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

Segalés Dalmau, Jessica; Perdiguero, Eusebio, 1968-; Serrano, Antonio L.; Sousa-Victor, Pedro; Ortet Cortada, Laura; Jardí, Mercè; Budanov, Andrei V.; García-Prat, Laura, 1987-; Sandri, Marco; Thomson, David M.; Karin, Michael; Hee Lee, Jun; Muñoz Cánoves, Pura, 1962-

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

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dc.contributor.author Segalés Dalmau, Jessica
dc.contributor.author Perdiguero, Eusebio, 1968-
dc.contributor.author Serrano, Antonio L.
dc.contributor.author Sousa-Victor, Pedro
dc.contributor.author Ortet Cortada, Laura
dc.contributor.author Jardí, Mercè
dc.contributor.author Budanov, Andrei V.
dc.contributor.author García-Prat, Laura, 1987-
dc.contributor.author Sandri, Marco
dc.contributor.author Thomson, David M.
dc.contributor.author Karin, Michael
dc.contributor.author Hee Lee, Jun
dc.contributor.author Muñoz Cánoves, Pura, 1962-
dc.date.accessioned 2020-04-21T07:38:34Z
dc.date.available 2020-04-21T07:38:34Z
dc.date.issued 2020
dc.description.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.
dc.description.sponsorship 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.
dc.format.mimetype application/pdf
dc.identifier.citation Segalés J, Perdiguero E, Serrano AL, Sousa-Victor P, Ortet L, Jardí M, Budanov AV, Garcia-Prat L, Sandri M, Thomson DM, Karin M, Hee Lee J, Muñoz-Cánoves P. Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals. Nat Commun. 2020; 11(1):189. DOI: 10.1038/s41467-019-13832-9
dc.identifier.doi http://dx.doi.org/10.1038/s41467-019-13832-9
dc.identifier.issn 2041-1723
dc.identifier.uri http://hdl.handle.net/10230/44283
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Nat Commun. 2020; 11(1):189
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/741966
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-67369-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-096068-B-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-70270-REDT
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/825825
dc.rights © 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/.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Autophagy
dc.subject.keyword Proteolysis
dc.subject.keyword Skeletal muscle
dc.title Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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