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

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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.