
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Weifang Xiang
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Meida Wang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
| | - Lian Zhang
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Guannan Wang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
| | - Baiqu Huang
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Jun Lu
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Yu Zhang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
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33
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Bae JH, Hong M, Jeong HJ, Kim H, Lee SJ, Ryu D, Bae GU, Cho SC, Lee YS, Krauss RS, Kang JS. Satellite cell-specific ablation of Cdon impairs integrin activation, FGF signalling, and muscle regeneration. J Cachexia Sarcopenia Muscle 2020; 11:1089-1103. [PMID: 32103583 PMCID: PMC7432598 DOI: 10.1002/jcsm.12563] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 12/04/2019] [Accepted: 02/09/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Perturbation in cell adhesion and growth factor signalling in satellite cells results in decreased muscle regenerative capacity. Cdon (also called Cdo) is a component of cell adhesion complexes implicated in myogenic differentiation, but its role in muscle regeneration remains to be determined. METHODS We generated inducible satellite cell-specific Cdon ablation in mice by utilizing a conditional Cdon allele and Pax7 CreERT2 . To induce Cdon ablation, mice were intraperitoneally injected with tamoxifen (tmx). Using cardiotoxin-induced muscle injury, the effect of Cdon depletion on satellite cell function was examined by histochemistry, immunostaining, and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. Isolated myofibers or myoblasts were utilized to determine stem cell function and senescence. To determine pathways related to Cdon deletion, injured muscles were subjected to RNA sequencing analysis. RESULTS Satellite cell-specific Cdon ablation causes impaired muscle regeneration with fibrosis, likely attributable to decreased proliferation, and senescence, of satellite cells. Cultured Cdon-depleted myofibers exhibited 32 ± 9.6% of EdU-positive satellite cells compared with 58 ± 4.4% satellite cells in control myofibers (P < 0.05). About 32.5 ± 3.7% Cdon-ablated myoblasts were positive for senescence-associated β-galactosidase (SA-β-gal) while only 3.6 ± 0.5% of control satellite cells were positive (P < 0.001). Transcriptome analysis of muscles at post-injury Day 4 revealed alterations in genes related to mitogen-activated protein kinase signalling (P < 8.29 e-5 ) and extracellular matrix (P < 2.65 e-24 ). Consistent with this, Cdon-depleted tibialis anterior muscles had reduced phosphorylated extracellular signal-regulated kinase (p-ERK) protein levels and expression of ERK targets, such as Fos (0.23-fold) and Egr1 (0.31-fold), relative to mock-treated control muscles (P < 0.001). Cdon-depleted myoblasts exhibited impaired ERK activation in response to basic fibroblast growth factor. Cdon ablation resulted in decreased and/or mislocalized integrin β1 activation in satellite cells (weak or mislocalized integrin1 in tmx = 38.7 ± 1.9%, mock = 21.5 ± 6%, P < 0.05), previously linked with reduced fibroblast growth factor (FGF) responsiveness in aged satellite cells. In mechanistic studies, Cdon interacted with and regulated cell surface localization of FGFR1 and FGFR4, likely contributing to FGF responsiveness of satellite cells. Satellite cells from a progeria model, Zmpste24-/- myofibers, showed decreased Cdon levels (Cdon-positive cells in Zmpste24-/- = 63.3 ± 11%, wild type = 90 ± 7.7%, P < 0.05) and integrin β1 activation (weak or mislocalized integrin β1 in Zmpste24-/- = 64 ± 6.9%, wild type = 17.4 ± 5.9%, P < 0.01). CONCLUSIONS Cdon deficiency in satellite cells causes impaired proliferation of satellite cells and muscle regeneration via aberrant integrin and FGFR signalling.
