{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:37:45Z","timestamp":1794011865011,"version":"4.8.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"48","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Ministry of Education-Singapore Academic Research Fund Award","award":["2022-MOET1-0004"],"award-info":[{"award-number":["2022-MOET1-0004"]}]},{"name":"Diana Koh Innovative Cancer Research Award","award":["Duke-NUS-DKICRA\/2024\/0001"],"award-info":[{"award-number":["Duke-NUS-DKICRA\/2024\/0001"]}]},{"name":"National Academy of Medicine","award":["MOH-001189-00"],"award-info":[{"award-number":["MOH-001189-00"]}]},{"DOI":"10.13039\/501100001349","name":"MOH | National Medical Research Council","doi-asserted-by":"publisher","award":["MOH-001208-00"],"award-info":[{"award-number":["MOH-001208-00"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Khoo Postdoctoral Fellowship Award","award":["Duke-NUS-KPFA\/2024\/0075"],"award-info":[{"award-number":["Duke-NUS-KPFA\/2024\/0075"]}]},{"name":"Ministry of Education-Singapore Academic Research Fund Award","award":["FY2025-MOET1-0004"],"award-info":[{"award-number":["FY2025-MOET1-0004"]}]},{"DOI":"10.13039\/501100001349","name":"MOH | National Medical Research Council","doi-asserted-by":"publisher","award":["MOH-001885-01"],"award-info":[{"award-number":["MOH-001885-01"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"MOH | National Medical Research Council","doi-asserted-by":"publisher","award":["MOH-001831-01"],"award-info":[{"award-number":["MOH-001831-01"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Khoo Postdoctoral Fellowship Award","award":["Duke-NUS-KPFA\/2025\/0078"],"award-info":[{"award-number":["Duke-NUS-KPFA\/2025\/0078"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,12,2]]},"abstract":"<jats:p>\n                    Skeletal muscle is essential for movement, respiration, and metabolism, with mTORC1 acting as a key regulator of protein synthesis and degradation. In aging muscle, mTORC1 becomes overactivated, contributing to sarcopenia, though the mechanisms remain unclear. Here, we identify DEAF1, a FOXO-regulated transcription factor, as a key upstream driver of mTORC1 in aged muscle. Elevated\n                    <jats:italic toggle=\"yes\">Deaf1<\/jats:italic>\n                    expression increases\n                    <jats:italic toggle=\"yes\">mTOR<\/jats:italic>\n                    transcription, leading to heightened mTORC1 activity, impaired proteostasis, and muscle senescence. Remarkably, exercise suppresses\n                    <jats:italic toggle=\"yes\">Deaf1<\/jats:italic>\n                    expression via FOXO activation, restoring mTORC1 balance and alleviating muscle aging. Conversely, FOXO inhibition or\n                    <jats:italic toggle=\"yes\">Deaf1<\/jats:italic>\n                    overexpression blocks exercise benefits on muscle health. These findings highlight DEAF1 as a critical link between FOXO and mTORC1 and suggest that targeting the FOXO\u2013DEAF1\u2013mTORC1 axis may offer therapeutic potential to preserve muscle function during aging.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2508893122","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T20:13:16Z","timestamp":1764015196000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":11,"title":["Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2357-9461","authenticated-orcid":false,"given":"Sze Mun","family":"Choy","sequence":"first","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kah Yong","family":"Goh","sequence":"additional","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7779-641X","authenticated-orcid":false,"given":"Wen Xing","family":"Lee","sequence":"additional","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0900-1437","authenticated-orcid":false,"given":"Weiyi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8855-7090","authenticated-orcid":false,"given":"Qian","family":"Gou","sequence":"additional","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya D.","family":"Gopal Krishnan","sequence":"additional","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Chee Ong","sequence":"additional","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenon","family":"Chua","sequence":"additional","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School","place":["Singapore, Singapore"]},{"name":"Department of Orthopaedic Surgery, Singapore General Hospital","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8589-2938","authenticated-orcid":false,"given":"Nathan","family":"Harmston","sequence":"additional","affiliation":[{"name":"Molecular Biosciences Division, Cardiff School of Biosciences, Cardiff University","place":["Cardiff, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8347-9891","authenticated-orcid":false,"given":"Hong-Wen","family":"Tang","sequence":"additional","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School","place":["Singapore, Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70218-7"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2020.tb00136.x"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24010297"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.12965\/jer.1836268.134"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00056.2021"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1999.276.1.C120"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1101-1014"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1249\/JES.0000000000000189"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2021945118"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.02.023"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.7.7.15537"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.5141"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/1423-0127-19-52"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2024.2374693"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.052007"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.03.010"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20780-2"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12943"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2016.03.008"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00141-19"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2014.04.025"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12891-020-03236-y"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12603-019-1255-1"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18140-1"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.10.007"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22158149"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2013.10.017"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.273"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13121"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.18632\/aging.100926"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12263-023-00725-2"},{"key":"e_1_3_4_32_2","article-title":"Muscle FOXO-specific overexpression and endurance exercise protect skeletal muscle and heart from defects caused by a high-fat diet in young Drosophila","volume":"16","author":"Jin J. H.","year":"2023","unstructured":"J. H. Jin, D. T. Wen, Y. L. Chen, W. Q. Hou, Muscle FOXO-specific overexpression and endurance exercise protect skeletal muscle and heart from defects caused by a high-fat diet in young Drosophila. Front. Biosci. (Landmark Ed) 16, 28 (2023).","journal-title":"Front. Biosci. (Landmark Ed)"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00421-011-2287-3"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00952.2011"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07813"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.583478"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7670"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41757-x"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-023-01820-z"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0007114521004918"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M413732200"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-05483-x"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.113175"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2015.06.019"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1159\/000375235"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2025.1614732"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13124"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.338"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11223587"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37876-0"},{"key":"e_1_3_4_51_2","unstructured":"N. Harmston H. Tang ChIP-seq of Deaf1 in myocytes. NCBI GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE293804. Deposited 4 April 2025."},{"key":"e_1_3_4_52_2","unstructured":"S. M. Choy Data from: DEAF1 ChIP-Seq analysis in C2C12 myocytes. GitHub. https:\/\/github.com\/harmstonlab\/Choy_et_al_deaf1. Deposited 4 April 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2508893122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T20:14:02Z","timestamp":1764015242000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2508893122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,24]]},"references-count":52,"journal-issue":{"issue":"48","published-print":{"date-parts":[[2025,12,2]]}},"alternative-id":["10.1073\/pnas.2508893122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2508893122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,24]]},"assertion":[{"value":"2025-04-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2508893122"}}