Loss of Gα13 exercise‐mimetically reprograms skeletal muscle through Rock2

Abstract

Skeletal muscle is a key organ in energy homeostasis owing to its high requirement for nutrients. Heterotrimeric G proteins converge signals from cell‐surface receptors, potentiating or blunting responses against environmental changes. Here, we report that muscle‐specific deletion of Gα13 promotes reprogramming of myofibers to oxidative type, with resultant increases in mitochondrial biogenesis and cellular respiration. Mechanistically, Gα13 and its downstream effector RhoA suppressed nuclear factor of activated T‐cells 1 (NFATc1), a chief regulator of myofiber conversion, through Rho‐associated kinase 2 (Rock2)‐mediated phosphorylation at Ser243. Ser243 phosphorylation of NFATc1 was reduced after exercise, but was higher in obese animals or diabetic patients. Consequently, Gα13 deletion in muscles enhanced whole‐body energy metabolism and increased insulin sensitivity, thus affording protection from diet‐induced obesity and hepatic steatosis. Our results define Gα13 as a switch regulator of myofiber reprogramming, implying modulations of Gα13 and its downstream effectors in skeletal muscle as a potential therapeutic approach to metabolic diseases.Support or Funding InformationThis work was supported by grants from the National Research Foundation of Korea (NRF), funded by the Korean government (MSIP) (2017K1A1A2004511).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.