Inserm U1016, Centre National de la Recherche Scientifique (CNRS), UMR8104, University Paris Descartes, Institut Cochin, Paris, France.
Cell Cycle. 2011 Aug 15;10(16):2640-6. doi: 10.4161/cc.10.16.17102.
Nutrition and physical activity have profound effects on skeletal muscle metabolism and growth. Regulation of muscle mass depends on a thin balance between growth-promoting and growth-suppressing factors. Over the past decade, the mammalian target of rapamycin (mTOR) kinase has emerged as an essential factor for muscle growth by mediating the anabolic response to nutrients, insulin, insulin-like growth factors and resistance exercise. As opposed to the mTOR signaling pathway, the AMP-activated protein kinase (AMPK) is switched on during starvation and endurance exercise to upregulate energy-conserving processes. Recent evidence indicates that mTORC1 (mTOR Complex 1) and AMPK represent two antagonistic forces governing muscle adaption to nutrition, starvation and growth stimulation. Animal knockout models with impaired mTORC1 signaling showed decreased muscle mass correlated with increased AMPK activation. Interestingly, AMPK inhibition in p70S6K-deficient muscle cells restores cell growth and sensitivity to nutrients. Conversely, muscle cells lacking AMPK have increased mTORC1 activation with increased cell size and protein synthesis rate. We also demonstrated that the hypertrophic action of MyrAkt is enhanced in AMPK-deficient muscle, indicating that AMPK acts as a negative feedback control to restrain muscle hypertrophy. Our recent results extend this notion by showing that AMPKα1, but not AMPKα2, regulates muscle cell size through the control of mTORC1 signaling. These results reveal the diverse functions of the two catalytic isoforms of AMPK, with AMPKα1 playing a predominant role in the control of muscle cell size and AMPKα2 mediating muscle metabolic adaptation. Thus, the crosstalk between AMPK and mTORC1 signaling is a highly regulated way to control changes in muscle growth and metabolic rate imposed by external cues.
营养和身体活动对骨骼肌代谢和生长有深远影响。肌肉量的调节取决于促进生长和抑制生长因素之间的微妙平衡。在过去十年中，雷帕霉素靶蛋白（mTOR）激酶已成为肌肉生长的必需因素，通过介导营养、胰岛素、胰岛素样生长因子和抗阻运动的合成代谢反应。与 mTOR 信号通路相反，在饥饿和耐力运动期间，AMP 激活的蛋白激酶（AMPK）被激活，以上调能量保存过程。最近的证据表明，mTORC1（mTOR 复合物 1）和 AMPK 代表两种拮抗力量，控制肌肉对营养、饥饿和生长刺激的适应。mTORC1 信号受损的动物敲除模型显示肌肉质量减少，与 AMPK 激活增加相关。有趣的是，在 p70S6K 缺陷的肌细胞中抑制 AMPK 可恢复细胞生长和对营养物质的敏感性。相反，缺乏 AMPK 的肌细胞具有增加的 mTORC1 激活，导致细胞大小和蛋白质合成率增加。我们还证明，MycAkt 的肥大作用在 AMPK 缺陷的肌肉中增强，表明 AMPK 作为负反馈控制来抑制肌肉肥大。我们最近的结果通过显示 AMPKα1（而不是 AMPKα2）通过控制 mTORC1 信号来调节肌细胞大小，扩展了这一概念。这些结果揭示了 AMPK 的两种催化同工型的不同功能，AMPKα1 在控制肌细胞大小方面起主要作用，而 AMPKα2 介导肌肉代谢适应。因此，AMPK 和 mTORC1 信号之间的串扰是一种高度调节的方式，可控制外部信号引起的肌肉生长和代谢率变化。
