Skeletal muscle mTORC1 regulates neuromuscular junction stability
Skeletal muscle mTORC1 regulates neuromuscular junction stability
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DOI：
10.1002/jcsm.12496
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发表时间：
2019-10-25
影响因子：
8.9
通讯作者：
Blaauw, Bert
中科院分区：
文献类型：
--
作者：
Baraldo, Martina;Geremia, Alessia;Blaauw, Bert
背景骨骼肌是一种可塑性组织，能够适应不同的刺激。已经确定，哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）信号传导是介导骨骼肌质量和功能增加的关键调节剂。然而，mTORC 1信号转导在成人骨骼肌稳态中的作用仍然没有很好的定义。方法诱导型、肌肉特异性Raptor和mTOR k.o.产生小鼠。分析缺失后1个月和7个月的肌肉，以评估肌肉组织学和肌肉力量。结果在缺失后1个月，我们发现肌肉的大小和收缩特性没有变化。然而，将Raptor的缺失延长至7个月，导致非常显著的表型，其特征在于虚弱、肌肉再生、线粒体功能障碍和自噬损伤。出乎意料的是，肌纤维中mTOR信号传导的减少伴随着纤维去神经支配标志物的出现，如神经细胞粘附分子（NCAM）的表达增加。mTOR或Raptor的肌肉特异性缺失或雷帕霉素的使用都足以诱导3-8%的NCAM阳性纤维（P < 0.01），肌肉纤维颤动和24%的检查纤维中的神经肌肉接头（NMJ）断裂（P < 0.001）。从机制上讲，用小肽Tat-beclin 1重新激活自噬足以防止Raptor k.o.中线粒体功能障碍和NCAM阳性纤维的出现。肌肉.结论我们的研究表明，骨骼肌纤维中的mTOR信号传导对于维持适当的纤维神经支配，保护肌纤维和运动神经元中的NMJ结构至关重要。此外，考虑到运动在影响NMJ的大多数病理中的有益作用，我们的研究结果表明，运动的这些有益作用的一部分是通过运动期间和运动后骨骼肌中mTORC 1的公认激活。
Background Skeletal muscle is a plastic tissue that can adapt to different stimuli. It is well established that Mammalian Target of Rapamycin Complex 1 (mTORC1) signalling is a key modulator in mediating increases in skeletal muscle mass and function. However, the role of mTORC1 signalling in adult skeletal muscle homeostasis is still not well defined. Methods Inducible, muscle-specific Raptor and mTOR k.o. mice were generated. Muscles at 1 and 7 months after deletion were analysed to assess muscle histology and muscle force. Results We found no change in muscle size or contractile properties 1 month after deletion. Prolonging deletion of Raptor to 7 months, however, leads to a very marked phenotype characterized by weakness, muscle regeneration, mitochondrial dysfunction, and autophagy impairment. Unexpectedly, reduced mTOR signalling in muscle fibres is accompanied by the appearance of markers of fibre denervation, like the increased expression of the neural cell adhesion molecule (NCAM). Both muscle-specific deletion of mTOR or Raptor, or the use of rapamycin, was sufficient to induce 3-8% of NCAM-positive fibres (P < 0.01), muscle fibrillation, and neuromuscular junction (NMJ) fragmentation in 24% of examined fibres (P < 0.001). Mechanistically, reactivation of autophagy with the small peptide Tat-beclin1 is sufficient to prevent mitochondrial dysfunction and the appearance of NCAM-positive fibres in Raptor k.o. muscles. Conclusions Our study shows that mTOR signalling in skeletal muscle fibres is critical for maintaining proper fibre innervation, preserving the NMJ structure in both the muscle fibre and the motor neuron. In addition, considering the beneficial effects of exercise in most pathologies affecting the NMJ, our findings suggest that part of these beneficial effects of exercise are through the well-established activation of mTORC1 in skeletal muscle during and after exercise.