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Affiliation(s)
- Ju-Hyeon Bae
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Mingi Hong
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hyeon-Ju Jeong
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Hyebeen Kim
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Sang-Jin Lee
- Research Institute of Pharmaceutical Science, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
| | - Dongryeol Ryu
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.,Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea
| | - Gyu-Un Bae
- Research Institute of Pharmaceutical Science, College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
| | - Sung Chun Cho
- Well Aging Research Center, DGIST, Daegu, Republic of Korea
| | - Young-Sam Lee
- Well Aging Research Center, DGIST, Daegu, Republic of Korea.,Department of New Biology, DGIST, Daegu, Republic of Korea
| | - Robert S Krauss
- Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jong-Sun Kang
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.,Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea
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34
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Park HS, Son HY, Choi MH, Son Y, Kim S, Hong HS, Park JU. Adipose-derived stem cells attenuate atopic dermatitis-like skin lesions in NC/Nga mice. Exp Dermatol 2020; 28:300-307. [PMID: 30688372 DOI: 10.1111/exd.13895] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 12/25/2018] [Accepted: 01/21/2019] [Indexed: 12/16/2022]
Abstract
There is an unmet need in novel therapeutics for atopic dermatitis (AD). We examined the effects of autologous adipose-derived stem cells (ADSCs) on AD-like skin lesions induced by the application of 2,4-dinitrochlorobenzene (DNCB) in NC/Nga mice. Autologous ADSCs and ADSC-conditioned medium (ADSC-CM) were injected intralesionally three times. Clinical severity and histopathologic findings were compared in sham naïve control, saline-treated, ADSC-treated, ADSC-CM-treated and 2.5% cortisone lotion-applied animals. The severity index, skin thickness, mast cell number, as well as expression levels of thymic stromal lymphopoietin, CD45, chemoattractant receptor-homologous molecule, chemokine ligand 9 and chemokine ligand 20 were significantly lower in mice treated with ADSC, ADSC-CM, or 2.5% cortisone lotion. Tissue levels of interferon-γ as well as serum levels of interleukin-33 and immunoglobulin E levels were also decreased in those groups. We conclude that autologous ADSCs improved DNCB-induced AD-like skin lesions in NC/Nga mice by reducing inflammation associated with Th2 immune response and interferon-γ.
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Affiliation(s)
- Hyun-Sun Park
- Department of Dermatology, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Hye-Youn Son
- Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Min-Ha Choi
- Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Youngsook Son
- Department of Genetic Engineering, Graduate School of Biotechnology, Kyung Hee University, Seoul, Korea
| | - Sundong Kim
- Senior Science Life Corporation, Seoul, Korea
| | - Hyun-Sook Hong
- Kyung Hee Institute for Regenerative Medicine, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Ji-Ung Park
- Department of Plastic and Reconstructive Surgery, Seoul National University Boramae Medical Center, Seoul, Korea
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35
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Zacharewicz E, Kalanon M, Murphy RM, Russell AP, Lamon S. MicroRNA-99b-5p downregulates protein synthesis in human primary myotubes. Am J Physiol Cell Physiol 2020; 319:C432-C440. [PMID: 32608991 DOI: 10.1152/ajpcell.00172.2020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
microRNAs (miRNAs) are important regulators of cellular homeostasis and exert their effect by directly controlling protein expression. We have previously reported an age-dependent negative association between microRNA-99b (miR-99b-5p) expression and muscle protein synthesis in human muscle in vivo. Here we investigated the role of miR-99b-5p as a potential negative regulator of protein synthesis via inhibition of mammalian target for rapamycin (MTOR) signaling in human primary myocytes. Overexpressing miR-99b-5p in human primary myotubes from young and old subjects significantly decreased protein synthesis with no effect of donor age. A binding interaction between miR-99b-5p and its putative binding site within the MTOR 3'-untranslated region (UTR) was confirmed in C2C12 myoblasts. The observed decline in protein synthesis was, however, not associated with a suppression of the MTOR protein but of its regulatory associated protein of mTOR complex 1 (RPTOR). These results demonstrate that modulating the expression levels of a miRNA can regulate protein synthesis in human muscle cells and provide a potential mechanism for muscle wasting in vivo.
