Significance: Skeletal muscles play essential roles in key body functions including breathing, locomotion, and glucose homeostasis; therefore, maintaining healthy skeletal muscles is important. Prolonged periods of muscle inactivity (e.g., bed rest, mechanical ventilation, or limb immobilization) result in skeletal muscle atrophy and weakness. Recent Advances: Disuse skeletal muscle atrophy occurs due to both accelerated proteolysis and decreased protein synthesis with proteolysis playing a leading role in some types of inactivity-induced atrophy. Although all major proteolytic systems are involved in inactivity-induced proteolysis in skeletal muscles, growing evidence indicates that both calpain and autophagy play an important role. Regulation of proteolysis in skeletal muscle is under complex control, but it is established that activation of both calpain and autophagy is directly linked to oxidative stress. Critical Issues: In this review, we highlight the experimental evidence that supports a cause and effect link between reactive oxygen species (ROS) and activation of both calpain and autophagy in skeletal muscle fibers during prolonged inactivity. We also review the sources of oxidant production in muscle fibers during inactivity-induced atrophy, and provide a detailed discussion on how ROS activates both calpain and autophagy during disuse muscle wasting. Future Directions: Future studies are required to delineate the specific mechanisms by which ROS activates both calpain and autophagy in skeletal muscles during prolonged periods of contractile inactivity. This knowledge is essential to develop the most effective strategies to protect against disuse muscle atrophy. Antioxid. Redox Signal. 33, 559-569.
Keywords: antioxidants; autophagy; calpain; oxidative stress; proteolysis; reactive oxygen species.