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Publication . Article . 2020

Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals

Segalés, Jessica; Perdiguero, Eusebio; Serrano, Antonio L.; Sousa-Victor, Pedro; Ortet, Laura; Jardí, Mercè; Budanov, Andrei V.; +6 Authors
Open Access  
Abstract
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.
The authors acknowledge funding from the Spanish Ministry of Science, Innovation and Universities, Spain (grants SAF2015-67369-R, RTI2018-096068-B-I00, and SAF 2015-70270-REDT, a María de Maeztu Unit of Excellence award to UPF [MDM-2014-0370], and the UPF-CNIC collaboration agreement, ERC-2016-AdG-741966, La Caixa-HEALTH (HR17-00040), MDA, UPGRADE-H2020-825825, AFM and DPP-E. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Work was also supported by the Ellison Medical Foundation (AG-SS-2440-10 to M.K. and AG-NS-0932-12 to J.H.L.), NIH (R01DK114131, R01DK111465, and R01DK102850 to J.H.L.), CARIPARO and H2020-MSCA-RISE-2014 (to M.S.), and the Russian Science Foundation (Grant 17-14-01420 to A.V.B.). J.S. acknowledges funding from a Juan de La Cierva Postdoctoral Fellowship.
© The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Subjects by Vocabulary

Microsoft Academic Graph classification: Skeletal muscle medicine.anatomical_structure medicine Cell biology mTORC1 Atrophy medicine.disease business.industry business Autophagy Sarcopenia Anabolism Muscle atrophy medicine.symptom Wasting

Library of Congress Subject Headings: lcsh:Science lcsh:Q

ACM Computing Classification System: ComputingMilieux_LEGALASPECTSOFCOMPUTING

Subjects

Article, Autophagy, Proteolysis, Skeletal muscle, Science, Q, General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Muscle, Skeletal, Animals, Mice, Inbred C57BL, Transgenic, Humans, Muscular Atrophy, Disease Models, Animal, Muscle Proteins, Heat-Shock Proteins, Nuclear Proteins, Signal Transduction, Gene Expression, Aging, Autophagy, Male, Sarcopenia, Forkhead Box Protein O1, Forkhead Box Protein O3, Mechanistic Target of Rapamycin Complex 1

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Funded byView all
EC| STEM-AGING
Project
STEM-AGING
Tissue regeneration and aging: the decisive quiescent stem-cell state
  • Funder: European Commission (EC)
  • Project Code: 741966
  • Funding stream: H2020 | ERC | ERC-ADG
Validated by funder
,
NIH| Protein inclusions in non-alcoholic steatohepatitis
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01DK114131-01A1
  • Funding stream: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
,
NIH| Mechanisms underlying Hepatoprotective Roles of Sestrin2
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01DK102850-01A1
  • Funding stream: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
,
EC| UPGRADE
Project
UPGRADE
Unlocking Precision Gene Therapy
  • Funder: European Commission (EC)
  • Project Code: 825825
  • Funding stream: H2020 | RIA
Validated by funder
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