@article{eb40859627e9464298ca3b12155bf61e,
title = "mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism",
abstract = "Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age-related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3's phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age-related muscle atrophy, and GDF signaling is a proposed mechanism.",
keywords = "aging, mTORC1, oxidative stress, signal transduction, skeletal muscle",
author = "Huibin Tang and Ken Inoki and Brooks, {Susan V.} and Hideki Okazawa and Myung Lee and Junying Wang and Michael Kim and Kennedy, {Catherine L.} and Macpherson, {Peter C.D.} and Xuhuai Ji and {Van Roekel}, Sabrina and Fraga, {Danielle A.} and Kun Wang and Jinguo Zhu and Yoyo Wang and Sharp, {Zelton D.} and Miller, {Richard A.} and Rando, {Thomas A.} and Daniel Goldman and Guan, {Kun Liang} and Shrager, {Joseph B.}",
note = "Funding Information: We are grateful to Dr. Dario Alessi (University of Dundee) for MCK-Cre mice. We thank Dr. Stephen E. Alway (University of Tennessee), Dr. Raymond A. Sobel (Stanford University), and Dr. John Faulkner (University of Michigan) for helpful advice. We thank Dr. Anne Brunet (Stanford University) and Dr. Xuedong Liu (University of Colorado Boulder) for reporter plasmids. We also thank the following for technical assistance: Boris Vidri, Pritish Iyer, Gabriel Sotomayor (University of Michigan), and Donna Yoshida (Stanford University). Some of the rapamycin-treated mice were provided by the NIA Interventions Testing Program (AG022303). This research is supported by NIH CA108941 and GM51586 (KLG), NIH 5RO1NS59848 and MDA (DG), VA merit review grant (JBS), NIH GM110019 and DK083491 (KI), and NIH AG-AG050676 (SVB). Funding Information: We are grateful to Dr. Dario Alessi (University of Dundee) for MCK‐ Cre mice. We thank Dr. Stephen E. Alway (University of Tennessee), Dr. Raymond A. Sobel (Stanford University), and Dr. John Faulkner (University of Michigan) for helpful advice. We thank Dr. Anne Brunet (Stanford University) and Dr. Xuedong Liu (University of Colorado Boulder) for reporter plasmids. We also thank the following for technical assistance: Boris Vidri, Pritish Iyer, Gabriel Sotomayor (University of Michigan), and Donna Yoshida (Stanford University). Some of the rapamycin‐treated mice were provided by the NIA Interventions Testing Program (AG022303). This research is sup‐ ported by NIH CA108941 and GM51586 (KLG), NIH 5RO1NS59848 and MDA (DG), VA merit review grant (JBS), NIH GM110019 and DK083491 (KI), and NIH AG‐AG050676 (SVB). Publisher Copyright: {\textcopyright} 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",
year = "2019",
month = jun,
doi = "10.1111/acel.12943",
language = "English (US)",
volume = "18",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "3",
}