PT  - JOURNAL ARTICLE
AU  - Jae-Sung You
AU  - Nilmani Singh
AU  - Adriana Reyes-Ordonez
AU  - Nidhi Khanna
AU  - Zehua Bao
AU  - Huimin Zhao
AU  - Jie Chen
TI  - ARHGEF3 regulates skeletal muscle regeneration and strength through autophagy
AID  - 10.1101/2020.02.28.970756
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.28.970756
4099  - http://biorxiv.org/content/early/2020/02/29/2020.02.28.970756.short
4100  - http://biorxiv.org/content/early/2020/02/29/2020.02.28.970756.full
AB  - Skeletal muscle regeneration is essential for restoring muscle function upon injury and for the maintenance of muscle health with aging. ARHGEF3, a Rho-specific GEF, negatively regulates myoblast differentiation via mammalian target of rapamycin complex 2 (mTORC2)-Akt signaling in a GEF-independent manner in vitro. Here, we investigated ARHGEF3’s role in skeletal muscle regeneration by creating ARHGEF3 KO mice. These mice exhibited no discernible phenotype under normal conditions. Upon injury, however, ARHGEF3 deficiency enhanced the mass, fiber size and function of regenerating muscles in both young and aged mice. Surprisingly, these effects were not mediated by mTORC2-Akt signaling, but by the GEF activity of ARHGEF3. Furthermore, ARHGEF3 KO promoted muscle regeneration through activation of autophagy, a process that is also critical for maintaining muscle strength. Accordingly, in old mice, ARHGEF3 depletion prevented muscle weakness by restoring autophagy flux. Collectively, our findings identify an unexpected link between ARHGEF3 and autophagy-related muscle pathophysiology.