SUMMARY
Accumulated fat in skeletal muscle, common in sedentary older individuals, compromises skeletal muscle health and function. Mechanistic understanding of how physical activity levels dictate fat accumulation represents a critical step towards establishment of therapies that promote healthy aging. Using a network paradigm that characterized the transcriptomic response of aged muscle to exercise versus immobilization protocols, this study uncovered a novel molecular cascade that regulates the fate of fibro-adipogenic progenitors (FAPs), the cell population primarily responsible for the fat accumulation. Specifically, gene set enrichment analyses (GSEA) with network propagation revealed Pgc1α as a functional hub of a large gene regulatory network underlying the regulation of FAPs by physical activity. Integrated in silico and in situ approaches to induce Pgc-1α overexpression promoted mitochondrial fatty acid oxidation and inhibited FAPs adipogenesis. These findings suggest that Pgc1α is a master regulator by which physical activity regulates fat accumulation in aged skeletal muscle.
Competing Interest Statement
The authors have declared no competing interest.