摘要
Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia,and increases the risk of many aging-related metabolic diseases.Here,we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging.A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types,indicating a higher susceptibility of skeletal muscle fiber to aging.We found a downregulation of Foxo3 in aged primate skeletal muscle,and identi-fied FOxo3 as a hub transcription factor maintaining skeletal muscle homeostasis.Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model,we revealed that silence of Foxo3 accelerates human myotube senescence,whereas genetic activation of endogenous FOxO3 alleviates human myotube aging.Altogether,based on a combination of monkey skeletal muscle and human myotube aging research models,we unraveled the pivotal role of the FOxO3 in safeguarding primate skeletal muscle from aging,providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-relateddisorders.
基金
supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA16000000)
the National Natural Science Foundation of China(Nos.82071588,81921006,82125011,92149301,92168201,92049116,32121001,82192863,91949209,92049304,82122024,82001477,31900523,81861168034,32000500,82271600,82201714)
the National Key Research and Development Program of China(Nos.2018YFC2000100,2020YFA0804000,2018YFA0107203,2020YFA0112200,2021YFF1201005,2021ZD0202401,2018YFC2000400,2020YFA0113400,2021YFE0111800,2022YFA1103700)
the Program of the Beijing Natural Science Foundation(No.Z190019)
K.C.Wong Education Foundation(Nos.GJTD-2019-06,GJTD-2019-08)
Beijing Medical Research(2021-8)
the Pilot Project for Public Welfare Development and Reform of Beijing-affliated Medical Research Institutes(No.11000022T000000461062)
Young Elite Scientists Sponsorship Program by CAST(Nos.YESS20200012,YESS20210002)
CAS Project for Young Scientists in Basic Research(No.YSBR-076,YSBR-012,YSBR-036)
Youth Innovation Promotion Association of CAS(Nos.E1CAZW0401,2020085,2022083)
the Informatization Plan of Chinese Academy of Sciences(Nos.CAS-WX2022SDC-XK14,CASWX2021SF-0301,CAS-WX2021SF-0101)
the Tencent Foundation(No.2021-1045),CAMS Innovation Fund for Medical Sciences(No.2021-12M-1-050)
the Fellowship of China Postdoctoral Science Foundation(2022M712216).
