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

本研究的目的是研究骨骼肌脂肪和碳水化合物氧化的调节，以应对营养扰动和运动。更具体地说，这些研究将研究特定的酶和蛋白质的调节，这些酶和蛋白质负责决定从脂肪到碳水化合物的燃料分配，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，允许进一步氧化和产生能量。因此，它作为一个调控门户，决定了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，并通过PDH磷酸酶1和2激活。这两种酶家族的活性平衡决定了复合物的活性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，因此可以在急性情况下（如运动）以不同的方式调节PDH复合物。复合物中这些异构体的相对浓度随着饥饿、高脂肪饮食、长时间运动和运动训练而发生适应性变化，因此对氧化葡萄糖的处理有深远的影响。我们的目标是了解特定同种异构体靶向上调背后的原因，以及它们如何促进燃料分配。我们还研究了储存在肌肉纤维中的脂肪的代谢调节，即细胞内脂质。它们被储存在脂滴中，脂滴被一种叫做PAT蛋白的蛋白质家族所包裹。在骨骼肌中，这些蛋白的功能和相互作用以及它们如何调节脂质酶几乎是未知的。我们的目标是了解这些蛋白质如何在细胞质溶胶和脂滴之间移动，以及这对酶调节意味着什么。总之，这些研究将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治疗方法（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。

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.