Kim, Ji-Hoon Park, Inkuk Shin, Hijai R. Rhee, Joonwoo Seo, Ji-Yun Jo, Young-Woo Yoo, Kyusang Hann, Sang-Hyeon Kang, Jong-Seol Park, Jieon Kim, Ye Lynne Moon, Ju-Yeon Choi, Man Ho Kong, Young-Yun 2024-01-19T15:32:19Z 2024-01-19T15:32:19Z 2021-09-02 2021-02 2190-5991 https://pubs.kist.re.kr/handle/201004/117476 Background With organismal aging, the hypothalamic-pituitary-gonadal (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. Methods We generated muscle stem cell (MuSC)-specific 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-term and long-term sex hormone signalling ablation, the MuSCs were functionally analysed, and their aging phenotypes were compared with those of geriatric mice (30-month-old). To investigate pathways associated with sex hormone signalling disruption, RNA sequencing and bioinformatic analyses were performed. Results Disrupting the HPG axis results in impaired muscle regeneration [wild-type (WT) vs. dKO, P < 0.0001; Veh vs. Antide, P = 0.004]. The expression of DNA damage marker (in WT = 7.0 +/- 1.6%, dKO = 32.5 +/- 2.6%, P < 0.01; in Veh = 13.4 +/- 4.5%, Antide = 29.7 +/- 5.5%, P = 0.028) and senescence-associated beta-galactosidase activity (in WT = 3.8 +/- 1.2%, dKO = 10.3 +/- 1.6%, P < 0.01; in Veh = 2.1 +/- 0.4%, Antide = 9.6 +/- 0.8%, P = 0.005), as well as the expression levels of senescence-associated genes, p16(Ink4a) and p21(Cip1), 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 transcription factor EB (Tfeb) and Tfeb target gene in MuSCs, suggesting that sex hormones directly induce the expression of Tfeb, a master regulator of the autophagy-lysosome pathway, and consequently autophagosome clearance. Transduction of the Tfeb in naturally aged MuSCs increased muscle mass [control geriatric MuSC transplanted tibialis anterior (TA) muscle = 34.3 +/- 2.9 mg, Tfeb-transducing geriatric MuSC transplanted TA muscle = 44.7 +/- 6.7 mg, P = 0.015] and regenerating myofibre size [eMyHC(+)tdTomato(+) myofibre cross-section area (CSA) in control vs. Tfeb, P = 0.002] after muscle injury. Conclusions 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. English WILEY SKELETAL-MUSCLE SATELLITE CELLS ANDROGEN RECEPTOR BETA PROTEOSTASIS REQUIREMENT SUPPRESSION QUIESCENCE PROMOTES The hypothalamic-pituitary-gonadal axis controls muscle stem cell senescence through autophagosome clearance Article 10.1002/jcsm.12653 1 JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v.12, no.1, pp.177 - 191 JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE 12 1 177 191 scie scopus 000592452900001 2-s2.0-85096746899 Geriatrics & Gerontology Medicine, General & Internal Geriatrics & Gerontology General & Internal Medicine Article SKELETAL-MUSCLE SATELLITE CELLS ANDROGEN RECEPTOR BETA PROTEOSTASIS REQUIREMENT SUPPRESSION QUIESCENCE PROMOTES Aging Muscle stem cell Muscle regeneration Cellular senescence Sex steroid hormones Autophagy