当前位置: X-MOL 学术J. Clin. Invest. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2017-09-18 , DOI: 10.1172/jci92067
Ja Hyun Koo , Tae Hyun Kim , Shi-Young Park , Min Sung Joo , Chang Yeob Han , Cheol Soo Choi , Sang Geon Kim

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.

中文翻译:

ģ α 13消融重编程的肌纤维氧化的表型,并增强全身代谢

骨骼肌由于对营养的高度需求而成为能量稳态的关键器官。异三聚体G蛋白会聚来自细胞表面受体的信号,从而增强或减弱针对环境变化的反应。在这里,我们表明小鼠中Gα13的肌肉特异性消融促进了肌纤维重编程为氧化型,从而导致线粒体生物发生和细胞呼吸增加。从机制上讲,Gα13及其下游效应子RhoA通过增加Ser243上与Rho相关的激酶2介导的(Rock2介导的)磷酸化,抑制了活化的T细胞1(NFATc1)的核因子,这是肌纤维转化的主要调节因子。运动后NFATc1的Ser243磷酸化降低,但在肥胖动物中更高。所以,肌肉中的Gα13消融增强了全身能量代谢,并增强了胰岛素敏感性,从而为饮食引起的肥胖症和肝脂肪变性提供了保护。我们的结果将Gα13定义为肌纤维重编程的开关调节剂,这暗示着对骨骼肌中Gα13及其下游效应子的调节是治疗代谢性疾病的潜在治疗方法。
更新日期:2017-10-03
down
wechat
bug