Background: Skeletal muscle atrophy is a prominent characteristic of many disease states, however, the extent of similarities and/or differences in the underpinning mechanisms between atrophying conditions in unclear. Two of the most prevalent and costly atrophic conditions are ageing and disuse, with resistance exercise training (RET) the most effective nonpharmacological countermeasure. We conducted gene-level and network-level meta-analyses to compare transcriptomic signatures of disuse and RET, plus young and older RET to establish the molecular features of, and therapeutic targets against, muscle atrophy in conditions of high socio-economic relevance.
Methods: Integrated gene- 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 from older (≥60 years) m. vastus lateralis muscle subjected to RET (≥3 weeks).
Results: Disuse and RET displayed predominantly distinct 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.
Conclusions: Transcriptional signatures of disuse are not simply the converse of RET, with limited opposing gene profiles. Therefore, the mechanisms of atrophy cannot be derived from studying hypertrophy alone. Moreover, this 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.