Collins Helen E, Pat Betty M, Zou Luyun, Litovsky Silvio H, Wende Adam R, Young Martin E, Chatham John C
Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham , Birmingham, Alabama.
Division of Cardiovascular Medicine, Department of Medicine, University of Alabama at Birmingham , Birmingham, Alabama.
Am J Physiol Heart Circ Physiol. 2019 May 1;316(5):H1014-H1026. doi: 10.1152/ajpheart.00544.2018. Epub 2018 Dec 21.
The endoplasmic reticulum/sarcoplasmic reticulum Ca sensor stromal interaction molecule 1 (STIM1), a key mediator of store-operated Ca entry, is expressed in cardiomyocytes and has been implicated in regulating multiple cardiac processes, including hypertrophic signaling. Interestingly, cardiomyocyte-restricted deletion of STIM1 (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 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 STIM1-KO hearts. Despite similar rates of fatty acid oxidation in control and STIM1-KO hearts ex vivo, 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 STIM1-KO hearts, consistent with cardiac insulin resistance. Interestingly, we observed abnormal mitochondria and increased lipid accumulation in 12-wk 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. 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.
内质网/肌浆网钙传感器基质相互作用分子1（STIM1）是储存性钙内流的关键介质，在心肌细胞中表达，并参与调节多种心脏过程，包括肥厚信号传导。有趣的是，心肌细胞特异性缺失STIM1（STIM1基因敲除）会导致小鼠出现年龄依赖性内质网应激、线粒体形态改变和扩张型心肌病。在此，我们验证了STIM1缺乏可能也会影响心脏代谢这一假说。从20周龄的STIM1基因敲除小鼠分离出的心脏，其氧化型和非氧化型葡萄糖利用率均显著降低。与葡萄糖利用率降低一致，STIM1基因敲除心脏中葡萄糖转运蛋白4的表达和AMP激活的蛋白激酶磷酸化均降低，而丙酮酸脱氢酶激酶4和丙酮酸脱氢酶磷酸化增加。尽管在体外对照心脏和STIM1基因敲除心脏中脂肪酸氧化速率相似，但与对照心脏相比，STIM1基因敲除心脏的脂质/甘油三酯含量增加，脂肪酸结合蛋白4、脂肪酸合酶、酰基辅酶A硫酯酶1、激素敏感性脂肪酶和脂肪甘油三酯脂肪酶的表达也增加，提示脂肪酸摄取与氧化之间可能存在失衡。在STIM1基因敲除心脏中观察到胰岛素介导的AKT磷酸化改变，这与心脏胰岛素抵抗一致。有趣的是，我们在12周龄的STIM1基因敲除心脏中观察到线粒体异常和脂质积累增加，表明这些变化可能引发随后的代谢功能障碍。这些结果首次证明，心肌细胞STIM1可能在调节心脏代谢中起关键作用。人们对基质相互作用分子1（STIM1）在心脏中的生理作用知之甚少。在此，我们首次证明，缺乏心肌细胞STIM1的心脏表现出心脏葡萄糖和脂质代谢失调。因此，这些结果提示STIM1在调节心脏代谢中可能具有潜在的新作用。
