The hypothalamic-pituitary-gonadal axis controls muscle stem cell senescence through autophagosome clearance
- The hypothalamic-pituitary-gonadal axis controls muscle stem cell senescence through autophagosome clearance
- 최만호; 김지훈; 박인국; 신희재; 이준우; 유규상; 한상헌; 강종설; 박지언; 김예린; 문주연; 공영윤; JiYun Seo; YoungWoo Jo
- HPG axis; muscle stem cell
- Issue Date
- Journal of Cachexia, Sarcopenia and Muscle
- VOL 12, NO 1-191
- Background: With organismal aging, the hypothalamic？pituitary？gonadal (HPG) activity gradually decreases, resulting in thesystemic 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 shortterm and longterm sex hormone signalling ablation, the MuSCs were functionally analysed, and their aging phenotypes were compared with those of geriatric mice (30monthold). 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 [wildtype (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 senescenceassociated βgalactosidase 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 senescenceassociated genes, p16Ink4a and p21Cip1, 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. T
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