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Affiliation(s)
- Evelyn Zacharewicz
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Ming Kalanon
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Robyn M Murphy
- Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, Victoria, Australia
| | - Aaron P Russell
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - Séverine Lamon
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
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36
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Uremic Sarcopenia: Clinical Evidence and Basic Experimental Approach. Nutrients 2020; 12:nu12061814. [PMID: 32570738 PMCID: PMC7353433 DOI: 10.3390/nu12061814] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/27/2020] [Accepted: 06/16/2020] [Indexed: 12/17/2022] Open
Abstract
Sustained physical activity extends healthy life years while a lower activity due to sarcopenia can reduce them. Sarcopenia is defined as a decrease in skeletal muscle mass and strength due not only to aging, but also from a variety of debilitating chronic illnesses such as cancer and heart failure. Patients with chronic kidney disease (CKD), who tend to be cachexic and in frail health, may develop uremic sarcopenia or uremic myopathy due to an imbalance between muscle protein synthesis and catabolism. Here, we review clinical evidence indicating reduced physical activity as renal function deteriorates and explore evidence-supported therapeutic options focusing on nutrition and physical training. In addition, although sarcopenia is a clinical concept and difficult to recapitulate in basic research, several in vivo approaches have been attempted, such as rodent subtotal nephrectomy representing both renal dysfunction and muscle weakness. This review highlights molecular mechanisms and promising interventions for uremic sarcopenia that were revealed through basic research. Extensive study is still needed to cast light on the many aspects of locomotive organ impairments in CKD and explore the ways that diet and exercise therapies can improve both outcomes and quality of life at every level.
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Heterochronic parabiosis regulates the extent of cellular senescence in multiple tissues. GeroScience 2020; 42:951-961. [PMID: 32285290 DOI: 10.1007/s11357-020-00185-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 03/24/2020] [Indexed: 12/14/2022] Open
Abstract
An increase in the burden of senescent cells in tissues with age contributes to driving aging and the onset of age-related diseases. Genetic and pharmacologic elimination of senescent cells extends both health span and life span in mouse models. Heterochronic parabiosis in mice has been used to identify bloodborne, circulating pro- and anti-geronic factors able to drive or slow aging, respectively. However, whether factors in the circulation also regulate senescence is unknown. Here, we measured the expression of senescence and senescence-associated secretory phenotype (SASP) markers in multiple tissues from 4- to 18-month-old male mice that were either isochronically or heterochronically paired for 2 months. In heterochronic parabionts, the age-dependent increase in senescence and SASP marker expression was reduced in old mice exposed to a young environment, while senescence markers were concurrently increased in young heterochronic parabionts. These findings were supported by geropathology analysis using the Geropathology Grading Platform that showed a trend toward reduced hepatic lesions in old heterochronic parabionts. In summary, these results demonstrate that senescence is regulated in part by circulating geronic factors and suggest that one of the possible mediators of the rejuvenating effects with heterochronic parabiosis is through the reduction of the senescent cell burden.
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Stem Cell Aging in Skeletal Muscle Regeneration and Disease. Int J Mol Sci 2020; 21:ijms21051830. [PMID: 32155842 PMCID: PMC7084237 DOI: 10.3390/ijms21051830] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/04/2020] [Accepted: 03/04/2020] [Indexed: 12/19/2022] Open
Abstract
Skeletal muscle comprises 30-40% of the weight of a healthy human body and is required for voluntary movements in humans. Mature skeletal muscle is formed by multinuclear cells, which are called myofibers. Formation of myofibers depends on the proliferation, differentiation, and fusion of muscle progenitor cells during development and after injury. Muscle progenitor cells are derived from muscle satellite (stem) cells (MuSCs), which reside on the surface of the myofiber but beneath the basement membrane. MuSCs play a central role in postnatal maintenance, growth, repair, and regeneration of skeletal muscle. In sedentary adult muscle, MuSCs are mitotically quiescent, but are promptly activated in response to muscle injury. Physiological and chronological aging induces MuSC aging, leading to an impaired regenerative capability. Importantly, in pathological situations, repetitive muscle injury induces early impairment of MuSCs due to stem cell aging and leads to early impairment of regeneration ability. In this review, we discuss (1) the role of MuSCs in muscle regeneration, (2) stem cell aging under physiological and pathological conditions, and (3) prospects related to clinical applications of controlling MuSCs.
