Effects of PDH activation by dichloroacetate in human skeletal muscle during exercise in hypoxia

During the onset of exercise in hypoxia, the increased lactate accumulation is associated with a delayed activation of pyruvate dehydrogenase (PDH; Pa rolin ML, Spreit LL, Hultman E, Hollidge-Horvat MG, Jones NL, and Heigen-ha user GJF. Am J Physiol Endocrinol Metab 278: E522-E534, 2000). The present study investigated whether activation of PDH with dichloroacetate (DCA) bef ore exercise would reduce lactate accumulation during exercise in acute hyp oxia by increasing oxidative phosphorylation. Six subjects cycled on two oc casions for 15 min at 55% of their normoxic maximal oxygen uptake after a s aline (control) or DCA infusion while breathing 11% O-2. Muscle biopsies of the vastus lateralis were taken at rest and after 1 and 15 min of exercise . DCA increased PDH activity at rest and at 1 min of exercise, resulting in increased acetyl-CoA concentration and acetylcarnitine concentration at re st and at 1 min. In the first minute of exercise, there was a trend toward a lower phosphocreatine (PCr) breakdown with DCA compared with control. Gly cogenolysis was lower with DCA, resulting in reduced lactate concentration ([lactate]), despite similar phosphorylase a mole fractions and posttransfo rmational regulators. During the subsequent 14 min of exercise, PDH activit y was similar, whereas PCr breakdown and muscle [lactate] were reduced with DCA. Glycogenolysis was lower with DCA, despite similar mole fractions of phosphorylase a, and was due to reduced posttransformational regulators. Th e results from the present study support the hypothesis that lactate produc tion is due in part to metabolic inertia and cannot solely be explained by an oxygen limitation, even under conditions of acute hypoxia.