STIM1 and metabolic flexibility

STIM1 和代谢灵活性

基本信息

批准号：
9895772
负责人：
DEBORAH M MUOIO
金额：
$ 57.57万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895772
关键词：
Address Affect Aging Attention Bioenergetics Biology Brain Calcium Calcium Signaling Carbon Cell Respiration Cell membrane Complex Cues Data Defect Development Diabetes Mellitus Disease Energy Metabolism Enzymes Epidemic Event Exercise Exercise Tolerance Fasting Fatigue Fatty acid glycerol esters Gene Expression Glucose Glucose Intolerance Glycolysis Homeostasis Human Image Impairment Insulin Insulin Resistance Integral Membrane Protein Knockout Mice Link Mediating Membrane Metabolic Metabolic Diseases Metabolism Methodology Mitochondria Molecular Multienzyme Complexes Mus Muscle Muscle Contraction Muscle Fibers Muscle Mitochondria Nature Non-Insulin-Dependent Diabetes Mellitus Nucleotides Nutrient Nutritional Obesity Outer Mitochondrial Membrane Overnutrition Oxidoreductase Performance Physical activity Physiology Play Prevalence Process Property Regulation Research Resolution Rodent Role STIM1 gene Sarcoplasmic Reticulum Signal Transduction Signaling Molecule Site Skeletal Muscle Stress Testing Tissues VDAC1 gene Voltage-Dependent Anion Channel Weight Gain Yeasts age related blood glucose regulation cardiometabolism clinically relevant combat dietary manipulation early onset exercise intensity exercise intolerance exercise training extracellular extracellular signal-regulated kinase 4 feeding flexibility glucose tolerance glucose uptake innovation insight metabolomics mitochondrial dysfunction mitochondrial metabolism mouse model muscle form muscle metabolism novel novel therapeutics oxidation physical inactivity programs pyruvate dehydrogenase response sensor skeletal muscle metabolism stem tool yeast two hybrid system

项目摘要

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.

胰岛素抵抗，糖尿病和肥胖等代谢疾病的患病率正在达到美国流行比例。身体上的不活动和营养不良是这些的主要贡献者状况。对体育活动和燃料供应如何联系骨骼肌肉的越来越多的了解全身代谢可能会产生对代谢疾病的重要机理见解并为新的治疗策略的发展做出贡献。骨骼中的钙信号传导肌肉对于肌肉收缩，代谢和基因表达至关重要。钙进入的作用已提供作为控制长期信号事件的机制，例如限制疲劳锻炼期间。我们的研究集中于基质相互作用分子1（stim1）的作用商店经营钙进入（SOCE）所需的钙传感器，作为骨骼的关键调节剂肌肉钙信号传导。我们当前的程序集中于STIM1在氧化中的作用代谢。我们的初步数据表明，Stim1的丧失会改变氧化代谢和损害肌肉表现。在这里，我们将确定由 STIM1信号传导的变化并建立刺激肌肉影响肌肉的机制代谢。本应用程序中提出的具体目的包括：确定STIM1如何调节代谢灵活性；确定STIM1如何调节线粒体钙信号传导和功能；并确定MAP4K4是否调节STIM1信号传导和骨骼肌代谢。我们将使用包括STIM1的转基因鼠标模型，高分辨率的方法钙成像，生物能和代谢组学以解决这些目标。我们提出的研究可以为钙在调节骨骼的代谢灵活中的作用提供新的见解肌肉，可能对肌肉代谢受损的治疗有重大影响与糖尿病和其他代谢疾病有关。