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Luca E, Turcekova K, Hartung A, Mathes S, Rehrauer H, Krützfeldt J. Genetic deletion of microRNA biogenesis in muscle cells reveals a hierarchical non-clustered network that controls focal adhesion signaling during muscle regeneration. Mol Metab 2020; 36:100967. [PMID: 32240622 PMCID: PMC7139120 DOI: 10.1016/j.molmet.2020.02.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 02/19/2020] [Accepted: 02/20/2020] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Decreased muscle mass is a major contributor to age-related morbidity, and strategies to improve muscle regeneration during ageing are urgently needed. Our aim was to identify the subset of relevant microRNAs (miRNAs) that partake in critical aspects of muscle cell differentiation, irrespective of computational predictions, genomic clustering or differential expression of the miRNAs. METHODS miRNA biogenesis was deleted in primary myoblasts using a tamoxifen-inducible CreLox system and combined with an add-back miRNA library screen. RNA-seq experiments, cellular signalling events, and glycogen synthesis, along with miRNA inhibitors, were performed in human primary myoblasts. Muscle regeneration in young and aged mice was assessed using the cardiotoxin (CTX) model. RESULTS We identified a hierarchical non-clustered miRNA network consisting of highly (miR-29a), moderately (let-7) and mildly active (miR-125b, miR-199a, miR-221) miRNAs that cooperate by directly targeting members of the focal adhesion complex. Through RNA-seq experiments comparing single versus combinatorial inhibition of the miRNAs, we uncovered a fundamental feature of this network, that miRNA activity inversely correlates to miRNA cooperativity. During myoblast differentiation, combinatorial inhibition of the five miRNAs increased activation of focal adhesion kinase (FAK), AKT, and p38 mitogen-activated protein kinase (MAPK), and improved myotube formation and insulin-dependent glycogen synthesis. Moreover, antagonizing the miRNA network in vivo following CTX-induced muscle regeneration enhanced muscle mass and myofiber formation in young and aged mice. CONCLUSION Our results provide novel insights into the dynamics of miRNA cooperativity and identify a miRNA network as therapeutic target for impaired focal adhesion signalling and muscle regeneration during ageing.
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Affiliation(s)
- Edlira Luca
- Division of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, 8091, Switzerland
| | - Katarina Turcekova
- Division of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, 8091, Switzerland; Competence Center Personalized Medicine UZH/ETH, ETH Zurich and University of Zurich, 8091, Switzerland
| | - Angelika Hartung
- Division of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, 8091, Switzerland
| | - Sebastian Mathes
- Division of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, 8091, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, 8091, Switzerland
| | - Hubert Rehrauer
- Functional Genomics Center Zurich UZH/ETH, ETH Zurich and University of Zurich, 8091, Switzerland
| | - Jan Krützfeldt
- Division of Endocrinology, Diabetes, and Clinical Nutrition, University Hospital Zurich, 8091, Switzerland; Competence Center Personalized Medicine UZH/ETH, ETH Zurich and University of Zurich, 8091, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, 8091, Switzerland.
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Chaillou T, Sanna I, Kadi F. Glutamine-stimulated in vitro hypertrophy is preserved in muscle cells from older women. Mech Ageing Dev 2020; 187:111228. [PMID: 32142719 DOI: 10.1016/j.mad.2020.111228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 02/27/2020] [Accepted: 02/29/2020] [Indexed: 01/16/2023]
Abstract
Age-related loss of muscle mass may result from reduced protein synthesis stimulation in response to anabolic stimuli, such as amino acid (AA) supplementation. The exact etiology of anabolic resistance to AA remains unclear. Therefore, the aim of this study was to investigate the anabolic response [cell size, protein synthesis and mechanistic target of rapamycin (mTOR) pathway] to the AA glutamine (a strong anabolic AA highly present in skeletal muscle) in myotubes obtained from 8 young (YW; 21-35 yrs) and 8 older (OW; 65-70 yrs) healthy women. This in vitro model of human primary myogenic cells explores the intrinsic behavior of muscle cells, while excluding potential influences of external factors. We showed that despite lower muscle mass, strength and cardiorespiratory fitness in OW compared to YW, myotube size (myotube diameter and area) and protein synthesis were not altered in OW, and glutamine-induced myotube hypertrophy and protein synthesis were preserved in OW. Apart from a lower glutamine-induced increase in P70S6 kinase phosphorylation in OW, no significant differences in other components of the mTOR pathway were observed between groups. Altogether, our data support the idea that the intrinsic capacity of muscle cells to respond to glutamine stimulation is preserved in healthy older women.
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Affiliation(s)
- Thomas Chaillou
- Department of Health Sciences, Örebro University, Örebro, Sweden.
| | - Igor Sanna
- Department of Health Sciences, Örebro University, Örebro, Sweden.
| | - Fawzi Kadi
- Department of Health Sciences, Örebro University, Örebro, Sweden.
