Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13832-9
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Funding
- Spanish Ministry of Science, Innovation and Universities, Spain [SAF2015-67369-R, RTI2018-096068-B-I00, SAF 2015-70270-REDT]
- Maria de Maeztu Unit of Excellence award [MDM-2014-0370]
- UPF-CNIC collaboration agreement [ERC-2016-AdG-741966]
- La Caixa-HEALTH [HR17-00040]
- MDA [UPGRADE-H2020-825825]
- AFM
- DPP-E
- Instituto de Salud Carlos III (ISCIII)
- Ministerio de Ciencia, Innovacion y Universidades (MCNU)
- Pro CNIC Foundation
- Severo Ochoa Center of Excellence [SEV-2015-0505]
- Ellison Medical Foundation [AG-SS-2440-10, AG-NS-0932-12]
- NIH [R01DK114131, R01DK111465, R01DK102850]
- CARIPARO
- H2020-MSCA-RISE-2014
- Russian Science Foundation [17-14-01420]
- Juan de La Cierva Postdoctoral Fellowship
- Russian Science Foundation [17-14-01420] Funding Source: Russian Science Foundation
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A unique property of skeletal muscle is its ability to adapt its mass to changes in activity. Inactivity, as in disuse or aging, causes atrophy, the loss of muscle mass and strength, leading to physical incapacity and poor quality of life. Here, through a combination of transcriptomics and transgenesis, we identify sestrins, a family of stress-inducible metabolic regulators, as protective factors against muscle wasting. Sestrin expression decreases during inactivity and its genetic deficiency exacerbates muscle wasting; conversely, sestrin overexpression suffices to prevent atrophy. This protection occurs through mTORC1 inhibition, which upregulates autophagy, and AKT activation, which in turn inhibits FoxO-regulated ubiquitin-proteasome-mediated proteolysis. This study reveals sestrin as a central integrator of anabolic and degradative pathways preventing muscle wasting. Since sestrin also protected muscles against aging-induced atrophy, our findings have implications for sarcopenia. Ageing is associated with muscle atrophy, which negatively impacts quality of life. Here the authors show that expression of sestrins decreases during inactivity and that their overexpression prevents atrophy in mice via modulation of autophagy and protein degradation.
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