The hypothalamic–pituitary–gonadal axis controls muscle stem cell senescence through autophagosome clearance
Abstract 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 systemicall...
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Wiley
2021-02-01
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Series: | Journal of Cachexia, Sarcopenia and Muscle |
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Online Access: | https://doi.org/10.1002/jcsm.12653 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ji‐Hoon Kim Inkuk Park Hijai R. Shin Joonwoo Rhee Ji‐Yun Seo Young‐Woo Jo Kyusang Yoo Sang‐Hyeon Hann Jong‐Seol Kang Jieon Park Ye Lynne Kim Ju‐Yeon Moon Man Ho Choi Young‐Yun Kong |
spellingShingle |
Ji‐Hoon Kim Inkuk Park Hijai R. Shin Joonwoo Rhee Ji‐Yun Seo Young‐Woo Jo Kyusang Yoo Sang‐Hyeon Hann Jong‐Seol Kang Jieon Park Ye Lynne Kim Ju‐Yeon Moon Man Ho Choi Young‐Yun Kong The hypothalamic–pituitary–gonadal axis controls muscle stem cell senescence through autophagosome clearance Journal of Cachexia, Sarcopenia and Muscle Aging Muscle stem cell Muscle regeneration Cellular senescence Sex steroid hormones Autophagy |
author_facet |
Ji‐Hoon Kim Inkuk Park Hijai R. Shin Joonwoo Rhee Ji‐Yun Seo Young‐Woo Jo Kyusang Yoo Sang‐Hyeon Hann Jong‐Seol Kang Jieon Park Ye Lynne Kim Ju‐Yeon Moon Man Ho Choi Young‐Yun Kong |
author_sort |
Ji‐Hoon Kim |
title |
The hypothalamic–pituitary–gonadal axis controls muscle stem cell senescence through autophagosome clearance |
title_short |
The hypothalamic–pituitary–gonadal axis controls muscle stem cell senescence through autophagosome clearance |
title_full |
The hypothalamic–pituitary–gonadal axis controls muscle stem cell senescence through autophagosome clearance |
title_fullStr |
The hypothalamic–pituitary–gonadal axis controls muscle stem cell senescence through autophagosome clearance |
title_full_unstemmed |
The hypothalamic–pituitary–gonadal axis controls muscle stem cell senescence through autophagosome clearance |
title_sort |
hypothalamic–pituitary–gonadal axis controls muscle stem cell senescence through autophagosome clearance |
publisher |
Wiley |
series |
Journal of Cachexia, Sarcopenia and Muscle |
issn |
2190-5991 2190-6009 |
publishDate |
2021-02-01 |
description |
Abstract 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 β‐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, 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. 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. |
topic |
Aging Muscle stem cell Muscle regeneration Cellular senescence Sex steroid hormones Autophagy |
url |
https://doi.org/10.1002/jcsm.12653 |
work_keys_str_mv |
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doaj-5c55131d0f054ccebc3bb718e07003a22021-02-18T07:17:13ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092021-02-0112117719110.1002/jcsm.12653The hypothalamic–pituitary–gonadal axis controls muscle stem cell senescence through autophagosome clearanceJi‐Hoon Kim0Inkuk Park1Hijai R. Shin2Joonwoo Rhee3Ji‐Yun Seo4Young‐Woo Jo5Kyusang Yoo6Sang‐Hyeon Hann7Jong‐Seol Kang8Jieon Park9Ye Lynne Kim10Ju‐Yeon Moon11Man Ho Choi12Young‐Yun Kong13School of Biological Sciences Seoul National University Seoul South KoreaSchool of Biological Sciences Seoul National University Seoul South KoreaDepartment of Molecular and Cell Biology University of California Berkeley CA USASchool of Biological Sciences Seoul National University Seoul South KoreaSchool of Biological Sciences Seoul National University Seoul South KoreaSchool of Biological Sciences Seoul National University Seoul South KoreaSchool of Biological Sciences Seoul National University Seoul South KoreaSchool of Biological Sciences Seoul National University Seoul South KoreaSchool of Biological Sciences Seoul National University Seoul South KoreaSchool of Biological Sciences Seoul National University Seoul South KoreaSchool of Biological Sciences Seoul National University Seoul South KoreaCollege of Pharmacy The Catholic University of Korea Gyeonggi‐do South KoreaMolecular Recognition Research Center KIST Seoul South KoreaSchool of Biological Sciences Seoul National University Seoul South KoreaAbstract 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 β‐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, 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. 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.https://doi.org/10.1002/jcsm.12653AgingMuscle stem cellMuscle regenerationCellular senescenceSex steroid hormonesAutophagy |