Oxidative stress, apoptosis, and proteolysis in skeletal muscle repair after unloading.

Andrianjafiniony T, Dupre-Aucouturier S, Letexier D, Couchoux H, Desplanches D. Oxidative stress, apoptosis, and proteolysis in skeletal muscle repair after unloading. Am J Physiol Cell Physiol 299: C307-C315, 2010. First published May 26, 2010; doi: 10.1152/ajpcell.00069.2010.-Although several lines of evidence link muscle-derived oxidants and inflammation to skeletal muscle wasting via regulation of apoptosis and proteolysis, little information is currently available on muscle repair. The present work was designed to study oxidative stress response, inflammatory cytokines, apoptotic, or proteolytic pathways during the early (1 and 5 days) and later (14 days) stages of the regrowth process subsequent to 14 days of hindlimb unloading. During the early stages of reloading, muscle mass recovery (day 5) was facilitated by transcriptional downregulation (day 1) of pathways involved in muscle proteolysis [mu-calpain, atrogin-1/muscle atrophy F-box (MAFbx), and muscle RING finger-1/(MuRF1) mRNA] and upregulation of an autophagy-related protein Beclin-1 (day 5). At the same time, oxidative stress (glutathione vs. glutathione disulfide ratio, superoxide dismutase, catalase activities) remained still enhanced, whereas the increased uncoupling protein 3 gene expression recovered. Increased caspase-9 (mitochondrial-driven apoptosis) and decreased caspase-12 (sarcoplasmic reticulum-mediated apoptosis) activation was also normalized at early stages (day 5). Conversely, the receptor-mediated apoptotic pathway initiated by ligand-induced (tumor necrosis factor-alpha, TNF-alpha) binding and promoting the activation of caspase-8 remained elevated until 14 days. Our data suggest that at early stages, muscle repair is mediated via the modulation of mitochondrial-driven apoptosis and muscle proteolysis. Despite full muscle mass recovery, oxidative stress and TNF-alpha-mediated apoptotic pathway are still activated till later stages of muscle remodeling.