Biozentrum; University of Basel; Basel, Switzerland; Neuromuscular Research Center; Departments of Neurology and Biomedicine; Pharmazentrum; Basel University Hospital; Basel, Switzerland.
Autophagy. 2013 Sep;9(9):1435-7. doi: 10.4161/auto.25722. Epub 2013 Jul 23.
Autophagy impairment has been implicated in several muscle disorders and in age-related dysfunction. Although previous reports pointed to FOXO as a positive regulator of autophagy in skeletal muscle, it remained unclear what is triggering autophagy. We found that TSC muscle knockout (TSCmKO) mice, characterized by specific depletion of TSC1 in skeletal muscle, and thus constant activation of MTORC1, develop a late-onset myopathy marked by the accumulation of autophagic substrates. In those mice, autophagy induction is blocked despite FOXO activation because of constant MTORC1-dependent inhibition of ULK1. Treatment of TSCmKO mice with rapamycin is sufficient to restore autophagy and to alleviate, at least in part, the myopathy. Inversely, inactivation of the MTORC1 pathway in RPTOR-depleted muscles triggers LC3B lipidation in spite of FOXO inhibition. In conclusion, MTORC1 constitutes the master regulator of autophagy induction in skeletal muscle and its deregulation leads to pathologic alterations of muscle homeostasis.
自噬功能障碍与多种肌肉疾病和与年龄相关的功能障碍有关。尽管之前的研究表明 FOXO 是骨骼肌自噬的正向调节因子，但触发自噬的原因仍不清楚。我们发现 TSC 肌肉敲除（TSCmKO）小鼠，其特征是骨骼肌中 TSC1 的特异性缺失，从而导致 MTORC1 的持续激活，会发展出一种以自噬底物积累为特征的迟发性肌病。在这些小鼠中，尽管 FOXO 被激活，但由于 MTORC1 依赖性的 ULK1 抑制，自噬诱导被阻断。用雷帕霉素治疗 TSCmKO 小鼠足以恢复自噬，并至少部分缓解肌病。相反，在 RPTOR 耗尽的肌肉中抑制 MTORC1 通路会导致 LC3B 脂质化，尽管 FOXO 被抑制。总之，MTORC1 是骨骼肌自噬诱导的主要调节因子，其失调会导致肌肉稳态的病理性改变。
