Mitochondrial dysregulation and muscle disuse atrophy.
Mitochondrial dysregulation and muscle disuse atrophy.
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DOI：
10.12688/f1000research.19139.1
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Yeo, Dongwook
中科院分区：
文献类型：
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作者：
Ji, Li Li;Yeo, Dongwook
众所周知，线粒体在骨骼肌对增强的收缩活性的代谢和生理适应中起关键作用。几种氧化还原敏感的信号通路，如PGC-1 α，AMPK，IGF/Akt/mTOR，SIRT，NF κ B和FoxO参与广泛的串扰，以调节重要的细胞功能，如线粒体生物发生，线粒体融合和裂变动力学，自噬/线粒体自噬，以及在改变的需求和压力下的细胞凋亡。然而，当肌肉停止收缩时，例如在固定和去神经支配期间，线粒体经历一系列有害的变化，其特征在于PGC-1 α和抗氧化剂防御的下调，ROS产生增加，FoxO、NF κ B和炎症活化，泛素化增强，以及最终的线粒体自噬和凋亡级联。线粒体稳态失调的表型结果是蛋白水解升高和肌肉萎缩。通过转基因或体内DNA转染的PGC-1 α过表达可以恢复线粒体稳态并逆转肌细胞萎缩的证明支持了“肌萎缩的有丝分裂稳态理论”。
It is well established that mitochondria play a critical role in the metabolic and physiological adaptation of skeletal muscle to enhanced contractile activity. Several redox-sensitive signaling pathways such as PGC-1alpha, AMPK, IGF/Akt/mTOR, SIRT, NFkappaB, and FoxO are involved with extensive crosstalk to regulate vital cellular functions such as mitochondrial biogenesis, mitochondrial fusion and fission dynamics, autophagy/mitophagy, and apoptosis under altered demand and stress. However, when muscles cease contraction, such as during immobilization and denervation, mitochondria undergo a series of detrimental changes characterized by downregulation of PGC-1alpha and antioxidant defense, increased ROS generation, activated FoxO, NFkappaB, and inflammation, enhanced ubiquitination, and finally mitophagy and apoptotic cascades. The phenotypic outcome of the discord of mitochondrial homeostasis is elevated proteolysis and muscle atrophy. The demonstration that PGC-1alpha overexpression via transgene or in vivo DNA transfection can restore mitochondrial homeostasis and reverse myocyte atrophy supports the "mitostasis theory of muscle atrophy".