Single-nucleus profiling unveils a geroprotective role of the FOXO3 in primate skeletal muscle aging

doi:10.1093/procel/pwac061

Protein Cell

2023, Vol. 14

Issue (7) : 497-512 https://doi.org/10.1093/procel/pwac061

RESEARCH ARTICLE

Single-nucleus profiling unveils a geroprotective role of the FOXO3 in primate skeletal muscle aging

Ying Jing^1,⁴, Yuesheng Zuo^4,^6,⁸, Yang Yu^10,¹², Liang Sun¹¹, Zhengrong Yu¹³, Shuai Ma^2,^5,⁷, Qian Zhao^3,⁹, Guoqiang Sun^1,⁴, Huifang Hu^2,^5,⁷, Jingyi Li^2,^5,⁷, Daoyuan Huang^3,⁹, Lixiao Liu^4,^6,⁸, Jiaming Li^4,^6,^8,¹⁴, Zijuan Xin^2,^5,⁷, Haoyan Huang^3,⁹, Juan Carlos Izpisua Belmonte¹⁶, Weiqi Zhang^4,^5,^6,^8,^14,¹⁵(

), Si Wang^3,^9,¹⁷(

), Jing Qu^1,^4,^5,⁷(

), Guang-Hui Liu^2,^3,^4,^5,⁷(

)

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, International 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

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Abstract

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 identified 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-related disorders.

Keywords single-nucleus RNA sequencing primate aging skeletal muscle FOXO3

Corresponding Author(s): Weiqi Zhang,Si Wang,Jing Qu,Guang-Hui Liu

Issue Date: 18 July 2023

Cite this article:

Ying Jing,Yuesheng Zuo,Yang Yu, et al. Single-nucleus profiling unveils a geroprotective role of the FOXO3 in primate skeletal muscle aging[J]. Protein Cell, 2023, 14(7): 497-512.

URL:

https://academic.hep.com.cn/pac/EN/10.1093/procel/pwac061
https://academic.hep.com.cn/pac/EN/Y2023/V14/I7/497

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