Indexed on: 25 Sep '19Published on: 24 Sep '19Published in: FEBS Journal
Physiological or pathological muscle disuse/inactivity or loss of the neural-muscular junction cause muscle atrophy. Atrophy-inducing conditions cause metabolic oxidative stress in the muscle tissue, activation of the ubiquitin-proteasome and of the autophagosome-lysosome systems, enhanced removal of the damaged proteins and organelles, and loss of muscle mass and strength. The signaling pathways that control these catabolic processes are only partially known. In this study, we systematically analyzed the role of p38α mitogen-activated protein kinase (MAPK) in denervation-mediated atrophy. Mice with attenuated activity of p38α (p38 ) are partially protected from muscle damage and atrophy. Denervated muscles of these mutant mice exhibit reduced signs of oxidative stress, decreased unfolded protein response (UPR) and lower levels of ubiquitinated proteins relative to denervated muscles of control mice. Further, whereas autopahagy flux is inhibited in denervated muscles of control mice, denervated muscles of p38 mice maintain normal level of autophagy flux. Last, muscle denervation affects differently the energy metabolism of muscles in normal and mutant mice; whereas denervation appears to increase mitochondrial oxidative metabolism in control mice, it elevates anaerobic glycolytic metabolism in p38 mice. Our results indicate, therefore, that attenuation of p38α activity in mice protects denervated muscles by reducing oxidative stress, lowering protein damage and improving the clearance of damaged mitochondria by autophagy. © 2019 Federation of European Biochemical Societies.