Regulation of fat/carbohydrate interaction in human skeletal muscle during exercise.

There has been continued interest in the regulation of fat and carbohydrate utilization in muscle tissue, as they are the main substrates for energy production during exercise in well fed humans. Many investigations have demonstrated that increasing fat availability increases fat oxidation and decreases carbohydrate use in the whole body and skeletal muscle. However, little work has been performed in skeletal muscle to identify the mechanisms, and specific biochemical signals which mediate these shifts in fuel selection. The classic work in this area, using contracting heart and resting diaphragm muscle, led to a theory that could explain reciprocal changes in fat and carbohydrate use from a biochemical perspective (glucose-fatty acid cycle). Using this information, we embarked on a number of studies demonstrating that the biochemical regulation of fat/carbohydrate interaction in human skeletal muscle during exercise is different than exists in the continually active heart and diaphragm muscles. By increasing the availability of free fatty acids to the working muscles, it was demonstrated that carbohydrate downregulation during moderate and intense aerobic exercise occurred mainly at glycogen phosphorylase, the enzyme that regulates the degradation of muscle glycogen. There was also coordinate downregulation of pyruvate dehydrogenase activity at low and moderate exercise intensities. We have also investigated the roles that carnitine palmitoyl-transferase I and its regulator malonyl-CoA play in governing the transport of long-chain fatty acids into the mitochondria for oxidation, and therefore the impact on carbohydrate use in human skeletal muscle. The regulation of Carnitine Palmitoyltransferase I (CPTI) activity appears to involve more than changes in the concentration of malonyl-CoA. Several additional mechanisms may exist that interact with or override the effects of malonyl-CoA during exercise, although this work is just beginning. The present work has identified several regulatory sites in the pathways of carbohydrate and fat metabolism that help explain the regulation of fat/carbohydrate interaction in human skeletal muscle during exercise.