CASK is a key organizer of the structural and electrical polarity of the cardiomyocyte

Abstract

Although the organization of the cardiomyocyte membrane into functional microdomains directly influences the anisotropic propagation of the action potential, the mechanisms underlying the rod-like structural organization of cardiomyocytes during postnatal development are poorly understood. We have previously shown in the adult cardiomyocyte that CASK regulates sodium channel expression at the lateral membrane in interaction with focal adhesion complexes. In addition, preliminary results have shown that the expression level of CASK evolves during postnatal development and is altered during post-infarction myocardial remodeling in rat. To unravel the implication of CASK in postnatal cardiomyocyte differentiation and in the acquisition of structural and electrical function. CASK viral constructs were designed to inhibit the expression of CASK in neonatal and adult cardiac myocytes, in vitro (Ad-shCASK) and in vivo (AAV-shCASK). Proteomic analysis shows that CASK invalidation differentially regulates the expression of different protein families between neonatal and adult myocytes, suggesting a different role for CASK during postnatal development. Immunostaining experiments on isolated neonatal cardiomyocytes showed that CASK is required for the correct organization of the cardiomyocyte cytoskeleton, and impact both mechanical and electrical junction formation. Neonatal cardiomyocytes invalidated for CASK display abnormal contractility, focal adhesion fragility, and anoikis. Echocardiography phenotyping of CASK-invalidated rats at the neonatal and adult stages reveals eccentric ventricular remodeling and decreased systolic performance. However, in neonatal CASK-invalidated rats, the contractile reserve is preserved and the cardiac output is increased. In addition, mild electrical remodeling is observed since only neonatal CASK-invalidated rats display QT prolongation and slowed heart rhythm. This study demonstrates that CASK confers the ability to orchestrate both cardiomyocyte molecular organization and tissue cohesion. CASK appears to be a key modulator in molecular arrangement of electrical and structural polarity of cardiomyocytes during postnatal development.