Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

Daniel J. Ham (), Anastasiya Börsch, Kathrin Chojnowska, Shuo Lin, Aurel B. Leuchtmann, Alexander S. Ham, Marco Thürkauf, Julien Delezie, Regula Furrer, Dominik Burri, Michael Sinnreich, Christoph Handschin, Lionel A. Tintignac, Mihaela Zavolan, Nitish Mittal () and Markus A. Rüegg ()
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Daniel J. Ham: University of Basel
Anastasiya Börsch: University of Basel
Kathrin Chojnowska: University of Basel
Shuo Lin: University of Basel
Aurel B. Leuchtmann: University of Basel
Alexander S. Ham: University of Basel
Marco Thürkauf: University of Basel
Julien Delezie: University of Basel
Regula Furrer: University of Basel
Dominik Burri: University of Basel
Michael Sinnreich: University of Basel
Christoph Handschin: University of Basel
Lionel A. Tintignac: University of Basel
Mihaela Zavolan: University of Basel
Nitish Mittal: University of Basel
Markus A. Rüegg: University of Basel

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Preserving skeletal muscle function is essential to maintain life quality at high age. Calorie restriction (CR) potently extends health and lifespan, but is largely unachievable in humans, making “CR mimetics” of great interest. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, is considered a potential CR mimetic and is proven to counteract age-related muscle loss. Therefore, we tested whether rapamycin acts via similar mechanisms as CR to slow muscle aging. Here we show that long-term CR and rapamycin unexpectedly display distinct gene expression profiles in geriatric mouse skeletal muscle, despite both benefiting aging muscles. Furthermore, CR improves muscle integrity in mice with nutrient-insensitive, sustained muscle mTORC1 activity and rapamycin provides additive benefits to CR in naturally aging mouse muscles. We conclude that rapamycin and CR exert distinct, compounding effects in aging skeletal muscle, thus opening the possibility of parallel interventions to counteract muscle aging.

Date: 2022
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DOI: 10.1038/s41467-022-29714-6

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