A crucial system severely affected in different chronic diseases is the antioxidative defense, leading to accumulation of reactive oxygen species (ROS). The discovery that deletion in the antioxidant genes shortens significantly the mouse life span, and that mutation in the major antioxidant enzyme SOD1 is associated with neurodegenerative diseases, has placed oxidative stress as a central mechanism in the pathogenesis of many pathological conditions. However, how such an oxidative insult plays a role in the disease-related decrease of muscle performance and mass remains largely unknown. We recently demonstrated that autophagy plays a dominant role in the promotion of muscle atrophy associated with local alteration in the activity of the antioxidant enzyme SOD1. In particular, transcription of autophagy-related genes, such as those encoding LC3, Cathepsin-L and Bnip3, is activated in response to localized accumulation of oxidative stress and is mediated by FoxO3. In addition, our study documents how the T-tubule might be the potential donor of membrane that forms sequestering autophagic vesicles. Here we discuss the sequence of events leading to muscle atrophy.