Role of pyruvate dehydrogenase in lactate production in exercising human skeletal muscle.

The mechanisms responsible for lactate production with increased intensity of muscle contraction are controversial. Some investigators suggest that the mitochondria are O2-limited, whereas others suggest that lactate production occurs when O2 to the mitochondria is adequate and that the increased lactate production is due to a "mass-action effect" when pyruvate production exceeds the rate of pyruvate oxidation. Pyruvate dehydrogenase is a rate-limiting enzyme for pyruvate entry into the tricarboxylic acid cycle; its catalytic activity influences both pyruvate oxidation and lactate production. Since lactate dehydrogenase is an equilibrium enzyme, increased lactate production will be due to a mass-action effect exerted by increases in pyruvate concentrations. Because the equilibrium constant of the lactate dehydrogenase reaction markedly favors lactate over pyruvate, small increases in pyruvate concentration will result in large increases in lactate concentration. At higher exercise intensities, which are more reliant on glycogen as substrate, the rate of pyruvate production exceeds the catalytic activity of pyruvate dehydrogenase, and lactate production occurs. Studies using dichloroacetate, induced acid-base changes, diet and short-term endurance training, indicate that lactate production is related to complex interactions of metabolic pathways and not related to inadequate O2 supply. As pyruvate dehydrogenase plays a central role in the integration of carbohydrate and fat metabolism, and in the entry of pyruvate into the tricarboxylic acid cycle, this enzyme plays a key role in lactate production.