Abstract
BackgroundSkeletal muscle atrophy manifests across numerous diseases; however, the extent of similarities/differences in causal mechanisms between atrophying conditions in unclear. Ageing and disuse represent two of the most prevalent and costly atrophic conditions, with resistance exercise training (RET) being the most effective lifestyle countermeasure. We employed gene‐level and network‐level meta‐analyses to contrast transcriptomic signatures of disuse and RET, plus young and older RET to establish a consensus on the molecular features of, and therapeutic targets against, muscle atrophy in conditions of high socio‐economic relevance.MethodsIntegrated gene‐level and network‐level meta‐analysis was performed on publicly available microarray data sets generated from young (18–35 years) m. vastus lateralis muscle subjected to disuse (unilateral limb immobilization or bed rest) lasting ≥7 days or RET lasting ≥3 weeks, and resistance‐trained older (≥60 years) muscle.ResultsDisuse and RET displayed predominantly separate transcriptional responses, and transcripts altered across conditions were mostly unidirectional. However, disuse and RET induced directly inverted expression profiles for mitochondrial function and translation regulation genes, with COX4I1, ENDOG, GOT2, MRPL12, and NDUFV2, the central hub components of altered mitochondrial networks, and ZMYND11, a hub gene of altered translation regulation. A substantial number of genes (n = 140) up‐regulated post‐RET in younger muscle were not similarly up‐regulated in older muscle, with young muscle displaying a more pronounced extracellular matrix (ECM) and immune/inflammatory gene expression response. Both young and older muscle exhibited similar RET‐induced ubiquitination/RNA processing gene signatures with associated PWP1, PSMB1, and RAF1 hub genes.ConclusionsDespite limited opposing gene profiles, transcriptional signatures of disuse are not simply the converse of RET. Thus, the mechanisms of unloading cannot be derived from studying muscle loading alone and provides a molecular basis for understanding why RET fails to target all transcriptional features of disuse. Loss of RET‐induced ECM mechanotransduction and inflammatory profiles might also contribute to suboptimal ageing muscle adaptations to RET. Disuse and age‐dependent molecular candidates further establish a framework for understanding and treating disuse/ageing atrophy.
Highlights
Skeletal muscle atrophy manifests across numerous diseases; the extent of similarities/differences in causal mechanisms between atrophying conditions in unclear
Enriched functional terms for differentially expressed (DE) gene lists and differentially regulated consensus modules are given in Tables S3 and S4, respectively
We further screened our base candidate gene lists for module hub genes contained within the corresponding rank–rank hypergeometric overlap (RRHO) gene list (Table S5)
Summary
Skeletal muscle atrophy manifests across numerous diseases; the extent of similarities/differences in causal mechanisms between atrophying conditions in unclear. We employed gene-level and network-level meta-analyses to contrast transcriptomic signatures of disuse and RET, plus young and older RET to establish a consensus on the molecular features of, and therapeutic targets against, muscle atrophy in conditions of high socio-economic relevance. As the largest tissue in the body, the functions of skeletal muscle extend beyond locomotion and structural support,[1] providing storage for glucose[2] and lipids[3] used for energy production and providing the largest amino acid reservoir for systemic release in times of organismal need.[4] muscle atrophy associates with increased risk of frailty-related falls,[5,6] increased incidence of metabolic disease,[7] and death.[8] muscle atrophy is a prominent feature of several of the World’s key health challenges including ageing, cardiovascular disease, obesity, diabetes, and cancer.[7,9] As a result, the most recently available estimates of annual cost for age-related atrophy (sarcopenia) alone is $18.5 billion (USA, 2000)[10] and £2.5 billion (UK, 2019).[11] Despite the high socio-economic relevance of maintaining healthy muscle mass, the mechanisms regulating muscle atrophy and, hypertrophy are incompletely understood. There is, a need to establish robust molecular features of atrophy and hypertrophy in order to efficiently promote targeted therapeutics with efficacy across atrophying conditions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
