The Novel Contribution of the ER/SR Ca 2+ Sensor STIM1 to Cardiac Function and Metabolism

Abstract

Store-operated Ca2+ entry (SOCE) occurs following ER/SR Ca2+ depletion and is mediated by the ER/SR Ca2+ sensor, Stromal Interaction molecule 1 (STIM1) and plasma membrane Orai1 channels. The role of SOCE in the heart has not been widely explored; however, we recently reported that cardiomyocyte restricted deletion of STIM1 (crSTIM1-KO) lead to increased ER stress, mitochondrial dysfunction, reduced cardiac function and the development of a dilated cardiomyopathy. Since Ca2+ plays a key role in the regulation of cardiac metabolism, we examined whether a lack of STIM1 altered cardiac metabolism.Using an isolated perfused working heart model we found that although contractile function was normal, hearts from 20 week crSTIM1-KO mice exhibited significantly reduced glucose oxidation and glycolysis, with no significant changes in oleate oxidation. Pyruvate dehydrogenase kinase 4 protein expression was increased in crSTIM1-KO hearts, consistent with the lower glucose oxidation. Although oleate oxidation was not changed, crSTIM1-KO hearts contained an increased number of lipid droplets compared to control hearts, which may indicate an imbalance between fatty acid uptake and subsequent oxidation. While it is widely accepted that Ca2+ plays a key role in the regulation of cardiac metabolism, the specific Ca2+ handling pathways have not been elucidated. The results from this study suggest for the first time that STIM1 mediated Ca2+ signaling may play a key role in regulating cardiac metabolism. This work was supported by NIH grant R21-HL-110366 (JCC) and the UAB Comprehensive Cardiovascular Center William W. Featheringill Postdoctoral Fellowship (HEC).