Downregulation of microRNA‐494 drives mitochondrial biogenesis and function in trained muscle

MicroRNAs (miRNAs) are key regulators of cellular processes, including mitochondrial function and energy metabolism. This study explores the regulation of miR-494 in skeletal muscle and circulation, investigating its response to exercise training and an acute exercise bout, its association with metabolic disorders, and the effects of electrical pulse stimulation (EPS). In addition, it validates the gene targets and physiological role of miR-494 using gain- and loss-of-function studies in primary human skeletal muscle cells. We demonstrate that miR-494 levels in both skeletal muscle and circulation are influenced by long-term exercise training, which induces adaptive changes, but remain unaffected by an acute bout of exercise. EPS does not alter miR-494 levels in cultured primary human skeletal muscle cells. Moreover, muscle miR-494 levels remain unchanged under various metabolic challenges, including obesity and type 2 diabetes. Genetic manipulation of miR-494 in primary human skeletal muscle cells modulates mitochondrial biogenesis and function, as well as lipid metabolism, through targeting PGC1A and SIRT1. Injection of a miR-494 inhibitor into skeletal muscle of mice supports the role of miR-494 in regulating Pgc1α mRNA, suggesting potential therapeutic implications. These findings highlight miR-494 as a significant modulator of mitochondrial dynamics and energy metabolism in skeletal muscle.