mTORC1 Promotes Denervation-Induced Muscle Atrophy Through a Mechanism Involving the Activation of FoxO and E3 Ubiquitin Ligases
mTORC1 Promotes Denervation-Induced Muscle Atrophy Through a Mechanism Involving the Activation of FoxO and E3 Ubiquitin Ligases
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DOI：
10.1126/scisignal.2004809
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发表时间：
2014-02-25
影响因子：
7.3
通讯作者：
Shrager, Joseph B.
中科院分区：
文献类型：
--
作者：
Tang, Huibin;Inoki, Ken;Shrager, Joseph B.
骨骼肌质量和功能由运动神经支配调节，去神经支配会导致肌肉萎缩。哺乳动物雷帕霉素靶蛋白复合物 1 (mTORC1) 的活性在去神经肌肉中显着增加，但其在去神经诱导的萎缩中的调节作用仍不清楚。在骨骼肌去神经支配后的早期阶段，涉及 II 类组蛋白脱乙酰酶和转录因子肌细胞生成素的途径介导去神经支配引起的肌肉萎缩。我们发现，在快肌去神经支配后的后期，mTORC1 的激活导致肌肉萎缩，并且通过雷帕霉素抑制 mTORC1 可以减轻去神经诱导的萎缩。通过基因删除 mTORC1 抑制剂 TSC1（结节性硬化症复合物 1）来激活 mTORC1，使小鼠对去神经诱导的肌肉萎缩敏感，并抑制 Akt 激酶活性，从而激活 FoxO 转录因子并增加编码 E3 泛素连接酶 atrogin [也称为 MAFbx（肌肉萎缩 F-box 蛋白）] 和 MuRF1（肌肉特异性无名指 1）。雷帕霉素治疗小鼠可恢复 Akt 活性，表明去神经诱导的 mTORC1 活性增加正在产生 Akt 的反馈抑制。骨骼肌中三种 FoxO 同工型的基因缺失可诱导肌肉肥大，并消除去神经后 E3 泛素连接酶的后期诱导，从而防止去神经引起的萎缩。这些数据表明，mTORC1通常被认为是合成代谢的重要组成部分，它是去神经后肌肉分解代谢和萎缩的核心。 mTORC1-FoxO 轴代表了神经源性肌肉萎缩的潜在治疗靶点。
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.