Differential response of skeletal muscles to mTORC1 signaling during atrophy and hypertrophy.
Differential response of skeletal muscles to mTORC1 signaling during atrophy and hypertrophy.
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DOI：
10.1186/2044-5040-3-6
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发表时间：
2013-03-06
期刊：
影响因子：
4.9
通讯作者：
Rüegg MA
中科院分区：
文献类型：
--
作者：
Bentzinger CF;Lin S;Romanino K;Castets P;Guridi M;Summermatter S;Handschin C;Tintignac LA;Hall MN;Rüegg MA
骨骼肌质量是由蛋白质合成和降解之间的平衡决定的。哺乳动物雷帕霉素复合体靶标1(MTORC1)是蛋白质翻译的主要调节者，与肌肉质量的控制有关。通过骨骼肌特异性缺失其必需成分猛禽，mTORC1失活会导致较小的肌肉和致命性营养不良。此外，通过改变线粒体生物发生的关键决定因素pGC-1α的表达，猛禽缺陷肌肉的氧化程度较低。这些结果表明，mTORC1的激活可能通过提供对肌肉萎缩的抵抗和增强氧化功能而有益于骨骼肌。在这里，我们通过删除肌肉纤维中的mTORC1抑制剂结节性硬化症复合体(TSC)来检验这一假说。用组织学、生化和分子生物学方法对Raptor或TSC1基因急性或永久缺失小鼠的骨骼肌进行了研究。通过消融协同肌肉或去神经支配来研究肌肉对机械负荷和神经输入变化的反应。猛禽的基因缺失或基因敲除导致mTORC1失活，足以阻止肌肉生长和加强肌肉萎缩。相反，通过敲除TSC短期激活mTORC1后，在快的胫骨前肌(TA)和慢速的比目鱼肌，在失神经支配时都会导致肌纤维肥大和抗萎缩。然而，令人惊讶的是，通过TSC1基因缺失持续激活mTORC1导致了除比目鱼肌以外的所有肌肉萎缩。相比之下，所有受检肌肉的氧化能力都增强了。TSC1缺陷的比目鱼肌一直是抗萎缩的，而TA在失神经后经历了正常的萎缩。此外，在超负荷时，与对照组相比，足底肌肉没有表现出增强的肥大。生化分析表明，肌肉萎缩的反应是通过mTORC1的反馈抑制抑制PKB/Akt的磷酸化，以及随后E3泛素连接酶MuRF1和Avergin-1/MAFbx表达的增加。相反，两种E3连接酶在比目鱼肌中的表达没有增加，这表明在该肌肉中存在代偿机制。我们的研究表明，mTORC1-和PKB/Akt-FoxO通路是紧密相连的，并且根据肌肉类型的不同而有不同的调控。这些结果表明，长期激活mTORC1信号轴并不是促进肌肉生长的治疗选择，因为它强烈地反馈诱导参与蛋白质降解的E3泛素连接酶。
Skeletal muscle mass is determined by the balance between protein synthesis and degradation. Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of protein translation and has been implicated in the control of muscle mass. Inactivation of mTORC1 by skeletal muscle-specific deletion of its obligatory component raptor results in smaller muscles and a lethal dystrophy. Moreover, raptor-deficient muscles are less oxidative through changes in the expression PGC-1α, a critical determinant of mitochondrial biogenesis. These results suggest that activation of mTORC1 might be beneficial to skeletal muscle by providing resistance to muscle atrophy and increasing oxidative function. Here, we tested this hypothesis by deletion of the mTORC1 inhibitor tuberous sclerosis complex (TSC) in muscle fibers. Skeletal muscles of mice with an acute or a permanent deletion of raptor or TSC1 were examined using histological, biochemical and molecular biological methods. Response of the muscles to changes in mechanical load and nerve input was investigated by ablation of synergistic muscles or by denervation . Genetic deletion or knockdown of raptor, causing inactivation of mTORC1, was sufficient to prevent muscle growth and enhance muscle atrophy. Conversely, short-term activation of mTORC1 by knockdown of TSC induced muscle fiber hypertrophy and atrophy-resistance upon denervation, in both fast tibialis anterior (TA) and slow soleus muscles. Surprisingly, however, sustained activation of mTORC1 by genetic deletion of Tsc1 caused muscle atrophy in all but soleus muscles. In contrast, oxidative capacity was increased in all muscles examined. Consistently, TSC1-deficient soleus muscle was atrophy-resistant whereas TA underwent normal atrophy upon denervation. Moreover, upon overloading, plantaris muscle did not display enhanced hypertrophy compared to controls. Biochemical analysis indicated that the atrophy response of muscles was based on the suppressed phosphorylation of PKB/Akt via feedback inhibition by mTORC1 and subsequent increased expression of the E3 ubiquitin ligases MuRF1 and atrogin-1/MAFbx. In contrast, expression of both E3 ligases was not increased in soleus muscle suggesting the presence of compensatory mechanisms in this muscle. Our study shows that the mTORC1- and the PKB/Akt-FoxO pathways are tightly interconnected and differentially regulated depending on the muscle type. These results indicate that long-term activation of the mTORC1 signaling axis is not a therapeutic option to promote muscle growth because of its strong feedback induction of the E3 ubiquitin ligases involved in protein degradation.
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影响因子：
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作者：
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DOI：
10.1152/ajpcell.1997.273.2.c371
发表时间：
1997-08-01
影响因子：
5.5
作者：
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通讯作者：
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