1Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sci Signal. 2014 Feb 25;7(314):ra18. doi: 10.1126/scisignal.2004809.
Skeletal muscle mass and function are regulated by motor innervation, and denervation results in muscle atrophy. The activity of mammalian target of rapamycin complex 1 (mTORC1) is substantially increased in denervated muscle, but its regulatory role in denervation-induced atrophy remains unclear. At early stages after denervation of skeletal muscle, a pathway involving class II histone deacetylases and the transcription factor myogenin mediates denervation-induced muscle atrophy. We found that at later stages after denervation of fast-twitch muscle, activation of mTORC1 contributed to atrophy and that denervation-induced atrophy was mitigated by inhibition of mTORC1 with rapamycin. Activation of mTORC1 through genetic deletion of its inhibitor TSC1 (tuberous sclerosis complex 1) sensitized mice to denervation-induced muscle atrophy and suppressed the kinase activity of Akt, leading to activation of FoxO transcription factors and increasing the expression of genes encoding E3 ubiquitin ligases atrogin [also known as MAFbx (muscle atrophy F-box protein)] and MuRF1 (muscle-specific ring finger 1). Rapamycin treatment of mice restored Akt activity, suggesting that the denervation-induced increase in mTORC1 activity was producing feedback inhibition of Akt. Genetic deletion of the three FoxO isoforms in skeletal muscle induced muscle hypertrophy and abolished the late-stage induction of E3 ubiquitin ligases after denervation, thereby preventing denervation-induced atrophy. These data revealed that mTORC1, which is generally considered to be an important component of anabolism, is central to muscle catabolism and atrophy after denervation. This mTORC1-FoxO axis represents a potential therapeutic target in neurogenic muscle atrophy.
骨骼肌质量和功能受运动神经支配调节，失神经会导致肌肉萎缩。在失神经肌肉中，哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）的活性显著增加，但它在失神经诱导的萎缩中的调节作用尚不清楚。在骨骼肌失神经后的早期阶段，涉及 II 类组蛋白去乙酰化酶和转录因子肌生成素的途径介导失神经诱导的肌肉萎缩。我们发现，在快肌失神经后的后期阶段，mTORC1 的激活导致萎缩，并且用雷帕霉素抑制 mTORC1 可以减轻失神经诱导的萎缩。通过基因敲除其抑制剂 TSC1（结节性硬化复合物 1）激活 mTORC1 使小鼠对失神经诱导的肌肉萎缩敏感，并抑制 Akt 的激酶活性，导致 FoxO 转录因子的激活，并增加编码 E3 泛素连接酶 atrogin[也称为 MAFbx（肌肉萎缩 F-box 蛋白）]和 MuRF1（肌肉特异性环指 1）的基因表达。雷帕霉素处理小鼠恢复了 Akt 的活性，表明失神经诱导的 mTORC1 活性增加产生了 Akt 的反馈抑制。骨骼肌中三个 FoxO 同工型的基因敲除诱导肌肉肥大，并消除失神经后晚期 E3 泛素连接酶的诱导，从而防止失神经诱导的萎缩。这些数据表明，通常被认为是合成代谢的重要组成部分的 mTORC1 是失神经后肌肉分解代谢和萎缩的核心。这个 mTORC1-FoxO 轴代表了神经源性肌肉萎缩的潜在治疗靶点。
