Dulbecco Telethon Institute, 35129 Padova, Italy.
Cell Metab. 2009 Dec;10(6):507-15. doi: 10.1016/j.cmet.2009.10.008.
The ubiquitin-proteasome and autophagy-lysosome pathways are the two major routes for protein and organelle clearance. In skeletal muscle, both systems are under FoxO regulation and their excessive activation induces severe muscle loss. Although altered autophagy has been observed in various myopathies, the specific role of autophagy in skeletal muscle has not been determined by loss-of-function approaches. Here, we report that muscle-specific deletion of a crucial autophagy gene, Atg7, resulted in profound muscle atrophy and age-dependent decrease in force. Atg7 null muscles showed accumulation of abnormal mitochondria, sarcoplasmic reticulum distension, disorganization of sarcomere, and formation of aberrant concentric membranous structures. Autophagy inhibition exacerbated muscle loss during denervation and fasting. Thus, autophagy flux is important to preserve muscle mass and to maintain myofiber integrity. Our results suggest that inhibition/alteration of autophagy can contribute to myofiber degeneration and weakness in muscle disorders characterized by accumulation of abnormal mitochondria and inclusions.
泛素-蛋白酶体和自噬-溶酶体途径是蛋白质和细胞器清除的两个主要途径。在骨骼肌中，这两个系统都受 FoxO 调节，它们的过度激活会导致严重的肌肉损失。尽管在各种肌病中都观察到了自噬的改变，但通过功能丧失方法尚未确定自噬在骨骼肌中的特定作用。在这里，我们报告说，关键的自噬基因 Atg7 在肌肉中的特异性缺失导致了严重的肌肉萎缩和随年龄增长的肌力下降。Atg7 缺失的肌肉表现出异常线粒体的积累、肌浆网扩张、肌节的紊乱以及异常同心膜结构的形成。自噬抑制在去神经和禁食期间加剧了肌肉损失。因此，自噬通量对于维持肌肉质量和保持肌纤维完整性很重要。我们的结果表明，自噬的抑制/改变可能导致以异常线粒体和包涵体积累为特征的肌肉疾病中的肌纤维变性和无力。
