Mechanical loading of tissue engineered skeletal muscle prevents dexamethasone induced myotube atrophy
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ORIGINAL PAPER
Mechanical loading of tissue engineered skeletal muscle prevents dexamethasone induced myotube atrophy Kathryn W. Aguilar‑Agon1 · Andrew J. Capel1 · Jacob W. Fleming1 · Darren J. Player2 · Neil R. W. Martin1 · Mark P. Lewis1 Received: 11 June 2020 / Accepted: 4 September 2020 © The Author(s) 2020
Abstract Skeletal muscle atrophy as a consequence of acute and chronic illness, immobilisation, muscular dystrophies and aging, leads to severe muscle weakness, inactivity and increased mortality. Mechanical loading is thought to be the primary driver for skeletal muscle hypertrophy, however the extent to which mechanical loading can offset muscle catabolism has not been thoroughly explored. In vitro 3D-models of skeletal muscle provide a controllable, high throughput environment and mitigating many of the ethical and methodological constraints present during in vivo experimentation. This work aimed to determine if mechanical loading would offset dexamethasone (DEX) induced skeletal muscle atrophy, in muscle engineered using the C2C12 murine cell line. Mechanical loading successfully offset myotube atrophy and functional degeneration associated with DEX regardless of whether the loading occurred before or after 24 h of DEX treatment. Furthermore, mechanical load prevented increases in MuRF-1 and MAFbx mRNA expression, critical regulators of muscle atrophy. Overall, we demonstrate the application of tissue engineered muscle to study skeletal muscle health and disease, offering great potential for future use to better understand treatment modalities for skeletal muscle atrophy. Keywords Dexamethasone · C2C12 · Hypertrophy · Skeletal muscle · Myotubes · Ubiquitin–proteasome
Introduction Skeletal muscle atrophy is known to occur as a consequence of acute and chronic illnesses (such as sepsis, chronic kidney disease and cancer cachexia), immobilisation or bed rest, muscular dystrophies, and aging. This can lead to severe muscle weakness, inactivity and reduced quality of life for the patients. Whilst the imbalance caused in all common forms of atrophy between protein synthesis and degradation is paramount in the aetiology of muscle atrophy (Jackman and Kandarian 2004; Lecker et al. 2004), the underpinning Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10974-020-09589-0) contains supplementary material, which is available to authorized users. * Mark P. Lewis [email protected] 1
School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough LE11 3TU, UK
Division of Surgery and Interventional Science, Faculty of Medical Sciences, University College London, London, UK
2
molecular mechanisms have yet to be fully defined. Nevertheless, under conditions of muscle atrophy the primary degradative pathway in skeletal muscle is the ubiquitin proteasome pathway (UPP). Transcriptional profiling has identified Muscle Atrophy F-box (MAFbx) and Muscle RING-finger protein-1 (MuRF-1) as two muscle-specific ubiquitin ligases, which express
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