Molecular Transducers of Human Skeletal Muscle Remodeling Under Different Loading States

Loading of skeletal muscle leads to remodeling of myofibrillar and extracellular matrix proteins to withstand metabolic stress and unloading results in the opposite. In humans, the heterogenous response to altered loading greatly complicates molecular modeling of the underpinning processes. We utilized a within-person paired Hypertrophy and Atrophy (‘HypAt’) strategy that reduced response heterogeneity by ~40%. We applied a new genome-wide transcriptome analysis methodology to model mRNA, the 3’ or 5’ untranslated regions (UTR, sites of translation regulation) and proteome-constrained networks. We discovered > 4 times more regulated genes compared with similarly sized studies while 1,000 genes were only modified at their UTRs. A core of 141 genes were consistently modulated in proportion to muscle growth, across three independent studies (n=100). This new model revealed, at a pathway level, direct interactions between the proteome features of exercise-trained muscle, and the molecular processes underpinning muscle aging and insulin sensitivity.