Autophagy-dependent regulation of skeletal muscle regeneration and strength by a RHOGEF.

Macroautophagy/autophagy plays a critical role in restoring/maintaining skeletal muscle function under normal conditions as well as during damage-induced regeneration. This homeostatic degradation mechanism, however, rapidly declines with aging leading to functional deterioration of skeletal muscles. ARHGEF3 is a RHOA- and RHOB-specific GEF capable of inhibiting myogenic AKT signaling independently of its GEF function. Our recent study reveals that ARHGEF3 negatively regulates skeletal muscle autophagy during injury-induced regeneration and normal aging. By enhancing autophagy, knockout augments the regenerative capacity of muscles in both young and regeneration-defective middle-aged mice and prevents age-related loss of muscle strength. We further show that the GEF activity of ARHGEF3 toward ROCK, but not its downstream target AKT, mediates its function in muscle regeneration. These findings suggest that ARHGEF3 may be a candidate therapeutic target for impaired muscle regeneration, age-related muscle weakness, and potentially other diseases arising from aberrant regulation of autophagy.