P38α MAPK coordinates the activities of several metabolic pathways that together induce atrophy of denervated muscles

Abstract

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 (p38AF) are partially protected from muscle damage and atrophy. Denervated (Den) muscles of these mutant mice exhibit reduced signs of oxidative stress, decreased unfolded protein response and lower levels of ubiquitinated proteins relative to Den muscles of control mice. Further, whereas autopahagy flux is inhibited in Den muscles of control mice, Den muscles of p38AF 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 p38AF mice. Our results indicate, therefore, that attenuation of p38α activity in mice protects Den muscles by reducing oxidative stress, lowering protein damage and improving the clearance of damaged mitochondria by autophagy.

Antioxidant Apigenin Relieves Age-Related Muscle Atrophy by Inhibiting Oxidative Stress and Hyperactive Mitophagy and Apoptosis in Skeletal Muscle of Mice

“…It is believed that protein synthesis and degradation in muscle are regulated by signaling transduction related to oxidative stress, autophagosome-lysosome systems, hormones, and so on ( 43 ). Mitochondria are the aerobic energy production site, and ROS as by-product of mitochondrial metabolism may cause mtDNA mutations and dysfunction, destroy antioxidant defensing system, and cause damage to tissues ( 28 , 44 ).…”

NeuroHeal Reduces Muscle Atrophy and Modulates Associated Autophagy

“…These findings suggest that autophagy deficiency plays a role in various forms of hereditary muscular dystrophy, including Bessler myopathy, Ullrich congenital muscular dystrophy, and Duchenne muscular dystrophy (DMD) [37]. More recently, Odeh and collaborators demonstrated that autophagy flux was slowed down or even blocked in denervated muscles [38]. Moreover, it has been reported that a correct autophagy flux is fundamental for myofiber survival [39,40] and satellite cells stemness [41].…”

p38 MAPK in Glucose Metabolism of Skeletal Muscle: Beneficial or Harmful?

“…Under these conditions, p38 MAPK upregulates E3 ligases like MAFbx/Atrogin1 and Murf1 targeting proteins for proteasome degradation [ 97 , 98 , 99 , 100 , 101 ]. Inhibition of p38 MAPK activity protects muscle from the oxidative damage and prevents proteolysis, and was, therefore, suggested as a potential target for the treatment of muscle atrophy [ 102 , 103 , 104 ]. The continuous activity of p38 MAPK is also involved in the etiology of inflammatory diseases and specifically bowel diseases, like ulcerative colitis and Crohn’s disease [ 105 ].…”

“…However, as mentioned before, since p38 MAPK activity is vital for mitochondrial function and oxidative metabolism, its inhibition may have adverse effects on muscle glucose metabolism [ 8 , 56 , 62 ]. Inhibition of p38 MAPK is anticipated to reduce skeletal muscle oxidative phosphorylation and compensate for the lost energy by increasing anaerobic glycolysis [ 102 ]. The prevailing model is that excessive calorie intake cause mitochondrial electron leak, accumulation of ROS, mitochondrial dysfunction, and insulin resistance [ 68 , 107 , 108 ].…”