Downregulation of NR4A3 during inactivity alters glucose metabolism and impairs translation in human skeletal muscle

The transcription factor NR4A3 is regulated by exercise and a potent modulator of skeletal muscle metabolism. We report here that physical inactivity decreased skeletal muscle NR4A3 levels, concomitant with mitochondrial function and proteostasis pathways. Silencing of NR4A3 in myotubes decreased glucose oxidation and increased lactate production. This coincided with greater signalling downstream of AMPK and elevated rates of fatty acid oxidation. While NR4A3 silencing reduced protein synthesis, mTORC1 signalling, and ribosomal transcription, overexpression of the canonical NR4A3 protein isoform augmented translation and cellular protein content. Moreover, restoration of NR4A3 levels rescued glucose oxidation in NR4A3-silenced myotubes and restored phosphorylation of mTORC1 substrates. NR4A3 depletion reduced myotube area and altered the abundance of contractile elements. Thus, downregulation of NR4A3 has adverse effects on skeletal muscle metabolism, myotube size, and contractile apparatus by directing mTORC1 signalling and ribosomal biogenesis. Our data demonstrate that NR4A3 controls skeletal muscle atrophy associated with physical inactivity.