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 10

Gα13-MKO protects mice from diet-induced insulin resistance.

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Gα13-MKO protects mice from diet-induced insulin resistance. (A–C) Nine-...
(A–C) Nine-week-old WT and Gα13-MKO mice were fed a ND or a HFD. After 9 weeks of HFD feeding, the mice were fasted overnight and then sacrificed (n = 6–8 each). (A) Fasting serum glucose and insulin levels. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from both parameters. (B) Representative H&E staining of pancreatic islets. Scale bar: 200 μm. (C) Maximal 2-deoxyglucose (2-DG) uptake assay using isolated soleus muscles. (D) Glucose tolerance test and (E) insulin tolerance test. Following overnight fasting, mice fed a ND or a HFD for 7 weeks were subjected to blood glucose measurement immediately after i.p. injection of glucose or insulin (n = 6–8 each). (F–I) Whole-body and tissue-specific insulin sensitivity was assessed in HFD-fed mice using a hyperinsulinemic-euglycemic clamp (n = 6–7 each). (F) Glucose infusion rate (GIR). (G) Hepatic glucose production (HGP) rates. (H) Whole-body glucose uptake, glycolysis, and glycogen synthesis rates. (I) 2-DG uptake rates in gastrocnemius immediately after a clamp assay. (J and K) Immunoblots for the markers of insulin sensitivity in soleus muscle. (J) Nine-week-old mice were fed a HFD for 9 weeks and then fasted overnight. (K) Mice of each genotype were fed a HFD for 9 weeks and then sacrificed 15 minutes after an i.p. insulin injection. (L) Schematic diagram illustrating how Gα13 and downstream signaling molecules regulate muscle fiber type and metabolic homeostasis. For J and K, each blot was obtained from samples run on parallel gels. For A and C–K, data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by Student’s t test.