BACKGROUND The balance between protein synthesis and degradation (proteostasis) is a determining factor for muscle size and function. Signalling via the mammalian target of rapamycin complex 1 (mTORC1) regulates proteostasis in skeletal muscle by affecting protein synthesis and autophagosomal protein degradation. Indeed, genetic inactivation of mTORC1 in developing and growing muscle causes atrophy resulting in a lethal myopathy. However, systemic dampening of mTORC1 signalling by its allosteric inhibitor rapamycin is beneficial at the organismal level and increases lifespan. Whether the beneficial effect of rapamycin comes at the expense of muscle mass and function is yet to be established. METHODS We conditionally ablated the gene coding for the mTORC1-essential component raptor in muscle fibres of adult mice [inducible raptor muscle-specific knockout (iRAmKO)]. We performed detailed phenotypic and biochemical analyses of iRAmKO mice and compared them with muscle-specific raptor knockout (RAmKO) mice, which lack raptor in developing muscle fibres. We also used polysome profiling and proteomics to assess protein translation and associated signalling in skeletal muscle of iRAmKO mice. RESULTS Analysis at different time points reveal that, as in RAmKO mice, the proportion of oxidative fibres decreases, but slow-type fibres increase in iRAmKO mice. Nevertheless, no significant decrease in body and muscle mass or muscle fibre area was detected up to 5 months post-raptor depletion. Similarly, ex vivo muscle force was not significantly reduced in iRAmKO mice. Despite stable muscle size and function, inducible raptor depletion significantly reduced the expression of key components of the translation machinery and overall translation rates. CONCLUSIONS Raptor depletion and hence complete inhibition of mTORC1 signalling in fully grown muscle leads to metabolic and morphological changes without inducing muscle atrophy even after 5 months. Together, our data indicate that maintenance of muscle size does not require mTORC1 signalling, suggesting that rapamycin treatment is unlikely to negatively affect muscle mass and function.

中文翻译：

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mTORC1信号对于成年久坐小鼠的肌肉质量和功能的维持不是必需的。

背景技术蛋白质合成与降解（蛋白稳态）之间的平衡是肌肉大小和功能的决定性因素。通过哺乳动物雷帕霉素复合物1（mTORC1）靶标发出的信号通过影响蛋白质合成和自噬体蛋白质降解来调节骨骼肌中的蛋白稳态。实际上，在发育中和生长中的肌肉中，mTORC1的基因失活会导致萎缩，从而导致致命的肌病。但是，通过变构抑制剂雷帕霉素对mTORC1信号的全身性抑制在机体水平上是有益的，并且可以延长寿命。雷帕霉素的有益作用是否以肌肉质量和功能为代价尚未确定。方法我们有条件地消除了成年小鼠肌肉纤维中编码mTORC1必需成分猛禽的基因[诱导性猛禽肌肉特异性敲除（iRAmKO）]。我们对iRAmKO小鼠进行了详细的表型和生化分析，并将它们与肌肉特异性猛禽敲除（RAmKO）小鼠进行了比较，后者在发育中的肌肉纤维中缺乏猛禽。我们还使用了多核糖体分析和蛋白质组学来评估iRAmKO小鼠骨骼肌中的蛋白质翻译和相关信号传导。结果在不同时间点的分析表明，与RAmKO小鼠一样，iRAmKO小鼠中氧化纤维的比例减少，而慢型纤维增加。然而，直到猛禽耗竭后5个月，身体和肌肉质量或肌纤维面积均未见明显下降。相似地，iRAmKO小鼠的离体肌肉力量并未显着降低。尽管肌肉大小和功能稳定，但可诱导的猛禽耗竭却明显降低了翻译机制关键成分的表达和总体翻译率。结论猛禽耗竭并因此完全抑制了完全生长的肌肉中的mTORC1信号传导会导致代谢和形态变化，即使在5个月后也不会引起肌肉萎缩。总之，我们的数据表明维持肌肉大小不需要mTORC1信号传导，这表明雷帕霉素治疗不太可能对肌肉质量和功能产生负面影响。结论猛禽耗竭并因此完全抑制了完全生长的肌肉中的mTORC1信号传导会导致代谢和形态变化，即使在5个月后也不会引起肌肉萎缩。总之，我们的数据表明维持肌肉大小不需要mTORC1信号传导，这表明雷帕霉素治疗不太可能对肌肉质量和功能产生负面影响。结论猛禽耗竭并因此完全抑制了完全生长的肌肉中的mTORC1信号传导会导致代谢和形态变化，即使在5个月后也不会引起肌肉萎缩。总之，我们的数据表明维持肌肉大小不需要mTORC1信号传导，这表明雷帕霉素治疗不太可能对肌肉质量和功能产生负面影响。