Skeletal muscle is a key organ in energy homeostasis owing to its high requirement for nutrients. Heterotrimeric G proteins converge with activated GPCRs to modulate cell-signaling pathways. Here, we report that muscle-specific ablation of Gα13 in mice promotes reprogramming of myofibers to the oxidative type, with resultant increases in mitochondrial biogenesis. Mechanistically, Gα13 and its downstream effector RhoA suppressed nuclear factor of activated T cells 1 (NFATc1), a chief regulator of myofiber conversion, by increasing Rock2-mediated phosphorylation at Ser243. Ser243 phosphorylation of NFATc1 was reduced after exercise, but was higher in obese animals. Consequently, Gα13 ablation in muscles enhanced whole-body energy metabolism, thus affording protection from diet-induced obesity and hepatic steatosis. In the absence of Gα13, Gα12 plays a role in mitochondrial regulation. Mechanistically, Gα12 stabilized SIRT1 protein through induction of USP22 via HIF-1α. Consistently, Gna12-KO mice fed a high-fat diet displayed greater susceptibility to diet-induced liver steatosis and obesity due to decrease in energy expenditure. Thus, Gα12 regulates SIRT1-dependent mitochondrial respiration through HIF-1α-dependent USP22 induction, which contributes to the regulation of mitochondrial energy expenditure.

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