Abstract
Cardiomyopathies affect individuals worldwide, without regard to age, sex and ethnicity and are associated with significant morbidity and mortality. Inherited cardiomyopathies account for a relevant part of these conditions. Although progresses have been made over the years, early diagnosis and curative therapies are still challenging. Understanding the events occurring in normal and diseased cardiac cells is crucial, as they are important determinants of overall heart function. Besides chemical and molecular events, there are also structural and mechanical phenomena that require to be investigated. Cell structure and mechanics largely depend from the cytoskeleton, which is composed by filamentous proteins that can be cross-linked via accessory proteins. Alpha-actinin 2 (ACTN2), filamin C (FLNC) and dystrophin are three major actin cross-linkers that extensively contribute to the regulation of cell structure and mechanics. Hereby, we review the current understanding of the roles played by ACTN2, FLNC and dystrophin in the onset and progress of inherited cardiomyopathies. With our work, we aim to set the stage for new approaches to study the cardiomyopathies, which might reveal new therapeutic targets and broaden the panel of genes to be screened.
Highlights
Cardiovascular disorders (CVDs) are a leading cause of death globally and inherited cardiac diseases represent an important epidemiological entity, with combined estimated prevalence of 3% in the general population [1]
Cardiovascular disorders are a major cause of death worldwide and inherited cardiomyopathies represent an important epidemiological entity
We have provided a collection of studies that show the connection between mutant cytoskeletal cross-linkers and inherited cardiomyopathies
Summary
Cardiovascular disorders (CVDs) are a leading cause of death globally and inherited cardiac diseases represent an important epidemiological entity, with combined estimated prevalence of 3% in the general population [1]. When focusing on the cell, the cytoskeleton is recognized as a major player in regulating structural and mechanical properties. It provides the cell with both scaffolding and signaling functions. Besides morphological features (filament length, bundle thickness, mesh size), the mechanical properties of actin networks are tuned by cross-linkers and their binding strength. Given the relevance of cross-linkers in determining the physical properties of a cell, we hereby review the cases of inherited cardiomyopathies caused—or likely caused—by aberrant actin-binding and crosslinking proteins, namely alpha-actinin 2 (ACTN2), filamin C (FLNC) and dystrophin. The original disease phenotype (i.e. ARVC) is characterized by prominent ventricular arrhythmias (with predominant right ventricle involvement) and impairment of ventricular systolic function [9,10]. Our work could hopefully represent the impetus for studying novel diagnostic approaches or targeted therapies based on cross-linkers
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