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The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia

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.·2020·Nature Communications
DOI 10.1038/s41467-020-18140-1PMC PMC7481251
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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.

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Metadata

Authors
Ham, D. J., Börsch, A., Lin, S., Thürkauf, M., Weihrauch, M., Reinhard, J. R., Delezie, J., Battilana, F., Wang, X., Kaiser, M. S., Guridi, M., Sinnreich, M., Rich, M. M., Mittal, N., Tintignac, L. A., Handschin, C., Zavolan, M., & Rüegg, M. A.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-09-09
Volume
11
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-020-18140-1
PMC
PMC7481251
Cited by
180
References
21
Language
en
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