{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T20:33:50Z","timestamp":1789245230960,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T00:00:00Z","timestamp":1606435200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF\u20102017R1A2B3007797 NRF\u20102020R1A5A1018081"],"award-info":[{"award-number":["NRF\u20102017R1A2B3007797 NRF\u20102020R1A5A1018081"]}],"id":[{"id":"10.13039\/501100003725","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":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>With organismal aging, the hypothalamic\u2013pituitary\u2013gonadal (HPG) activity gradually decreases, resulting in the systemic functional declines of the target tissues including skeletal muscles. Although the HPG axis plays an important role in health span, how the HPG axis systemically prevents functional aging is largely unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated muscle stem cell (MuSC)\u2010specific androgen receptor (Ar) and oestrogen receptor 2 (Esr2) double knockout (dKO) mice and pharmacologically inhibited (Antide) the HPG axis to mimic decreased serum levels of sex steroid hormones in aged mice. After short\u2010term and long\u2010term sex hormone signalling ablation, the MuSCs were functionally analysed, and their aging phenotypes were compared with those of geriatric mice (30\u2010month\u2010old). To investigate pathways associated with sex hormone signalling disruption, RNA sequencing and bioinformatic analyses were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Disrupting the HPG axis results in impaired muscle regeneration [wild\u2010type (WT) vs. dKO, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001; Veh vs. Antide, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.004]. The expression of DNA damage marker (in WT\u00a0=\u00a07.0\u00a0\u00b1\u00a01.6%, dKO\u00a0=\u00a032.5\u00a0\u00b1\u00a02.6%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01; in Veh\u00a0=\u00a013.4\u00a0\u00b1\u00a04.5%, Antide\u00a0=\u00a029.7\u00a0\u00b1\u00a05.5%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.028) and senescence\u2010associated \u03b2\u2010galactosidase activity (in WT\u00a0=\u00a03.8\u00a0\u00b1\u00a01.2%, dKO\u00a0=\u00a010.3\u00a0\u00b1\u00a01.6%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01; in Veh\u00a0=\u00a02.1\u00a0\u00b1\u00a00.4%, Antide\u00a0=\u00a09.6\u00a0\u00b1\u00a00.8%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.005), as well as the expression levels of senescence\u2010associated genes, <jats:italic>p16<\/jats:italic><jats:sup><jats:italic>Ink4a<\/jats:italic><\/jats:sup> and <jats:italic>p21<\/jats:italic><jats:sup><jats:italic>Cip1<\/jats:italic><\/jats:sup>, was significantly increased in the MuSCs, indicating that genetic and pharmacological inhibition of the HPG axis recapitulates the progressive aging process of MuSCs. Mechanistically, the ablation of sex hormone signalling reduced the expression of <jats:italic>transcription factor EB (Tfeb)<\/jats:italic> and Tfeb target gene in MuSCs, suggesting that sex hormones directly induce the expression of Tfeb, a master regulator of the autophagy\u2013lysosome pathway, and consequently autophagosome clearance. Transduction of the Tfeb in naturally aged MuSCs increased muscle mass [control geriatric MuSC transplanted tibialis anterior (TA) muscle\u00a0=\u00a034.3\u00a0\u00b1\u00a02.9\u00a0mg, Tfeb\u2010transducing geriatric MuSC transplanted TA muscle\u00a0=\u00a044.7\u00a0\u00b1\u00a06.7\u00a0mg, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.015] and regenerating myofibre size [eMyHC<jats:sup>+<\/jats:sup>tdTomato<jats:sup>+<\/jats:sup> myofibre cross\u2010section area (CSA) in control vs. Tfeb, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.002] after muscle injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data show that the HPG axis systemically controls autophagosome clearance in MuSCs through Tfeb and prevents MuSCs from senescence, suggesting that sustained HPG activity throughout life regulates autophagosome clearance to maintain the quiescence of MuSCs by preventing senescence until advanced age.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12653","type":"journal-article","created":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T08:29:38Z","timestamp":1606465778000},"page":"177-191","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The hypothalamic\u2013pituitary\u2013gonadal axis controls muscle stem cell senescence through autophagosome clearance"],"prefix":"10.1002","volume":"12","author":[{"given":"Ji\u2010Hoon","family":"Kim","sequence":"first","affiliation":[{"name":"School of Biological Sciences Seoul National University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inkuk","family":"Park","sequence":"additional","affiliation":[{"name":"School of Biological Sciences Seoul National University  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hijai R.","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology University of California  Berkeley CA USA"},{"name":"The Paul F. 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