Modelling in vivo skeletal muscle ageing in vitro using three-dimensional bioengineered constructs
Adam P. Sharples
Muscle Cellular and Molecular Physiology Research Group (MCMPRG), Institute for Sport and Physical Activity Research (ISPAR Bedford), University of Bedfordshire, Bedford, UK
Cellular and Molecular Physiology, Musculoskeletal Biology Research Group, School of Sport, Exercise and Health Science, Loughborough University, Loughborough, UK
Search for more papers by this authorDarren J. Player
Muscle Cellular and Molecular Physiology Research Group (MCMPRG), Institute for Sport and Physical Activity Research (ISPAR Bedford), University of Bedfordshire, Bedford, UK
Cellular and Molecular Physiology, Musculoskeletal Biology Research Group, School of Sport, Exercise and Health Science, Loughborough University, Loughborough, UK
Search for more papers by this authorNeil R. W. Martin
Muscle Cellular and Molecular Physiology Research Group (MCMPRG), Institute for Sport and Physical Activity Research (ISPAR Bedford), University of Bedfordshire, Bedford, UK
Cellular and Molecular Physiology, Musculoskeletal Biology Research Group, School of Sport, Exercise and Health Science, Loughborough University, Loughborough, UK
Search for more papers by this authorVivek Mudera
Institute of Orthopaedics and Musculoskeletal Sciences, UCL Division of Surgery & Interventional Science, Stanmore Campus, University College London (UCL), London, UK
Search for more papers by this authorClaire E. Stewart
Faculty of Science and Engineering, Institute for Biomedical Research into Human Movement and Health (IRM), Manchester Metropolitan University, John Dalton Building, Oxford Road, Manchester, UK
Search for more papers by this authorMark P. Lewis
Cellular and Molecular Physiology, Musculoskeletal Biology Research Group, School of Sport, Exercise and Health Science, Loughborough University, Loughborough, UK
Muscle Cellular and Molecular Physiology Research Group (MCMPRG), Institute for Sport and Physical Activity Research (ISPAR Bedford), University of Bedfordshire, Bedford, UK
Cranfield Health, Cranfield University, Cranfield, Bedfordshire, UK
School of Life and Medical Sciences, University College London (UCL), London, UK
Search for more papers by this authorAdam P. Sharples
Muscle Cellular and Molecular Physiology Research Group (MCMPRG), Institute for Sport and Physical Activity Research (ISPAR Bedford), University of Bedfordshire, Bedford, UK
Cellular and Molecular Physiology, Musculoskeletal Biology Research Group, School of Sport, Exercise and Health Science, Loughborough University, Loughborough, UK
Search for more papers by this authorDarren J. Player
Muscle Cellular and Molecular Physiology Research Group (MCMPRG), Institute for Sport and Physical Activity Research (ISPAR Bedford), University of Bedfordshire, Bedford, UK
Cellular and Molecular Physiology, Musculoskeletal Biology Research Group, School of Sport, Exercise and Health Science, Loughborough University, Loughborough, UK
Search for more papers by this authorNeil R. W. Martin
Muscle Cellular and Molecular Physiology Research Group (MCMPRG), Institute for Sport and Physical Activity Research (ISPAR Bedford), University of Bedfordshire, Bedford, UK
Cellular and Molecular Physiology, Musculoskeletal Biology Research Group, School of Sport, Exercise and Health Science, Loughborough University, Loughborough, UK
Search for more papers by this authorVivek Mudera
Institute of Orthopaedics and Musculoskeletal Sciences, UCL Division of Surgery & Interventional Science, Stanmore Campus, University College London (UCL), London, UK
Search for more papers by this authorClaire E. Stewart
Faculty of Science and Engineering, Institute for Biomedical Research into Human Movement and Health (IRM), Manchester Metropolitan University, John Dalton Building, Oxford Road, Manchester, UK
Search for more papers by this authorMark P. Lewis
Cellular and Molecular Physiology, Musculoskeletal Biology Research Group, School of Sport, Exercise and Health Science, Loughborough University, Loughborough, UK
Muscle Cellular and Molecular Physiology Research Group (MCMPRG), Institute for Sport and Physical Activity Research (ISPAR Bedford), University of Bedfordshire, Bedford, UK
Cranfield Health, Cranfield University, Cranfield, Bedfordshire, UK
School of Life and Medical Sciences, University College London (UCL), London, UK
Search for more papers by this authorSummary
Degeneration of skeletal muscle (SkM) with age (sarcopenia) is a major contributor to functional decline, morbidity and mortality. Methodological implications often make it difficult to embark on interventions in already frail and diseased elderly individuals. Using in vitro three-dimensional (3D) bioengineered skeletal muscle constructs that model aged phenotypes and incorporate a representative extracellular matrix (collagen), are under tension, and display morphological and transcript expression of mature skeletal muscle may more accurately characterize the SkM niche. Furthermore, an in vitro model would provide greater experimental manipulation with regard to gene, pharmacological and exercise (mechanical stretch/electrical stimulation) therapies and thus strategies for combating muscle wasting with age. The present study utilized multiple population-doubled (MPD) murine myoblasts compared with parental controls (CON), previously shown to have an aged phenotype in monolayer cultures (Sharples et al., 2011), seeded into 3D type I collagen matrices under uniaxial tension. 3D bioengineered constructs incorporating MPD cells had reduced myotube size and diameter vs. CON constructs. MPD constructs were characterized by reduced peak force development over 24 h after cell seeding, reduced transcript expression of remodelling matrix metalloproteinases, MMP2 and MMP9, with reduced differentiation/hypertrophic potential shown by reduced IGF-I, IGF-IR, IGF-IEa, MGF mRNA. Increased IGFBP2 and myostatin in MPD vs. CON constructs also suggested impaired differentiation/reduced regenerative potential. Overall, 3D bioengineered skeletal muscle constructs represent an in vitro model of the in vivo cell niche with MPD constructs displaying similar characteristics to ageing/atrophied muscle in vivo, thus potentially providing a future test bed for therapeutic interventions to contest muscle degeneration with age.
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