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Wang MJ, Chen J, Chen F, Liu Q, Sun Y, Yan C, Yang T, Bao Y, Hu YP. Rejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging. Aging Dis 2019; 10:871-882. [PMID: 31440391 PMCID: PMC6675530 DOI: 10.14336/ad.2018.1119] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 11/19/2018] [Indexed: 12/22/2022] Open
Abstract
Although aging is a physiological process, it has raised interest in the science of aging and rejuvenation because of the increasing burden on the rapidly aging global population. With advanced age, there is a decline in homeostatic maintenance and regenerative responsiveness to the injury of various tissues, thereby contributing to the incidence of age-related diseases. The primary cause of the functional declines that occur along with aging is considered to be the exhaustion of stem cell functions in their corresponding tissues. Age-related changes in the systemic environment, the niche, and stem cells contribute to this loss. Thus, the reversal of stem cell aging at the cellular level might lead to the rejuvenation of the animal at an organismic level and the prevention of aging, which would be critical for developing new therapies for age-related dysfunction and diseases. Here, we will explore the effects of aging on stem cells in different tissues. The focus of this discussion is on pro-youth interventions that target intrinsic stem cell properties, environmental niche component, systemic factors, and senescent cellular clearance, which are promising for developing strategies related to the reversal of aged stem cell function and optimizing tissue repair processes.
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Affiliation(s)
- Min-Jun Wang
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Jiajia Chen
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Fei Chen
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Qinggui Liu
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Yu Sun
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Chen Yan
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Tao Yang
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
| | - Yiwen Bao
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China.,2Department of Diagnostic radiology, University of Hong Kong, Hong Kong 999077, China
| | - Yi-Ping Hu
- 1Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai 200433, China
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Belli R, Bonato A, De Angelis L, Mirabilii S, Ricciardi MR, Tafuri A, Molfino A, Gorini S, Leigheb M, Costelli P, Caruso M, Muscaritoli M, Ferraro E. Metabolic Reprogramming Promotes Myogenesis During Aging. Front Physiol 2019; 10:897. [PMID: 31354530 PMCID: PMC6636331 DOI: 10.3389/fphys.2019.00897] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 06/27/2019] [Indexed: 12/23/2022] Open
Abstract
Sarcopenia is the age-related progressive loss of skeletal muscle mass and strength finally leading to poor physical performance. Impaired myogenesis contributes to the pathogenesis of sarcopenia, while mitochondrial dysfunctions are thought to play a primary role in skeletal muscle loss during aging. Here we studied the link between myogenesis and metabolism. In particular, we analyzed the effect of the metabolic modulator trimetazidine (TMZ) on myogenesis in aging. We show that reprogramming the metabolism by TMZ treatment for 12 consecutive days stimulates myogenic gene expression in skeletal muscle of 22-month-old mice. Our data also reveal that TMZ increases the levels of mitochondrial proteins and stimulates the oxidative metabolism in aged muscles, this finding being in line with our previous observations in cachectic mice. Moreover, we show that, besides TMZ also other types of metabolic modulators (i.e., 5-Aminoimidazole-4-Carboxamide Ribofuranoside-AICAR) can stimulate differentiation of skeletal muscle progenitors in vitro. Overall, our results reveal that reprogramming the metabolism stimulates myogenesis while triggering mitochondrial proteins synthesis in vivo during aging. Together with the previously reported ability of TMZ to increase muscle strength in aged mice, these new data suggest an interesting non-invasive therapeutic strategy which could contribute to improving muscle quality and neuromuscular communication in the elderly, and counteracting sarcopenia.
