ROS and nNOS in the regulation of disuse-induced skeletal muscle atrophy

Abstract

Skeletal muscles are our biomechanical engine, generating force and power for movement. Therefore, skeletal muscles are also a primary center of metabolic activity, serving as a sink for glucose and substrate storage of amino acids. In order to respond to changing mechanical demands, skeletal muscles adapt their mass to overloading and unloading by altering the balance between protein synthesis and protein degradation. Mechanical unloading, or disuse, elicits rapid skeletal muscle fiber atrophy, where the underlying mechanisms regulation of protein synthesis and degradation appear to center around an Akt-FoxO3a axis, NFkappaB, and proteolytic pathways including calpains and the ubiquitin- proteasome system. Recent research has focused on the process of mechanotransduction, the ability to sense and as contributory to unloading-induced muscle atrophy, as a trigger of muscle remodeling. A recently discovered mechanotransductive phenomenon is the translocation of the mu-splice variant of neuronal nitric oxide synthase (nNOSµ) from the cell membrane to the cytosol. Recently, our laboratory causally linked translocation of nNOSµ in unloaded skeletal muscle with elevated oxidative stress. Sources of reactive oxygen species (ROS) during unloading may include mitochondria, xanthine oxidase, and NADPH oxidase-2 (Nox2). The combination of increase oxidative stress and reduced stress response proteins (e.g., heat shock proteins) permits the rapid degradation of contractile proteins and removal of partially oxidized proteins. Detailed discussion of the pathways involved are discussed within our review.