STIM1 and metabolic flexibility

胰岛素抵抗、糖尿病和肥胖症等代谢性疾病的患病率正在达到 在美国流行的比例。缺乏身体活动和营养过剩是造成这些问题的主要原因 条件增加对身体活动和燃料供应如何联系骨骼肌的理解 与全身代谢可能产生重要的机制见解代谢疾病 并有助于开发新的治疗策略。骨骼肌钙信号通路 肌肉对于肌肉收缩、代谢和基因表达至关重要。钙进入的作用 作为一种控制长期信号事件的机制， 在运动中。我们的研究集中在基质相互作用分子1（STIM 1）的作用， 钙传感器需要储存操作的钙进入（SOCE），作为骨骼肌的关键调节因子， 肌肉钙信号我们目前的研究重点是STIM 1在氧化应激中的作用。 新陈代谢.我们的初步数据表明，STIM 1的缺失改变了氧化代谢， 损害肌肉的性能。在这里，我们将建立代谢产生的具体变化， STIM 1信号的变化，并建立STIM 1影响肌肉的机制 新陈代谢.本申请中提出的具体目的包括：确定STIM 1如何调节 代谢灵活性;确定STIM 1如何调节线粒体钙信号传导和功能; 并确定MAP 4K 4是否调节STIM 1信号传导和骨骼肌代谢。我们 将使用包括STIM 1的转基因小鼠模型，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肌代谢灵活性中的作用提供新的见解。 并且可能对肌肉代谢受损的治疗具有重要意义 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.