Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism
Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism
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DOI：
10.1172/jci92067
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发表时间：
2017-10-02
影响因子：
15.9
通讯作者：
Kim, Sang Geon
中科院分区：
文献类型：
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作者：
Koo, Ja Hyun;Kim, Tae Hyun;Kim, Sang Geon
骨骼肌对营养物质的需求量很大，是维持能量平衡的重要器官。异源三聚体G蛋白汇聚来自细胞表面受体的信号，以增强或减弱对环境变化的反应。在这里，我们表明，肌肉特异性消融的G α 13在小鼠中促进重编程的肌纤维的氧化型，从而增加线粒体生物合成和细胞呼吸。从机制上讲，G α 13及其下游效应物RhoA通过增加Rho相关激酶2介导的（Rock2介导的）Ser243磷酸化来抑制活化T细胞核因子1（NFATc1），NFATc1是肌纤维转化的主要调节因子。运动后NFATc1的Ser243磷酸化水平降低，但在肥胖动物中更高。因此，肌肉中的G α 13消融增强了全身能量代谢并增加了胰岛素敏感性，从而提供了对饮食诱导的肥胖和肝脂肪变性的保护。我们的研究结果将G α 13定义为肌纤维重编程的开关调节因子，这意味着骨骼肌中G α 13及其下游效应物的调节是治疗代谢性疾病的潜在治疗方法。
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 G alpha 13 in mice promotes reprogramming of myofibers to the oxidative type, with resultant increases in mitochondrial biogenesis and cellular respiration. Mechanistically, G alpha 13 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, G alpha 13 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 G alpha 13 as a switch regulator of myofiber reprogramming, implying that modulations of G alpha 13 and its downstream effectors in skeletal muscle are a potential therapeutic approach to treating metabolic diseases.