Department of Biochemistry, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Pre-Clinical Research Authority, Technion-Israel Institute of Technology, Haifa, Israel.
FEBS J. 2020 Jan;287(1):73-93. doi: 10.1111/febs.15070. Epub 2019 Oct 22.
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 (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 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 Den muscles by reducing oxidative stress, lowering protein damage and improving the clearance of damaged mitochondria by autophagy.
生理性或病理性肌肉废用/不活动或神经肌肉接头丧失会导致肌肉萎缩。导致萎缩的条件会导致肌肉组织发生代谢性氧化应激，激活泛素蛋白酶体和自噬溶酶体系统，增强对受损蛋白质和细胞器的清除，导致肌肉质量和力量的丧失。控制这些分解代谢过程的信号通路知之甚少。在这项研究中，我们系统地分析了 p38α 丝裂原活化蛋白激酶（MAPK）在去神经介导的萎缩中的作用。p38α 活性减弱的小鼠（p38 ）部分免受肌肉损伤和萎缩的影响。与对照小鼠的去神经（Den）肌肉相比，这些突变小鼠的 Den 肌肉表现出氧化应激减少、未折叠蛋白反应降低和泛素化蛋白水平降低。此外，虽然对照小鼠的 Den 肌肉中的自噬通量受到抑制，但 p38 小鼠的 Den 肌肉维持正常的自噬通量。最后，肌肉去神经以不同的方式影响正常和突变小鼠的肌肉能量代谢；虽然去神经似乎增加了对照小鼠的线粒体氧化代谢，但它增加了 p38 小鼠的无氧糖酵解代谢。因此，我们的研究结果表明，在小鼠中减弱 p38α 活性可通过减少氧化应激、降低蛋白质损伤和改善自噬对受损线粒体的清除来保护 Den 肌肉。
