ARHGEF3 Regulates Skeletal Muscle Regeneration and Strength through Autophagy

Jae-Sung You, Nilmani Singh, Adriana Reyes-Ordonez, Nidhi Khanna, Zehua Bao, Huimin Zhao, Jie Chen

Research output: Contribution to journalArticlepeer-review


Skeletal muscle regeneration after injury is essential for maintaining muscle function throughout aging. ARHGEF3, a RhoA/B-specific GEF, negatively regulates myoblast differentiation through Akt signaling independently of its GEF activity in vitro. Here, we report ARHGEF3's role in skeletal muscle regeneration revealed by ARHGEF3-KO mice. These mice exhibit indiscernible phenotype under basal conditions. Upon acute injury, however, ARHGEF3 deficiency enhances the mass/fiber size and function of regenerating muscles in both young and regeneration-defective middle-aged mice. Surprisingly, these effects occur independently of Akt but via the GEF activity of ARHGEF3. Consistently, overexpression of ARHGEF3 inhibits muscle regeneration in a Rho-associated kinase-dependent manner. We further show that ARHGEF3 KO promotes muscle regeneration through activation of autophagy, a process that is also critical for maintaining muscle strength. Accordingly, ARHGEF3 depletion in old mice prevents muscle weakness by restoring autophagy. Taken together, our findings identify a link between ARHGEF3 and autophagy-related muscle pathophysiology.

Original languageEnglish (US)
Article number108594
Pages (from-to)108594
JournalCell Reports
Issue number1
StatePublished - Jan 5 2021


  • Skeletal muscle, Regeneration, Aging, Strength, Muscle quality, ARHGEF3, XPLN, Akt, RhoA, ROCK, Autophagy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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