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Affiliation(s)
- Roberta Belli
- Department of Translational and Precision Medicine (Formerly Department of Clinical Medicine), Sapienza University of Rome, Rome, Italy
| | - Agnese Bonato
- Institute of Cell Biology and Neurobiology, National Research Council (CNR), Rome, Italy
| | | | - Simone Mirabilii
- Hematology, Sant’Andrea University Hospital, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Maria Rosaria Ricciardi
- Hematology, Sant’Andrea University Hospital, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Agostino Tafuri
- Hematology, Sant’Andrea University Hospital, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessio Molfino
- Department of Translational and Precision Medicine (Formerly Department of Clinical Medicine), Sapienza University of Rome, Rome, Italy
| | - Stefania Gorini
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Rome, Italy
| | - Massimiliano Leigheb
- Department of Orthopaedics and Traumatology, Hospital “Maggiore della Carità”, Università del Piemonte Orientale (UPO), Novara, Italy
| | - Paola Costelli
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Maurizia Caruso
- Institute of Cell Biology and Neurobiology, National Research Council (CNR), Rome, Italy
| | - Maurizio Muscaritoli
- Department of Translational and Precision Medicine (Formerly Department of Clinical Medicine), Sapienza University of Rome, Rome, Italy
| | - Elisabetta Ferraro
- Department of Orthopaedics and Traumatology, Hospital “Maggiore della Carità”, Università del Piemonte Orientale (UPO), Novara, Italy
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
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Zhu P, Zhang C, Gao Y, Wu F, Zhou Y, Wu WS. The transcription factor Slug represses p16 Ink4a and regulates murine muscle stem cell aging. Nat Commun 2019; 10:2568. [PMID: 31189923 PMCID: PMC6561969 DOI: 10.1038/s41467-019-10479-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 05/14/2019] [Indexed: 01/21/2023] Open
Abstract
Activation of the p16Ink4a-associated senescence pathway during aging breaks muscle homeostasis and causes degenerative muscle disease by irreversibly dampening satellite cell (SC) self-renewal capacity. Here, we report that the zinc-finger transcription factor Slug is highly expressed in quiescent SCs of mice and functions as a direct transcriptional repressor of p16Ink4a. Loss of Slug promotes derepression of p16Ink4a in SCs and accelerates the entry of SCs into a fully senescent state upon damage-induced stress. p16Ink4a depletion partially rescues defects in Slug-deficient SCs. Furthermore, reduced Slug expression is accompanied by p16Ink4a accumulation in aged SCs. Slug overexpression ameliorates aged muscle regeneration by enhancing SC self-renewal through active repression of p16Ink4a transcription. Our results identify a cell-autonomous mechanism underlying functional defects of SCs at advanced age. As p16Ink4a dysregulation is the chief cause for regenerative defects of human geriatric SCs, these findings highlight Slug as a potential therapeutic target for aging-associated degenerative muscle disease. Muscle regeneration depends on self-renewal of muscle stem cells but how this is regulated on aging is unclear. Here, the authors identify Slug as regulating p16Ink4a in quiescent muscle stem cells, and when Slug expression reduces in aged stem cells, p16Ink4a accumulates, causing regenerative defects.
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Affiliation(s)
- Pei Zhu
- Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Chunping Zhang
- Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Yongxing Gao
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Furen Wu
- Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Yalu Zhou
- Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Wen-Shu Wu
- Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
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44
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Jung HW, Choi JH, Jo T, Shin H, Suh JM. Systemic and Local Phenotypes of Barium Chloride Induced Skeletal Muscle Injury in Mice. Ann Geriatr Med Res 2019; 23:83-89. [PMID: 32743293 PMCID: PMC7387593 DOI: 10.4235/agmr.19.0012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/12/2019] [Accepted: 05/25/2019] [Indexed: 01/10/2023] Open
Abstract
Skeletal muscle regeneration in mice has traditionally been studied using local freeze burn or snake venom injection models. More recently, a barium chloride (BaCl2)-induced muscle injury model has been established and is gaining popularity due to the relatively simple procedure and accessibility to required reagents. Here we sought to characterize the local and systemic effects of BaCl2-induced muscle injury. For this study, a 1.2% BaCl2 solution was locally administered to the tibialis anterior (TA) muscle and local and systemic phenotypes were analyzed at different timepoints. When 50 μL of the solution was injected unilaterally in the TA muscle, no mortality was observed. However, when 100 μL of the solution was injected, 50% of the mice died within 24 h. Serum analysis of the mice injected with 50 μL of BaCl2 solution at days 1 and 7 revealed changes resembling rhabdomyolysis. At day 1 post-injection of 50 μL of the BaCl2 solution, acute suppurative inflammation was observed in gross examination of the TA muscle, while extensive hemorrhagic necrosis was revealed on histological examination. At day 7, regenerated myofibers with centralized nuclei appeared with the resolution of acute inflammatory infiltration and the muscle tissue displayed molecular signatures consistent with myofiber differentiation. The overall muscle injury and regeneration phenotypes in the BaCl2-induced muscle injury model were similar to those of the well-established freeze burn or snake venom injection models. Taken together, the BaCl2-induced muscle injury model is comparable to conventional muscle injury and regeneration models, with considerations for possible systemic effects.
