Effects of Cyclase-Associated Protein 2 α-ACTIN Induced Isoform Exchange on Actomyosin Interactions

Abstract

Cyclase-associated protein 2 (CAP2) plays a critical role in thin filament maturation bymediating the exchange of α-actin isoforms within the sarcomere. In CAP2 knockout (CAP2-KO) mice, this process is disrupted, resulting in a significant increase in smooth muscle actin (SMA) and skeletal actin (SKA) and decreased levels of cardiac actin (CAA). Therefore, CAP2-KO disease correlates the altered isoform profile with cardiac dysfunction and the development of dilated cardiomyopathy (DCM). Using single-cell mechanics, this study shows that CAP2-KO cardiomyocytes have significantly reduced force production at maximal calcium activation, which is rescued by an overexpression of CAA. In vitro motility (IVM) assays demonstrate that only regulated thin filaments display functional differences in actin-myosin interactions between isoforms, likely mediated through SMA’s increased binding to the troponin complex. These findings support a model in which α-actin isoform expression impacts actomyosin interactions indirectly through regulation by accessory proteins, contributing to the contractile dysfunction seen in CAP2-KO hearts.