Figure 9.

Schematic summary of roles of ROCK1 and ROCK2 in regulating nonsarcomeric cytoskeleton, autophagy, and fibrosis in cardiomyocytes. A) Double ROCK deletion in adult cardiomyocytes results in reduced nonsarcomeric cytoskeleton assembly (reduced p-MLC and p-FAK), resulting in increased baseline autophagy through inhibition of AKT/mTOR/ULK signaling and beneficial antifibrotic effects during the aging process. B) ROCK2 deletion in cardiomyocytes is profibrotic and associated with compensatory increased ROCK1 activity, which increases nonsarcomeric cytoskeleton assembly and AKT/mTOR/ULK signaling, resulting in inhibiting baseline autophagy. C) ROCK1 deletion in cardiomyocytes is protective in the context of doxorubicin cardiotoxicity, in part, because of reduced Beclin 1–mediated autophagy activity, resulting in improved autophagic flux when lysosome function is impaired by doxorubicin. The baseline autophagy regulated by AKT/mTOR/ULK is not affected because of the presence of ROCK2, which maintains nonsarcomeric cytoskeleton.