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

这项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，这些研究将检查特定酶和蛋白质的调节，这些酶和蛋白质负责确定从脂肪到碳水化合物的燃料分配，例如丙酮酸脱氢酶(PDH)复合体。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，它起着调节门户的作用，确定碳水化合物和脂肪氧化对能量产生的相对贡献。该复合体通过内源性PDH激酶1、2和4的磷酸化失活，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处于活性形式的复合体的比例和碳水化合物的氧化速度。每种异构体对细胞效应物都有自己独特的反应，因此在急性情况下，如运动，可以不同地调节PDH复合体。这些异构体在复合体中的相对浓度随着饥饿、高脂饮食、长期运动和运动训练的变化而发生适应性变化，从而对氧化葡萄糖的处置产生深远的影响。我们的目标是了解特定异构体定向上调背后的原因(S)，以及它们如何促进燃料分配。我们还在研究储存在肌肉纤维中的脂肪的代谢调节，称为肌细胞内脂类。这些蛋白质储存在脂滴中，脂滴上覆盖着一系列称为PAT蛋白的蛋白质。在骨骼肌中，这些蛋白质的功能和这些蛋白质的相互作用以及它们如何调节脂酶几乎是未知的。我们的目标是了解这些蛋白质如何在胞浆和脂滴之间移动，以及这对酶的调节意味着什么。这些研究将一起深入了解肌肉燃料使用的潜在机制，并最终可能导致潜在的治疗方法(药物、营养和积极生活方式的改变)，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.