Segalés Dalmau, JessicaPerdiguero, Eusebio, 1968-Serrano, Antonio L.Sousa-Victor, PedroOrtet Cortada, LauraJardí, MercèBudanov, Andrei V.García-Prat, Laura, 1987-Sandri, MarcoThomson, David M.Karin, MichaelHee Lee, JunMuñoz Cánoves, Pura, 1962-2020-04-212020-04-212020Segalés 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/s41467-019-13832-92041-1723http://hdl.handle.net/10230/44283A 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.application/pdfeng© 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-019-13832-9AutophagyProteolysisSkeletal muscleinfo:eu-repo/semantics/openAccess