STIM1 and metabolic flexibility

胰岛素抵抗、糖尿病和肥胖等代谢性疾病的患病率正在达到 美国的流行病比例。缺乏体力活动和营养过剩是造成这些问题的主要原因 条件。增加对体力活动和燃料供应如何将骨骼肌联系在一起的理解 全身新陈代谢可能会对代谢性疾病产生重要的机械学见解 并为开发新的治疗策略做出贡献。骨骼中的钙信号 肌肉是肌肉收缩、新陈代谢和基因表达的关键。钙离子内流的作用 已经被提供作为一种控制长期信号事件的机制，例如限制疲劳 在锻炼的时候。我们的研究集中在基质相互作用分子1(STIM1)的作用上。 作为骨骼的关键调节器，商店操作的钙进入(SOCE)所需的钙传感器 肌肉钙信号。我们目前的研究重点是STIM1在氧化过程中的作用 新陈代谢。我们的初步数据表明，STIM1的丢失改变了氧化代谢和 会损害肌肉的性能。在这里，我们将建立新陈代谢产生的特定变化 STIM1信号的变化及STIM1影响肌肉的机制 新陈代谢。本申请中提出的具体目标包括：确定STIM1如何监管 代谢灵活性；确定STIM1如何调节线粒体钙信号和功能； 并确定MAP4K4是否调节STIM1信号转导和骨骼肌代谢。我们 将使用包括STIM1转基因小鼠模型的方法，高分辨率 钙成像、生物能量学和代谢组学来解决这些目标。我们提出的研究 可能为钙在调节骨骼代谢灵活性中的作用提供新的见解 可能对肌肉代谢受损的治疗有重大意义 与糖尿病和其他代谢性疾病有关。

The prevalence of metabolic diseases such as insulin resistance, diabetes and obesity are reaching epidemic proportions in the US. Physical inactivity and overnutrition are major contributors to these conditions. An increased understanding of how physical activity and fuel supply links skeletal muscle with whole body metabolism is likely to yield important mechanistic insights into metabolic disease and to contribute to the development of novel therapeutic strategies. Calcium signaling in skeletal muscle is critical for muscle contraction, metabolism, and gene expression. The role of calcium entry has been offered as a mechanism for controlling long-term signaling events such as limiting fatigue during exercise. Our research centers on the role of stromal interaction molecule 1 (STIM1), a calcium sensor required for store-operated calcium entry (SOCE), as a key regulator of skeletal muscle calcium signaling. Our current program is focused on the role of STIM1 in oxidative metabolism. Our preliminary data demonstrate that loss of STIM1 alters oxidative metabolism and impairs muscle performance. Here, we will establish the specific changes in metabolism produced by changes in STIM1 signaling and establish the mechanisms through which STIM1 influences muscle metabolism. Specific Aims proposed in this application include: to determine how STIM1 regulates metabolic flexibility; to determine how STIM1 regulates mitochondrial calcium signaling and function; and to determine whether MAP4K4 regulates STIM1 signaling and skeletal muscle metabolism. We will use methodologies that include genetically modified mouse models of STIM1, high resolution calcium imaging, bioenergetics, and metabolomics to address these aims. The studies we propose may provide novel insight to the role of calcium in regulating the metabolic flexibility of skeletal muscle and are likely to have significant implications for the treatment of impaired muscle metabolism associated with diabetes mellitus and other metabolic diseases.