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 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 2

Loss of Gα13 causes a skeletal muscle switch to the oxidative phenotype.

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Loss of Gα13 causes a skeletal muscle switch to the oxidative phenotype....
(A) PCR analysis using tail genomic DNA from WT C57BL/6 mice, WT littermates (Gna13fl/fl), and Gα13-MKO (Ckmm-Cre+ Gna13fl/fl) mice. (B) qPCR analyses of 3 samples each and immunoblots for Gα13 in the indicated tissues. Twelve-week-old mice were fasted overnight prior to sacrifice. (C) Global gene expression analysis. RNA was isolated from soleus muscles from mice of the indicated genotypes and hybridized to Affymetrix exon arrays. (D) Dorsal view of skinned WT and Gα13-MKO mice 35 weeks after birth. Enhanced larger images are shown in Supplemental Figure 1B. (E) H&E staining and wet weight of hind limb muscles. G, gastrocnemius; S, soleus. (F) Representative immunohistochemical images of tibialis anterior muscles from 12-week-old WT or Gα13-MKO mice using specific antibodies for each of the fiber types (n = 3). Myofiber types in the indicated tissues were quantified. (G) Representative histochemical staining of SDH enzymatic activity in tibialis anterior muscles (n = 3–4 per genotype). Myofibers with high SDH activity were quantified. Scale bars: 200 μm (E–G). For B and E–G, data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by Student’s t test. G, gastrocnemius.