Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism
Ja Hyun Koo, Tae Hyun Kim, Shi-Young Park, Min Sung Joo, Chang Yeob Han, Cheol Soo Choi, Sang Geon Kim
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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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 9

Gα13-MKO protects mice from diet-induced adiposity with increased fatty acid metabolism.

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Gα13-MKO protects mice from diet-induced adiposity with increased fatty ...
(A–H) Nine-week-old WT or Gα13-MKO mice were fed a ND or a HFD. After 9 weeks of HFD feeding, the mice were fasted overnight and then sacrificed. (A) Body weight gains (n = 6–8 each). (B) Determination of fat and lean mass in HFD-fed WT and Gα13-MKO mice using nuclear magnetic resonance (n = 8 each). (C) Oil red O staining of tibialis anterior after HFD feeding. Scale bar: 200 μm. (D) Relative triglyceride levels in mouse soleus muscles normalized with protein levels (n = 6–8 each). (E) In vivo energy balance. Food intake, energy expenditure, and OCR were analyzed in mice housed in individual metabolic cages (n = 8 each). (F) Ex vivo fatty acid uptake assay (n = 3 each). Muscles were freshly isolated from mice of each genotype, incubated in a medium containing [3H]-palmitate acid for 30 minutes, and lysed for scintillation counting. (G) qPCR assays for transcripts of the genes associated with lipid uptake and oxidation (n = 6–8 each). (H) H&E-stained images of skeletal muscles and liver and data on skeletal muscle and liver weights and liver/body weight ratios (n = 6–8 each). Scale bars: 200 μm. For A, B, and D–H, data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by Student’s t test.