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

Ying Jing; Yuesheng Zuo; Yang YU; Liang Sun; Zhengrong YU; Shuai MA; Qian Zhao; Guoqiang Sun; Huifang HU; Jingyi LI; Daoyuan Huang; Lixiao Liu; Jiaming LI; Zijuan Xin; Haoyan Huang; Juan Carlos Izpisua Belmonte; Weiqi Zhang; Si Wang; Jing QU; Guang-hui Liu

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

Author: Ying JING ¹ ; Yuesheng ZUO ² ; Yang YU ³ ; Liang SUN ⁴ ; Zhengrong YU ⁵ ; Shuai MA ⁶ ; Qian ZHAO ⁷ ; Guoqiang SUN ¹ ; Huifang HU ⁶ ; Jingyi LI ⁶ ; Daoyuan HUANG ⁷ ; Lixiao LIU ² ; Jiaming LI ² ; Zijuan XIN ⁶ ; Haoyan HUANG ⁷ ; Juan Carlos Izpisua BELMONTE ⁸ ; Weiqi ZHANG ² ; Si WANG ⁷ ; Jing QU ¹ ; Guang-Hui LIU ⁶
Author Information

1. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
2. University of Chinese Academy of Sciences, Beijing 100049, China.
3. Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University Third Hospital, Beijing 100191, China.
4. 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.
5. Department of Orthopaedics, Peking University First Hospital, Beijing 100034, China.
6. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
7. Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
8. Altos Labs, Inc., San Diego, CA 94022, USA.
Publication Type:Research Support, Non-U.S. Gov't
Keywords: FOXO3; aging; primate; single-nucleus RNA sequencing; skeletal muscle
MeSH: Animals; Humans; Sarcopenia/metabolism*; Forkhead Box Protein O3/metabolism*; Muscle, Skeletal/metabolism*; Aging/metabolism*; Primates/metabolism*
From: Protein & Cell 2023;14(7):497-512
CountryChina
Language:English
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.