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Affiliation(s)
- Hee-Won Jung
- Graduate School of Medical Science and Engineering, Korea Advanced Institute for Science and Technology, Daejeon, Korea
| | - Jin-Hyuk Choi
- Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute for Science and Technology, Daejeon, Korea
| | - Taehee Jo
- Graduate School of Medical Science and Engineering, Korea Advanced Institute for Science and Technology, Daejeon, Korea
| | - Hyemi Shin
- Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute for Science and Technology, Daejeon, Korea
| | - Jae Myoung Suh
- Graduate School of Medical Science and Engineering, Korea Advanced Institute for Science and Technology, Daejeon, Korea
- Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute for Science and Technology, Daejeon, Korea
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Bechshøft CJL, Jensen SM, Schjerling P, Andersen JL, Svensson RB, Eriksen CS, Mkumbuzi NS, Kjaer M, Mackey AL. Age and prior exercise in vivo determine the subsequent in vitro molecular profile of myoblasts and nonmyogenic cells derived from human skeletal muscle. Am J Physiol Cell Physiol 2019; 316:C898-C912. [PMID: 30917034 DOI: 10.1152/ajpcell.00049.2019] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The decline in skeletal muscle regenerative capacity with age is partly attributed to muscle stem cell (satellite cell) dysfunction. Recent evidence has pointed to a strong interaction between myoblasts and fibroblasts, but the influence of age on this interaction is unknown. Additionally, while the native tissue environment is known to determine the properties of myogenic cells in vitro, how the aging process alters this cell memory has not been established at the molecular level. We recruited 12 young and 12 elderly women, who performed a single bout of heavy resistance exercise with the knee extensor muscles of one leg. Five days later, muscle biopsies were collected from both legs, and myogenic cells and nonmyogenic cells were isolated for in vitro experiments with mixed or separated cells and analyzed by immunostaining and RT-PCR. A lower myogenic fusion index was detected in the cells from the old versus young women, in association with differences in gene expression levels of key myogenic regulatory factors and senescence, which were further altered by performing exercise before tissue sampling. Coculture with nonmyogenic cells from the elderly led to a higher myogenic differentiation index compared with nonmyogenic cells from the young. These findings show that the in vitro phenotype and molecular profile of human skeletal muscle myoblasts and fibroblasts is determined by the age and exercise state of the original in vivo environment and help explain how exercise can enhance muscle stem cell function in old age.
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Affiliation(s)
- Cecilie J L Bechshøft
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Simon M Jensen
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Peter Schjerling
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Jesper L Andersen
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Rene B Svensson
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Christian S Eriksen
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Nonhlanhla S Mkumbuzi
- Division of Exercise Science and Sports Medicine, Department of Human Biology, University of Cape Town, Newlands, South Africa
| | - Michael Kjaer
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Abigail L Mackey
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.,Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
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The Growth Differentiation Factor 11 is Involved in Skin Fibroblast Ageing and is Induced by a Preparation of Peptides and Sugars Derived from Plant Cell Cultures. Mol Biotechnol 2019; 61:209-220. [DOI: 10.1007/s12033-019-00154-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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47
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Franco I, Fernandez-Gonzalo R, Vrtačnik P, Lundberg TR, Eriksson M, Gustafsson T. Healthy skeletal muscle aging: The role of satellite cells, somatic mutations and exercise. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2019; 346:157-200. [DOI: 10.1016/bs.ircmb.2019.03.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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48
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Inflammation-associated miR-155 activates differentiation of muscular satellite cells. PLoS One 2018; 13:e0204860. [PMID: 30273359 PMCID: PMC6166968 DOI: 10.1371/journal.pone.0204860] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 09/14/2018] [Indexed: 11/25/2022] Open
Abstract
Tissue renewal and muscle regeneration largely rely on the proliferation and differentiation of muscle stem cells called muscular satellite cells (MuSCs). MuSCs are normally quiescent, but they are activated in response to various stimuli, such as inflammation. Activated MuSCs proliferate, migrate, differentiate, and fuse to form multinucleate myofibers. Meanwhile, inappropriate cues for MuSC activation induce premature differentiation and bring about stem cell loss. Recent studies revealed that stem cell regulation is disrupted in various aged tissues. We found that the expression of microRNA (miR)-155, which is an inflammation-associated miR, is upregulated in MuSCs of aged muscles, and this upregulation activates the differentiation process through suppression of C/ebpβ, which is an important molecule for maintaining MuSC self-renewal. We also found that Notch1 considerably repressed miR-155 expression, and loss of Notch1 induced miR-155 overexpression. Our findings suggest that miR-155 can act as an activator of muscular differentiation and might be responsible for accelerating aging-associated premature differentiation of MuSCs.
