Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart

ABSTRACT

Store-operated Ca²⁺ entry (SOCE) is an essential Ca²⁺ signaling and homeostatic mechanism present in nearly all animal cells. SOCE refers to influx of Ca²⁺ into cells that is activated by depletion of endoplasmic or sarcoplasmic reticulum stores (ER/SR) Ca²⁺ stores. In the SOCE pathway, STIM proteins function as Ca²⁺ sensors in the ER, and upon ER Ca²⁺ store depletion STIM rearranges to ER-plasma membrane junctions where it activates Orai Ca²⁺ influx channels. Multiple studies have implicated STIM and Orai mediated SOCE in the pathogenesis of cardiac hypertrophy. Importantly however, the functional roles of SOCE in normal heart physiology have not been well defined. We have addressed this in Drosophila melanogaster, a powerful animal model of cardiac development and physiology. We show that heart specific suppression of Drosophila Stim and Orai resulted in reduced contractility consistent with dilated cardiomyopathy, characterized by increased end diastolic and end systolic dimensions and decreased fractional shortening. Reduced contractility was apparent in larval hearts and became more pronounced in adults. Myofibers were disorganized and more widely spaced in larval and adult hearts with Stim and Orai RNAi as compared to controls, possibly reflecting decompensation or upregulated stress response signaling due to altered Ca²⁺ homeostasis. Lastly, we show that reduced heart function significantly affected animal health and viability, as animals with heart specific Stim and Orai suppression exhibited significant delays in post-embryonic development and adults died significantly earlier than controls. Collectively, our results demonstrate that SOCE is essential for normal heart physiology and establish Drosophila as an important model for delineation of functional SOCE roles in cardiomyocytes.