The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia
The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia
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DOI：
10.1038/s41467-020-18140-1
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发表时间：
2020-09-09
影响因子：
16.6
通讯作者：
Ruegg, Markus A.
中科院分区：
文献类型：
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作者：
Ham, Daniel J.;Borsch, Anastasiya;Ruegg, Markus A.
随着许多发达国家的人类平均寿命延长到80多岁，与年龄相关的肌肉损失(骨质疏松症)的社会负担正在增加。MTORC1促进骨骼肌肥大，但也会推动机体衰老。在这里，我们解决的问题是mTORC1的激活或抑制是否有利于骨骼肌的衰老。我们证明，用雷帕霉素慢性抑制mTORC1对衰老的小鼠骨骼肌是压倒性的，但不是全部的，而遗传的，肌肉纤维特异性的mTORC1激活足以诱导肌萎缩症的分子特征。通过整合年轻和老年小鼠全面的生理学和广泛的基因表达谱，以及mTORC1基因的遗传激活或药物抑制，我们建立了表型支持的、mTORC1型的多肌肉基因表达图谱，SarcoAtlas(https://sarcoatlas.scicore.unibas.ch/)，)，作为一个用户友好的基因发现工具。我们发现肌肉量减少的主要驱动因素是肌肉间的差异，并确定神经肌肉连接是mTORC1驱动的肌肉老化的焦点。
With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (https://sarcoatlas.scicore.unibas.ch/), as a user-friendly gene discovery tool. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging.