Nuclear entry of AS160 as a transcriptional regulator of satellite cells for muscle regeneration

Xinyu Yang, Ye Cao, Yuwei Zhou, Qing Yao, Ping Rong, Xu Wang, Qiaoli Chen, Weikuan Feng, Li Zhang, Heng Ai, Dahai Zhu, Lei Fang, Tong-Jin Zhao, Xinhua Ye (), Hong-Yu Wang () and Shuai Chen ()
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Xinyu Yang: Nanjing University
Ye Cao: Nanjing University
Yuwei Zhou: Nanjing University
Qing Yao: The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University
Ping Rong: Nanjing University
Xu Wang: Anhui Medical University
Qiaoli Chen: Nanjing University
Weikuan Feng: Nanjing University
Li Zhang: Guangzhou Regenerative Medicine and Health Guangdong Laboratory
Heng Ai: Guangzhou Regenerative Medicine and Health Guangdong Laboratory
Dahai Zhu: Peking Union Medical College
Lei Fang: Nanjing University
Tong-Jin Zhao: Shanghai Qi Zhi Institute
Xinhua Ye: The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University
Hong-Yu Wang: Nanjing University
Shuai Chen: Nanjing University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Dysfunction of muscle satellite cells is linked to diabetic myopathy. The mechanisms vitiating muscle satellite cell proliferative activity in diabetes are not well understood. Here, we show that AS160, a key cytosolic Rab-GTPase activating protein (RabGAP) in insulin signaling, is a moonlighting protein regulating muscle satellite cell proliferation as a transcriptional co-factor. Deletion of AS160, but not its GAP-inactive mutation, impairs muscle satellite cell proliferation and consequent muscle regeneration, and exacerbates age-related sarcopenia. Mechanistically, Thr642 phosphorylation of AS160 promotes its translocation into the nucleus where AS160 functions as a co-factor of Signal Transducer and Activator of Transcription 3 (STAT3). AS160 binds to STAT3 to enhance the transcription of myogenic cascades and consequent muscle satellite cell proliferation. Disruption of the AS160-STAT3 interaction, or inhibition of AS160-Thr642 phosphorylation, inhibits muscle satellite cell proliferation and impairs muscle regeneration. Together, our findings reveal a moonlighting function of AS160 as a transcriptional co-factor in the nucleus, and have therapeutic implications for muscle regeneration.

Date: 2025
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DOI: 10.1038/s41467-025-64220-5

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