Network‐based systematic dissection of exercise‐induced inhibition of myosteatosis in older individuals.

Key points Accumulated fat in skeletal muscle (i.e. myosteatosis), common in sedentary older individuals, compromises skeletal muscle health and function. A mechanistic understanding of how physical activity levels dictate fat accumulation represents a critical step towards establishment of therapies that promote healthy ageing. Using a network medicine paradigm that characterized the transcriptomic response of aged muscle to exercise <italic>versus</italic> immobilization protocols, this study explored the shared molecular cascade that regulates the fate of fibro‐adipogenic progenitors (FAPs), the cell population primarily responsible for fat accumulation. Specifically, gene set enrichment analyses with network propagation revealed <italic>Pgc‐1α</italic> as a functional hub of a large gene regulatory network underlying the regulation of FAPs by physical activity in aged muscle, but not in young counterparts. Integrated <italic>in silico</italic> and <italic>in situ</italic> approaches to induce <italic>Pgc‐1α</italic> overexpression in aged muscle promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis. These findings suggest that the <italic>Pgc‐1α</italic>–mitochondrial fatty acid oxidation axis is a shared mechanism by which physical activity regulates age‐related myosteatosis. The network medicine paradigm introduced provides mechanistic insight into exercise adaptation in elderly skeletal muscle and offers translational opportunities to advance exercise prescription for older populations. Fat accumulation is a quintessential feature of aged skeletal muscle. While increasing physical activity levels has been proposed as an effective strategy to reduce the fat in skeletal muscle (i.e. myosteatosis), the molecular cascade underlying these benefits has been poorly defined. This study implemented a series of network medicine approaches and uncovered <italic>Pgc‐1α</italic> as a mechanistic driver of the regulation of fibro‐adipogenic progenitors (FAPs) by physical activity. Integrated <italic>in silico</italic> and <italic>in situ</italic> approaches to induce <italic>Pgc‐1α</italic> overexpression promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis. Together, the findings of the current study suggest a novel hypothesis that physical activity reduces myosteatosis via upregulation of <italic>Pgc‐1α</italic>‐mediated mitochondrial fatty acid oxidation and subsequent inhibition of FAP adipogenesis. [ABSTRACT FROM AUTHOR]