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

• Published in: Biology open Vol. 9; no. 3
• Main Authors: Petersen, Courtney E, Wolf, Matthew J, Smyth, Jeremy T
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 11-03-2020; The Company of Biologists
• Subjects: Adults; Animal models; Animals; Biomarkers; Calcium (reticular); Calcium - metabolism; Calcium channels; Calcium Channels - metabolism; Calcium influx; Calcium ions; Calcium Signaling; Calcium signalling; cardiac; Cardiomyopathy; Cardiomyopathy, Dilated - etiology; Cardiomyopathy, Dilated - metabolism; Cardiomyopathy, Dilated - pathology; Depletion; Dilated cardiomyopathy; Disease Models, Animal; Disease Susceptibility; Drosophila; Drosophila - metabolism; Embryogenesis; Embryonic growth stage; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Fruit flies; Heart; Heart function; Hypertrophy; Insects; Larvae; Membrane junctions; Muscle contraction; Myocardium - metabolism; Myocardium - pathology; Myocardium - ultrastructure; orai; Pathogenesis; Physiology; RNA-mediated interference; Signaling; stim; store-operated calcium entry; Stromal Interaction Molecule 1 - metabolism; STIM; Cardiomyopathy; Cardiac; Drosophila; Store-operated calcium entry; Orai
• ISSN: 2046-6390; 2046-6390
• DOI: 10.1242/bio.049999

Store-operated Ca
entry (SOCE) is an essential Ca
signaling mechanism present in most animal cells. SOCE refers to Ca
influx that is activated by depletion of sarco/endoplasmic reticulum (S/ER) Ca
stores. The main components of SOCE are STIM and Orai. STIM proteins function as S/ER Ca
sensors, and upon S/ER Ca
depletion STIM rearranges to S/ER-plasma membrane junctions and activates Orai Ca
influx channels. Studies have implicated SOCE in cardiac hypertrophy pathogenesis, but SOCE's role in normal heart physiology remains poorly understood. We therefore analyzed heart-specific SOCE function in
, a powerful animal model of cardiac physiology. We show that heart-specific suppression of
and
in larvae and adults resulted in reduced contractility consistent with dilated cardiomyopathy. Myofibers were also highly disorganized in
and
RNAi hearts, reflecting possible decompensation or upregulated stress signaling. Furthermore, we show that reduced heart function due to SOCE suppression adversely affected animal viability, as heart specific
and
RNAi animals exhibited significant delays in post-embryonic development and adults died earlier than controls. Collectively, our results demonstrate that SOCE is essential for physiological heart function, and establish
as an important model for understanding the role of SOCE in cardiac pathophysiology.