STIM1 and its role in regulating cardiac metabolism

与心血管疾病相关的死亡率显著下降；然而， 心力衰竭继续增加，5年存活率保持在~50%，这突显了改善的必要性 我们对这种疾病的分子基础的了解。心脏需要高水平的 代谢灵活性，使其能够持续适应全天不断变化的工作负荷需求。 底物利用率和激素水平也随着禁食/喂养周期的变化而波动，这进一步要求心脏 新陈代谢灵活性。心脏代谢灵活性的丧失是心脏病的反复出现的特征，观察到 在肥厚、心力衰竭和糖尿病心肌病期间。同样，钙离子动态平衡的失调 这是许多心脏病病因的共同因素。钙是一种公认的调节因子 心脏代谢和线粒体功能，通过直接变构相互作用，翻译后 修饰和转录事件。然而，尽管钙离子在心脏调节中的作用已被证实 能量代谢，涉及的特定的钙离子处理途径没有很好的描述和他们的 维持代谢灵活性的作用尚不清楚。基质相互作用分子-1(STIM1)是一种 位于ER/SR中的普遍表达和进化高度保守的蛋白质，负责 在非兴奋性细胞中调节不同的钙信号通路，并被认为是ALL的核心要素 哺乳动物的钙信号系统。尽管大约20年前在心脏发现了STIM1， 我们对STIM1在成年心肌细胞中的生理作用的了解尚不清楚 有争议的。我们最近报道了心肌细胞STIM1(crSTIM1-KO)的缺失导致收缩 36周龄时出现功能障碍和扩张性心肌病。在幼年crSTIM1-KO小鼠发病前 收缩功能障碍表现为糖代谢受损和胰岛素信号转导增加 脂肪堆积和造脂蛋白的上调。这种代谢表型与 糖尿病期间观察到的心脏代谢特征，这是代谢不灵活的一个典型例子。 总而言之，这些观察结果导致了一种假设，即STIM1是以前未被识别的 心脏代谢和线粒体功能的调节以及STIM1的减少参与了 糖尿病对心脏的不良影响。为了检验这一假设，我们将1)充分定义 哪些STIM1调节心脏代谢；2)建立STIM1影响心脏代谢的机制 线粒体在心脏中的功能和3)决定糖尿病如何调节STIM1水平以及 STIM1有助于糖尿病对心脏的不利影响。成功地完成这项提案 将为STIM1在调节心脏代谢和线粒体中的作用提供重要的新见解 并为更好地理解STIM1的贡献奠定了基础 疾病状态下心脏代谢不灵活和收缩功能障碍的调节失调。

Mortality rates associated with cardiovascular disease have decreased significantly; however, the incidence of heart failure continues to grow and 5-year survival rates remain at ~50%, underscoring the need to improve our knowledge of the molecular underpinnings of this disease. The heart requires a high level of metabolic flexibility to enable it to continuously adapt to changing workload demands throughout the day. Substrate availability and hormone levels also fluctuate with fasting/feeding cycles, further demanding cardiac metabolic flexibility. Loss of cardiac metabolic flexibility is a recurrent feature of cardiac disease, observed during hypertrophy, heart failure and diabetic cardiomyopathy. Similarly, dysregulation of Ca2+ homeostasis is a common element underlying the etiology of many cardiac diseases. Calcium is an established regulator of cardiac metabolism and mitochondrial function, through direct allosteric interactions, posttranslational modifications, and transcriptional events. However, despite established roles of Ca2+ in regulating cardiac energy metabolism, the specific Ca2+ handling pathways involved are not well characterized and their role in maintaining metabolic flexibility is not known. STromal Interaction Molecule-1 (STIM1) is a ubiquitously expressed and highly evolutionarily conserved protein located in the ER/SR that is responsible for regulating diverse Ca2+ signaling pathways in non-excitable cells and is recognized as a core element of all mammalian Ca2+ signaling systems. Despite discovery of STIM1 in the heart approximately 20 years ago, our knowledge about the physiological role of STIM1 in adult cardiomyocytes remains unclear and controversial. We recently reported that cardiomyocyte deletion of STIM1 (crSTIM1-KO) precipitates contractile dysfunction and dilated cardiomyopathy by 36 weeks of age. In young crSTIM1-KO mice prior to onset of contractile dysfunction there was impaired glucose metabolism and insulin signaling combined with increased lipid accumulation and an upregulation of lipogenic proteins. This metabolic phenotype is very similar to the cardiac metabolic signature observed during diabetes, a well characterized example of metabolic inflexibility. Collectively, these observations have led to the hypothesis that STIM1 is a previously unrecognized regulator of cardiac metabolism and mitochondrial function and that decreased STIM1 contributes to the adverse effects of diabetes on the heart. To test this hypothesis, we will 1) Define fully the extent to which STIM1 regulates cardiac metabolism; 2) Establish the mechanisms by which STIM1 influences mitochondrial function in the heart and 3) Determine how diabetes regulates STIM1 levels and whether loss of STIM1 contributes to the adverse effects of diabetes on the heart. The successful completion of this proposal will provide significant new insights into the role of STIM1 in regulating cardiac metabolism and mitochondrial function and provide the foundation for improved understanding regarding the contribution of STIM1 dysregulation to cardiac metabolic inflexibility and contractile dysfunction during disease states.