Myopalladin's Role in Cardiac Muscle Function and Disease

Abstract

Decades of research have provided fundamental insight into the human heart's structure and function. Yet, most cardiac malformations remain a mystery as scientists and clinicians continue to examine how inherited mutations and aging affect the normal biological functions of proteins associated with cardiac dysfunction. Recently, mutations in the muscle protein myopalladin have been linked to the pathogenesis of cardiomyopathy. Myopalladin is a sarcomeric protein that is thought to have an important role in maintaining sarcomere structure, signaling and regulation of gene expression in response to muscle stress. Myopalladin and palladin belong to a family of closely related immunoglobulin (Ig)‐domain‐containing proteins that have essential, but unclear roles in organizing the actin cytoskeleton. Recent work in the Beck lab has shown that the C‐terminal Ig domains of palladin bind directly to actin and increases both the rate of actin polymerization and the stability of actin filaments. The fact that a number of mutations in myopalladin are located within the analogous actin‐binding region suggests that a disruption in actin regulation may occur in cardiomyopathy. Thus, we hypothesized that myopalldin also binds directly to actin and increases both the rate of actin polymerization and the stability of actin filaments. To study the capability of myopalladin to bind and crosslink actin filaments, co‐sedimentation assays were performed between purified F‐actin and myopalladin Ig domains at various concentrations. The results suggest that Ig3 domain of myopalladin is the minimal domain required for both the binding and bundling of F‐actin. Pyrene fluorescence was used to monitor the polymerization rate of G‐actin in the presence of increasing concentrations of the various Ig domain of myopalladin. Our data reveals that myopalladin increases both the rate and extent of actin polymerization. From our data, we propose that myopalladin is involved in sarcomere structure and function through regulation of actin dynamics. We suggest that myopalladin may act both as a scaffold, binding directly to actin and other actin binding proteins at the Z‐disc, and by regulating actin thin filament turnover.Support or Funding InformationThis project was supported by the Kansas INBRE under grant number P20 GM103418; The WSU Carl and Rozina Cassat Regional Institute on Aging Grant (2016); and Wichita State University.