TY - JOUR
T1 - ARHGEF3 Regulates Skeletal Muscle Regeneration and Strength through Autophagy
AU - You, Jae-Sung
AU - Singh, Nilmani
AU - Reyes-Ordonez, Adriana
AU - Khanna, Nidhi
AU - Bao, Zehua
AU - Zhao, Huimin
AU - Chen, Jie
N1 - Funding Information:
We thank Fuming Pan and the Transgenic Mouse Facility at the University of Illinois at Urbana-Champaign for pronuclear injection of TALEN mRNA and creation of founder transgenic mice. This work was supported by grants from the National Institutes of Health to J.C. ( AR048914 and GM089771 ).
Publisher Copyright:
© 2020 The Authors
PY - 2021/1/5
Y1 - 2021/1/5
N2 - 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.
AB - 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.
KW - Skeletal muscle, Regeneration, Aging, Strength, Muscle quality, ARHGEF3, XPLN, Akt, RhoA, ROCK, Autophagy
UR - http://www.scopus.com/inward/record.url?scp=85098666067&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098666067&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2020.108594
DO - 10.1016/j.celrep.2020.108594
M3 - Article
C2 - 33406419
SN - 2211-1247
VL - 34
SP - 108594
JO - Cell Reports
JF - Cell Reports
IS - 1
M1 - 108594
ER -