Metabolic effects of partial reversal of pyruvate dehydrogenase activity by dichloroacetate in sepsis

Abstract

The metabolic effects of dichloroacetate on carbohydrate metabolism were investigated in normal fed, sterile inflammatory, and chronic septic animals. Chronic sepsis, but not sterile inflammation, was associated with elevated plasma, liver, and skeletal muscle lactate concentrations. Sodium dichloroacetate significantly reduced both plasma and intracellular pyruvate and lactate concentrations in all conditions examined, while plasma glucose concentrations remained unchanged. Decreased tissue metabolite concentrations were associated with a significantly increased active pyruvate dehydrogenase complex in liver and skeletal muscle in each of the conditions examined. In liver, dichloroacetate fully activated (greater than 85%) the pyruvate dehydrogenase complex under all conditions. In skeletal muscle from chronic septic animals, the dichloroacetate-induced increases in active pyruvate dehydrogenase were significantly less than those observed in non-septic animals. The data suggest that although dichloroacetate can partially reverse the sepsis-induced effects on skeletal muscle pyruvate dehydrogenase activity, there may be additional regulatory factors in skeletal muscle from septic animals. The dichloroacetate stimulation of the pyruvate dehydrogenase activity may provide a pharmacological method for reducing the elevated lactate concentrations observed in chronic severe sepsis.