Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism
Ja Hyun Koo, … , Cheol Soo Choi, Sang Geon Kim
Ja Hyun Koo, … , Cheol Soo Choi, Sang Geon Kim
Published October 2, 2017; First published September 18, 2017
Citation Information: J Clin Invest. 2017;127(10):3845-3860. https://doi.org/10.1172/JCI92067.
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Research Article Metabolism Muscle biology

Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism

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 to potentiate or blunt responses against environmental changes. Here, we show that muscle-specific ablation of Gα13 in mice promotes reprogramming of myofibers to the 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, by increasing Rho-associated kinase 2–mediated (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 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 that modulations of Gα13 and its downstream effectors in skeletal muscle are a potential therapeutic approach to treating metabolic diseases.

Authors

Ja Hyun Koo, Tae Hyun Kim, Shi-Young Park, Min Sung Joo, Chang Yeob Han, Cheol Soo Choi, Sang Geon Kim

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Figure 1

Skeletal muscle Gα13 expression correlates with metabolic alterations.

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Skeletal muscle Gα13 expression correlates with metabolic alterations. (...
(A) Tissue distribution of Gα (GNA) subunits in microarray and RNA-seq experiments using human tissues. The data were extracted from GEO GSE10347 and GSE30611. FPKM, fragments per kilobase of transcript per million mapped reads. (B and C) qPCR analysis of Gα13 in mouse tissues. C57BL/6 mice were fasted overnight prior to sacrifice (n = 3 each). Different sets of mice were used in B and C. TA, tibialis anterior; EDL, extensor digitorum longus; Quad, quadriceps. (D) Relative expression of Gα subunits in human quadriceps before or after exercise. Data were extracted from GEO GSE9103. (E and F) Levels of Gα13 protein (E) and transcripts (F) in soleus muscle before and 4 hours after 1 hour of exercise (n = 4 each). (G) Immunostaining for Gα13 in skeletal muscles of a healthy volunteer and a diabetic patient. Scale bar: 100 μm. (H) Immunoblots for Gα13 and GTP-bound RhoA in tibialis anterior muscles from mice fed a normal diet (ND) or a HFD for 13 weeks (n = 5–6 each). For E and H, each blot was obtained from samples run on parallel gels. For B, C, and E–H, data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by Student’s t test.