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Heisterberg MF, Andersen JL, Schjerling P, Lund A, Dalskov S, Jønsson AO, Warming N, Fogelstrøm M, Kjaer M, Mackey AL. Losartan has no additive effect on the response to heavy-resistance exercise in human elderly skeletal muscle. J Appl Physiol (1985) 2018; 125:1536-1554. [PMID: 30091666 DOI: 10.1152/japplphysiol.00106.2018] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Our purpose here was to investigate the potential of blocking the angiotensin II type I receptor (AT1R) on the hypertrophy response of elderly human skeletal muscle to 4 mo of heavy-resistance exercise training. Fifty-eight healthy elderly men (+65 yr) were randomized into three groups, consuming either AT1R blocker (losartan, 100 mg/day) or placebo for 4 mo. Two groups performed resistance training (RT) and were treated with either losartan or placebo, and one group did not train but was treated with losartan. Quadriceps muscle biopsies, MR scans, and strength tests were performed at baseline and after 8 and 16 wk. Biopsies were sectioned for immunohistochemistry to determine the number of satellite cells, capillaries, fiber type distribution, and fiber area. Gene expression levels of myostatin, connective tissue, and myogenic signaling pathways were determined by real-time RT-PCR. Four months of heavy-resistance training led in both training groups to expected improvements in quadriceps (∼3-4%) and vastus lateralis (∼5-6%), cross-sectional area, and type II fiber area (∼10-18%), as well as dynamic (∼13%) and isometric (∼19%) quadriceps peak force, but with absolutely no effect of losartan on these outcomes. Furthermore, no changes were seen in satellite cell number with training, and most gene targets failed to show any changes induced by training or losartan treatment. We conclude that there does not appear to be any effect of AT1R blocking in elderly men during 4 mo of resistance training. Therefore, we do not find any support for using AT1R blockers for promoting muscle adaptation to training in humans. NEW & NOTEWORTHY Animal studies have suggested that blocking angiotensin II type I receptor (AT1R) enhances muscle regeneration and prevents disuse atrophy, but studies in humans are limited. Focusing on hypertrophy, satellite cells, and gene expression, we found that AT1R blocking did not result in any greater responses with 4 mo of resistance training. These results do not support previous findings and question the value of blocking AT1R in the context of preserving aging human muscle.
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Affiliation(s)
- Mette Flindt Heisterberg
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Jesper L Andersen
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Peter Schjerling
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Alberte Lund
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Simone Dalskov
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Anders Overgård Jønsson
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Nichlas Warming
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Mathilde Fogelstrøm
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Michael Kjaer
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Abigail L Mackey
- Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.,Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
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Egawa T, Ohno Y, Yokoyama S, Goto A, Ito R, Hayashi T, Goto K. The effect of advanced glycation end products on cellular signaling molecules in skeletal muscle. THE JOURNAL OF PHYSICAL FITNESS AND SPORTS MEDICINE 2018. [DOI: 10.7600/jpfsm.7.229] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Tatsuro Egawa
- Laboratory of Health and Exercise Sciences, Graduate School of Human and Environmental Studies, Kyoto University
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University
- Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University
| | - Yoshitaka Ohno
- Laboratory of Physiology, School of Health Sciences, Toyohashi SOZO University
| | - Shingo Yokoyama
- Laboratory of Physiology, School of Health Sciences, Toyohashi SOZO University
| | - Ayumi Goto
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University
- Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University
| | - Rika Ito
- Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University
| | - Tatsuya Hayashi
- Laboratory of Sports and Exercise Medicine, Graduate School of Human and Environmental Studies, Kyoto University
| | - Katsumasa Goto
- Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University
- Laboratory of Physiology, School of Health Sciences, Toyohashi SOZO University
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