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Updated: Jan 11, 2026

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

Xinyu Yang1,2, Ye Cao1,2, Yinqiu Mu1,2

  • 1State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, China.

Nature Communications
|November 18, 2025
PubMed

Insights

TBC1D1 retains the AS160-STAT3 complex in the cytosol, inhibiting muscle satellite cell (MuSC) proliferation. Phosphorylation releases this complex, promoting muscle regeneration, suggesting TBC1D1 as a therapeutic target.

Area of Science:

  • Muscle stem cell biology
  • Cellular signaling pathways
  • Protein-protein interactions

Background:

  • AS160, a Rab GTPase activating protein (RabGAP), acts as a transcriptional co-activator for STAT3, regulating muscle satellite cell (MuSC) proliferation.
  • The precise regulation of the AS160-STAT3 complex remains poorly understood.

Purpose of the Study:

  • To elucidate the regulatory mechanism of the AS160-STAT3 complex in MuSCs.
  • To investigate the role of TBC1D1 in controlling AS160-STAT3 complex localization and MuSC function.

Main Methods:

  • Co-immunoprecipitation assays to detect protein complex formation.
  • In vitro kinase assays to assess TBC1D1 phosphorylation.
  • Analysis of MuSC proliferation and muscle regeneration in TBC1D1 knockout and mutant models.

Main Results:

  • TBC1D1 forms a super-complex with AS160 and STAT3, sequestering the AS160-STAT3 complex in the cytosol.
  • Phosphorylation of TBC1D1 at Thr596 by protein kinase B disrupts the TBC1D1-AS160 interaction, releasing the AS160-STAT3 complex.
  • A non-phosphorylatable TBC1D1 mutant impairs MuSC proliferation and muscle repair, while TBC1D1 deficiency enhances MuSC proliferation and regeneration.

Conclusions:

  • TBC1D1 acts as a negative regulator of MuSC proliferation by maintaining the AS160-STAT3 complex in the cytosol.
  • TBC1D1-mediated regulation of AS160-STAT3 localization is critical for muscle regeneration.
  • TBC1D1 represents a potential therapeutic target for enhancing muscle repair and regeneration.

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