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Single-nucleus profiling unveils a geroprotective role of the Foxo3 in primate skeletal muscle aging

查看全文 作　　者：Ying [1,4]Jing;Yuesheng [4,6,8]Zuo;Yang [10,12]Yu;Liang [11]Sun;Zhengrong [13]Yu;Shuai [2,5,7]Ma;Qian [3,9]Zhao;Guoqiang [1,4]Sun;Huifang [2,5,7]Hu;Jingyi [2,5,7]Li;Daoyuan [3,9]Huang;Lixiao [4,6,8]Liu;Jiaming [4,6,8,14]Li;Zijuan [2,5,7]Xin;Haoyan [3,9]Huang;Juan Carlos Izpisua [16]Belmonte;Weiqi [4,5,6,8,14,15]Zhang;Si [3,9,17]Wang;Jing [1,4,5,7]Qu;Guang-Hui [2,3,4,5,7]Liu 高影响力作者 机构地区：[1]State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China;[2]State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China;[3]Advanced Innovation Center for Human Brain Protection,National Clinical Research Center for Geriatric Disorders,Xuanwu Hospital Capital Medical University,Beijing 100053,China;[4]University of Chinese Academy of Sciences,Beijing 100049,China;[5]Institute for Stem Cell and Regeneration,Chinese Academy of Sciences,Beijing 100101,China;[6]CAS Key Laboratory of Genomic and Precision Medicine,Beijing Institute of Genomics,Chinese Academy of Sciences,Beijing 100101,China;[7]Beijing Institute for Stem Cell and Regenerative Medicine,Beijing 100101,China;[8]China National Center for Bioinformation,Beijing 100101,China;[9]Aging Translational Medicine Center,Intemational Center for Aging and Cancer,Beijing Municipal Geriatric Medical Research Center,Xuanwu Hospital,Capital Medical University,Beijing 100053,China;[10]Department of Obstetrics and Gynecology,Center for Reproductive Medicine,Peking University Third Hospital,Beijing 100191,China;[11]The Key Laboratory of Geriatrics,Beijing Institute of Geriatrics,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing Hospital/National Center of Gerontology of National Health Commission,Beijing 100730,China;[12]Clinical Stem Cell Research Center,Peking University Third Hospital,Beijing 100191,China;[13]Department of Orthopaedics,Peking University First Hospital,Beijing 100034,China;[14]Sino-Danish College,University of Chinese Academy of Sciences,Beijing 101408,China;[15]Sino-Danish Center for Education and Research,Beijing 101408,China;[16]Altos Labs,Inc.,San Diego,CA 94022,USA;[17]The Fifth People's Hospital of Chongqing,Chongqing 400062,China高影响力机构 出　　处：《Protein & Cell》索引2023年第14卷第7期,共16页高影响力期刊 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). 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. 关 键 词：single-nucleus RNA sequencing PRIMATE AGING skeletal muscle FOxO3
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