Septins regulate heart contractility through modulation of cardiomyocyte store-operated calcium entry

Abstract

Highly regulated cardiomyocyte Ca2+ fluxes drive heart contractions. Recent findings from multiple organisms demonstrate that the specific Ca2+ transport mechanism known as store-operated Ca2+ entry (SOCE) is essential in cardiomyocytes for proper heart function, and SOCE dysregulation results in cardiomyopathy. Mechanisms that regulate SOCE in cardiomyocytes are poorly understood. Here we tested the role of cytoskeletal septin proteins in cardiomyocyte SOCE regulation. Septins are essential SOCE modulators in other cell types, but septin functions in cardiomyocytes are nearly completely unexplored. We show using targeted genetics and intravital imaging of heart contractility in Drosophila that cardiomyocyte-specific depletion of septins 1, 2, and 4 results in heart dilation that phenocopies the effects of SOCE suppression. Heart dilation caused by septin 2 depletion was suppressed by SOCE upregulation, supporting the hypothesis that septin 2 is required in cardiomyocytes for sufficient SOCE function. A major function of SOCE is to support SERCA-dependent sarco/endoplasmic reticulum (S/ER) Ca2+ stores, and augmenting S/ER store filling by SERCA overexpression also suppressed the septin 2 phenotype. We also ruled out several potential SOCE-independent septin functions, as septin 2 phenotypes were not due to septin function during development and septin 2 was not required for z-disk organization as defined by -actinin labeling. These results demonstrate, for the first time, an essential role of septins in cardiomyocyte physiology and heart function that is due, at least in part, to septin regulation of SOCE function.