Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
J Biol Chem. 2013 Jan 11;288(2):1125-34. doi: 10.1074/jbc.M112.399949. Epub 2012 Dec 3.
Drastic protein degradation occurs during muscle atrophy induced by denervation, fasting, immobility, and various systemic diseases. Although the ubiquitin-proteasome system is highly up-regulated in denervated muscles, the involvement of autophagy and protein synthesis has been controversial. Here, we report that autophagy is rather suppressed in denervated muscles even under autophagy-inducible starvation conditions. This is due to a constitutive activation of mammalian target of rapamycin complex 1 (mTORC1). We further reveal that denervation-induced mTORC1 activation is dependent on the proteasome, which is likely mediated by amino acids generated from proteasomal degradation. Protein synthesis and ribosome biogenesis are paradoxically increased in denervated muscles in an mTORC1-dependent manner, and mTORC1 activation plays an anabolic role against denervation-induced muscle atrophy. These results suggest that denervation induces not only muscle degradation but also adaptive muscle response in a proteasome- and mTORC1-dependent manner.
在失神经、禁食、不动和各种全身性疾病引起的肌肉萎缩过程中会发生剧烈的蛋白质降解。尽管在去神经支配的肌肉中泛素-蛋白酶体系统高度上调，但自噬和蛋白质合成的参与一直存在争议。在这里，我们报告即使在自噬诱导的饥饿条件下，失神经支配的肌肉中自噬也受到抑制。这是由于哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）的组成性激活。我们进一步揭示，去神经诱导的 mTORC1 激活依赖于蛋白酶体，这可能是由蛋白酶体降解产生的氨基酸介导的。蛋白合成和核糖体生物发生在失神经支配的肌肉中以 mTORC1 依赖性方式反常增加，并且 mTORC1 激活在对抗失神经支配引起的肌肉萎缩方面发挥了合成代谢作用。这些结果表明，去神经支配不仅会引起肌肉降解，而且还会以蛋白酶体和 mTORC1 依赖性方式引起适应性肌肉反应。
