Upregulation of Store Operated Ca2+ Entry pathologically impairs Drosophila cardiac function
posterposted on 21.04.2020 by Courtney E. Petersen, Jeremy T. Smyth
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More than 300,000 people in the United States die of heart failure each year. Heart failure occurs when heart muscle cannot fully contract, and invariably involves dysregulation of the Ca2+ transport mechanisms that drive cardiomyocyte contractility. Thorough understanding of cardiomyocyte Ca2+ transport mechanisms is therefore essential for the development of novel heart failure therapeutics. To this end, our lab recently demonstrated that the store operated Ca2+ entry (SOCE) mechanism of Ca2+ transport is essential for proper Drosophila heart contractility. SOCE is mediated by STIM proteins, which function as Ca2+ sensors in the ER/SR, and Orai Ca2+ influx channels in the plasma membrane. Numerous animal studies have demonstrated that upregulation of SOCE in cardiomyocytes induces pathological cardiac hypertrophy and heart failure. Interestingly however, humans with gain-of-function mutations in STIM1 or Orai1 exhibit varying degrees of skeletal muscle myopathy and platelet dysfunction, but not cardiac hypertrophy or other cardiac complications. To better understand how upregulated SOCE alters cardiomyocyte physiology, we generated a transgenic Drosophila model that expresses a Stim mutant which confers constitutive Ca2+ influx activity (StimCA) due to two aspartate to alanine changes in the Ca2+ binding EF-hand domain.Heart-specific expression of StimCA also significantly impaired animal development, as 80% of these animals died as larvae and pupariation of surviving larvae was delayed by approximately two days compared to W1118 driven StimCA controls. Intravital imaging of adult heart contractility revealed that heart specific expression of StimCA reduced end-diastolic and end-systolic dimensions and decreased heart rate, consistent with significantly impaired heart function. Furthermore, microCT analysis showed heart specific expression of StimCA increased heart wall thickness, suggesting that decreased heart diameters observed in intravital imaging may result from increases in heart wall thickness. Collectively our results demonstrate that heart specific upregulation of the SOCE pathway pathologically impairs Drosophila cardiac function resulting in cardiac hypertrophy and hypertrophic cardiomyopathy. Moving forward, we plan to directly measure cardiomyocyte Ca2+ in vivo to determine how StimCA expression affects Ca2+ physiology and dynamics.