TBC1D1 functions as a negative regulator of satellite cells for muscle regeneration

Xinyu Yang, Ye Cao, Yinqiu Mu, Yuwei Zhou, Li Zhang, Heng Ai, Dahai Zhu, Shuai Chen () and Hong-Yu Wang ()
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Xinyu Yang: Nanjing University
Ye Cao: Nanjing University
Yinqiu Mu: Nanjing University
Yuwei Zhou: Nanjing University
Li Zhang: Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory
Heng Ai: Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory
Dahai Zhu: Institute of Basic Medical Science, Chinese Academy of Medical Sciences, School of Basic Medical Sciences, Peking Union Medical College
Shuai Chen: Nanjing University
Hong-Yu Wang: Nanjing University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract The Rab GTPase activating protein (RabGAP) AS160 translocates from the cytosol into the nucleus acting as a transcriptional co-activator of Signal Transducer and Activator of Transcription 3 (STAT3) to regulate proliferation of muscle satellite cells (MuSCs). How this AS160–STAT3 complex is regulated remains largely unclear yet. Here, we show that TBC1D1, a RabGAP related to AS160, forms a super-complex with AS160 and STAT3 to retain the AS160–STAT3 complex in the cytosol. Phosphorylation of TBC1D1-Thr596 by protein kinase B dissociates TBC1D1 from AS160 thus releasing the cytosolic retention of the AS160–STAT3 complex. A non-phosphorylatable alanine substitution of Thr596 inhibits MuSC proliferation and impairs repair of injured muscle. In contrast, TBC1D1 deficiency, but not its GAP-inactive mutation, promotes MuSC proliferation and muscle regeneration. Thus, TBC1D1 is a negative regulator of MuSC proliferation through cytosolic retention of the AS160–STAT3 complex and might be a valuable therapeutic target for muscle regeneration.

Date: 2025
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DOI: 10.1038/s41467-025-65141-z

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