| First Author | Collins HE | Year | 2019 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 316 |
| Issue | 5 | Pages | H1014-H1026 |
| PubMed ID | 30575437 | Mgi Jnum | J:277808 |
| Mgi Id | MGI:6295655 | Doi | 10.1152/ajpheart.00544.2018 |
| Citation | Collins HE, et al. (2019) Novel role of the ER/SR Ca(2+) sensor STIM1 in the regulation of cardiac metabolism. Am J Physiol Heart Circ Physiol 316(5):H1014-H1026 |
| abstractText | The endoplasmic reticulum/sarcoplasmic reticulum Ca(2+) sensor stromal interaction molecule 1 (STIM1), a key mediator of store-operated Ca(2+) entry, is expressed in cardiomyocytes and has been implicated in regulating multiple cardiac processes, including hypertrophic signaling. Interestingly, cardiomyocyte-restricted deletion of STIM1 ((cr)STIM1-KO) results in age-dependent endoplasmic reticulum stress, altered mitochondrial morphology, and dilated cardiomyopathy in mice. Here, we tested the hypothesis that STIM1 deficiency may also impact cardiac metabolism. Hearts isolated from 20-wk-old (cr)STIM1-KO mice exhibited a significant reduction in both oxidative and nonoxidative glucose utilization. Consistent with the reduction in glucose utilization, expression of glucose transporter 4 and AMP-activated protein kinase phosphorylation were all reduced, whereas pyruvate dehydrogenase kinase 4 and pyruvate dehydrogenase phosphorylation were increased, in (cr)STIM1-KO hearts. Despite similar rates of fatty acid oxidation in control and (cr)STIM1-KO hearts ex vivo, (cr)STIM1-KO hearts contained increased lipid/triglyceride content as well as increased fatty acid-binding protein 4, fatty acid synthase, acyl-CoA thioesterase 1, hormone-sensitive lipase, and adipose triglyceride lipase expression compared with control hearts, suggestive of a possible imbalance between fatty acid uptake and oxidation. Insulin-mediated alterations in AKT phosphorylation were observed in (cr)STIM1-KO hearts, consistent with cardiac insulin resistance. Interestingly, we observed abnormal mitochondria and increased lipid accumulation in 12-wk (cr)STIM1-KO hearts, suggesting that these changes may initiate the subsequent metabolic dysfunction. These results demonstrate, for the first time, that cardiomyocyte STIM1 may play a key role in regulating cardiac metabolism. NEW & NOTEWORTHY Little is known of the physiological role of stromal interaction molecule 1 (STIM1) in the heart. Here, we demonstrate, for the first time, that hearts lacking cardiomyocyte STIM1 exhibit dysregulation of both cardiac glucose and lipid metabolism. Consequently, these results suggest a potentially novel role for STIM1 in regulating cardiac metabolism. |
