Regulation of fuel utilization in mammalian skeletal muscle: effect of diet and exercise

哺乳动物骨骼肌燃料利用的调节：饮食和运动的影响

• 批准号: 229767-2011
• 负责人: Peters, Sandra
• 金额: $ 1.75万
• 依托单位: Brock University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=546914
• 关键词: Regulation; fuel; utilization; mammalian; skeletal

The goal of this research is to examine the regulation of skeletal muscle fat and carbohydrate oxidation in response to nutritional perturbations and exercise. More specifically these studies will examine the regulation of specific enzymes and proteins responsible for determining fuel partitioning from fat to carbohydrate such as the pyruvate dehydrogenase (PDH) complex. This mitochondrial enzyme catalyzes the conversion of pyruvate to acetyl-coenzyme A, permitting further oxidation and energy production. As such, it acts as a regulatory gateway, determining the relative contributions of carbohydrate and fat oxidation to energy production. This complex is inactivated through phosphorylation by intrinsic PDH kinases 1, 2 and 4, and activated by PDH phosphatases 1 and 2.The balance in activity between these two enzyme families determines the proportion of the complex which is in the active form and the rate of carbohydrate oxidation. Each of the isoforms has its own unique responses to cellular effectors, and therefore can regulate the PDH complex differently in acute situations such as exercise. The relative concentrations of these isoforms in the complex change adaptively in response to starvation, high-fat diet, prolonged exercise, and exercise training and therefore have profound effects on oxidative glucose disposal. Our goal is to understand the reason(s) behind the targeted up-regulation of the specific isoforms and how they contribute to fuel partitioning. We are also examining the metabolic regulation of fat stored within muscle fibres known as intramyocellular lipids. These are stored in lipid droplets that are coated with a family of proteins called PAT proteins. The function of these proteins and the interaction of these proteins and how they regulate lipid enzymes is virtually unknown in skeletal muscle. Our goal is to understand how these proteins move between the cytosol and the lipid droplet and what this means to enzymatic regulation.Together these studies will give insight into underlying mechanisms involved in muscle fuel use, and may ultimately lead to potential therapies (pharmaceutical, nutritional, and active lifestyle changes) that will enhance our overall quality of life.

这项研究的目的是检查骨骼肌脂肪和碳水化合物氧化对营养扰动和运动的反应的调节。 更具体地说，这些研究将检查负责确定燃料从脂肪到碳水化合物分配的特定酶和蛋白质的调节，例如丙酮酸脱氢酶（PDH）复合物。这种线粒体酶催化丙酮酸转化为乙酰辅酶 A，从而进一步氧化和产生能量。因此，它充当监管门户，确定碳水化合物和脂肪氧化对能量​​产生的相对贡献。该复合物通过内在 PDH 激酶 1、2 和 4 的磷酸化而失活，并被 PDH 磷酸酶 1 和 2 激活。这两个酶家族之间的活性平衡决定了复合物处于活性形式的比例和碳水化合物氧化的速率。每种异构体对细胞效应物都有其独特的反应，因此可以在运动等紧急情况下以不同的方式调节 PDH 复合物。复合物中这些亚型的相对浓度会响应饥饿、高脂肪饮食、长时间运动和运动训练而适应性变化，因此对氧化葡萄糖处理具有深远的影响。我们的目标是了解特定异构体定向上调背后的原因以及它们如何促进燃料分配。我们还在研究储存在肌纤维内的脂肪（称为肌细胞内脂质）的代谢调节。它们储存在脂滴中，脂滴上涂有 PAT 蛋白家族的蛋白质。这些蛋白质的功能、这些蛋白质的相互作用以及它们如何调节脂质酶在骨骼肌中实际上是未知的。我们的目标是了解这些蛋白质如何在细胞质和脂滴之间移动，以及这对酶调节意味着什么。这些研究将共同​​深入了解肌肉燃料使用的潜在机制，并可能最终导致潜在的疗法（药物、营养和积极的生活方式改变），从而提高我们的整体生活质量。