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- Title
The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia.
- Authors
Ham, Daniel J.; Börsch, Anastasiya; Lin, Shuo; Thürkauf, Marco; Weihrauch, Martin; Reinhard, Judith R.; Delezie, Julien; Battilana, Fabienne; Wang, Xueyong; Kaiser, Marco S.; Guridi, Maitea; Sinnreich, Michael; Rich, Mark M.; Mittal, Nitish; Tintignac, Lionel A.; Handschin, Christoph; Zavolan, Mihaela; Rüegg, Markus A.
- Abstract
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. mTORC1 expression is increased during ageing of muscle, and on the other hand, its activation promotes muscle hypertrophy. Here, the authors assess whether mTORC1 has positive or negative effects on ageing, and show that its long-term inhibition preserves muscle mass and function and neuromuscular junction integrity, whereas muscle-specific activation is associated with sarcopenia.
- Subjects
MYONEURAL junction; SKELETAL muscle; MUSCLE growth; GENE expression profiling; MUSCLE mass; MUSCLE aging
- Publication
Nature Communications, 2020, Vol 11, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-18140-1