Laboratoire de Biologie Moléculaire de la Cellule, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5239, IFR128, Université de Lyon, Equipe Différenciation Neuromusculaire, Ecole Normale Supérieure, 69364 Lyon Cedex 07, France.
J Cell Biol. 2009 Dec 14;187(6):859-74. doi: 10.1083/jcb.200903131.
Mammalian target of rapamycin (mTOR) is a key regulator of cell growth that associates with raptor and rictor to form the mTOR complex 1 (mTORC1) and mTORC2, respectively. Raptor is required for oxidative muscle integrity, whereas rictor is dispensable. In this study, we show that muscle-specific inactivation of mTOR leads to severe myopathy, resulting in premature death. mTOR-deficient muscles display metabolic changes similar to those observed in muscles lacking raptor, including impaired oxidative metabolism, altered mitochondrial regulation, and glycogen accumulation associated with protein kinase B/Akt hyperactivation. In addition, mTOR-deficient muscles exhibit increased basal glucose uptake, whereas whole body glucose homeostasis is essentially maintained. Importantly, loss of mTOR exacerbates the myopathic features in both slow oxidative and fast glycolytic muscles. Moreover, mTOR but not raptor and rictor deficiency leads to reduced muscle dystrophin content. We provide evidence that mTOR controls dystrophin transcription in a cell-autonomous, rapamycin-resistant, and kinase-independent manner. Collectively, our results demonstrate that mTOR acts mainly via mTORC1, whereas regulation of dystrophin is raptor and rictor independent.
哺乳动物雷帕霉素靶蛋白（mTOR）是细胞生长的关键调节剂，它与 Raptor 和rictor 结合，分别形成 mTOR 复合物 1（mTORC1）和 mTORC2。Raptor 对于氧化肌的完整性是必需的，而 rictor 则是可有可无的。在这项研究中，我们表明，肌肉特异性的 mTOR 失活会导致严重的肌病，导致过早死亡。mTOR 缺陷的肌肉表现出与缺乏 Raptor 的肌肉相似的代谢变化，包括氧化代谢受损、线粒体调节改变以及与蛋白激酶 B/Akt 过度激活相关的糖原积累。此外，mTOR 缺陷的肌肉表现出基础葡萄糖摄取增加，而全身葡萄糖稳态基本保持。重要的是，mTOR 的缺失会加剧慢氧化和快糖酵解肌肉中的肌病特征。此外，mTOR 而不是 Raptor 和 rictor 的缺失会导致肌肉中肌营养不良蛋白含量减少。我们提供的证据表明，mTOR 以细胞自主、雷帕霉素抗性和激酶非依赖性的方式控制肌营养不良蛋白的转录。总之，我们的结果表明，mTOR 主要通过 mTORC1 发挥作用，而肌营养不良蛋白的调节则与 Raptor 和 rictor 无关。
