{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T03:46:24Z","timestamp":1789875984657,"version":"4.0.1"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T00:00:00Z","timestamp":1668643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["OFIRG18nov\u20100093"],"award-info":[{"award-number":["OFIRG18nov\u20100093"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"publisher","award":["108\u2010Z\u201004"],"award-info":[{"award-number":["108\u2010Z\u201004"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007155","name":"Medical Research Council Canada","doi-asserted-by":"publisher","award":["MC\u2010A654\u20105QB40"],"award-info":[{"award-number":["MC\u2010A654\u20105QB40"]}],"id":[{"id":"10.13039\/501100007155","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Chronic mTORC1 activation in skeletal muscle is linked with age\u2010associated loss of muscle mass and strength, known as sarcopenia. Genetic activation of mTORC1 by conditionally ablating mTORC1 upstream inhibitor TSC1 in skeletal muscle accelerates sarcopenia development in adult mice. Conversely, genetic suppression of mTORC1 downstream effectors of protein synthesis delays sarcopenia in natural aging mice. mTORC1 promotes protein synthesis by activating ribosomal protein S6 kinases (S6Ks) and inhibiting eIF4E\u2010binding proteins (4EBPs). Whole\u2010body knockout of S6K1 or muscle\u2010specific over\u2010expression of a 4EBP1 mutant transgene (4EBP1mt), which is resistant to mTORC1\u2010mediated inhibition, ameliorates muscle loss with age and preserves muscle function by enhancing mitochondria activities, despite both transgenic mice showing retarded muscle growth at a young age. Why repression of mTORC1\u2010mediated protein synthesis can mitigate progressive muscle atrophy and dysfunction with age remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mice with myofiber\u2010specific knockout of TSC1 (TSC1mKO), in which mTORC1 is hyperactivated in fully differentiated myofibers, were used as a mouse model of sarcopenia. To elucidate the role of mTORC1\u2010mediated protein synthesis in regulating muscle mass and physiology, we bred the 4EBP1mt transgene or <jats:italic>S6k1<\/jats:italic> floxed mice into the TSC1mKO mouse background to generate 4EBP1mt\u2010TSC1mKO or S6K1\u2010TSC1mKO mice, respectively. Functional and molecular analyses were performed to assess their role in sarcopenia development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we show that 4EBP1mt\u2010TSC1mKO, but not S6K1\u2010TSC1mKO, preserved muscle mass (36.7% increase compared with TSC1mKO, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and strength (36.8% increase compared with TSC1mKO, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) at the level of control mice. Mechanistically, 4EBP1 activation suppressed aberrant protein synthesis (two\u2010fold reduction compared with TSC1mKO, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and restored autophagy flux without relieving mTORC1\u2010mediated inhibition of ULK1, an upstream activator of autophagosome initiation. We discovered a previously unidentified phenotype of lysosomal failure in TSC1mKO mouse muscle, in which the lysosomal defect was also conserved in the naturally aged mouse muscle, whereas 4EBP1 activation enhanced lysosomal protease activities to compensate for impaired autophagy induced by mTORC1 hyperactivity. Consequently, 4EBP1 activation relieved oxidative stress to prevent toxic aggregate accumulation (0.5\u2010fold reduction compared with TSC1mKO, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) in muscle and restored mitochondrial homeostasis and function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identify 4EBP1 as a communication hub coordinating protein synthesis and degradation to protect proteostasis, revealing therapeutic potential for activating lysosomal degradation to mitigate sarcopenia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13121","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T07:42:40Z","timestamp":1668757360000},"page":"198-213","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Activation of <scp>eIF4E<\/scp>\u2010binding\u2010protein\u20101 rescues <scp>mTORC1<\/scp>\u2010induced sarcopenia by expanding lysosomal degradation capacity"],"prefix":"10.1002","volume":"14","author":[{"given":"Elisa M.","family":"Crombie","sequence":"first","affiliation":[{"name":"Department of Physiology, Yong Loo Lin School of Medicine National University of Singapore  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seonyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, Yong Loo Lin School of Medicine National University of Singapore  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Adamson","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging  Novato California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Physiology, Yong Loo Lin School of Medicine National University of Singapore  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