Effects of dichloroacetate infusion on human skeletal muscle metabolism atthe onset of exercise

This study investigated whether dichloroacetate (DCA) decreases the relianc e on substrate level phosphorylation during the transition from rest to mod erate-intensity exercise in humans. Nine subjects cycled at similar to 65% of maximal oxygen uptake ((V) over dot o(2max)) after a saline or DCA (100 mg/kg body wt) infusion, with muscle biopsies taken at rest and at 30 s and 2 and 10 min of exercise. DCA infusion increased pyruvate dehydrogenase (P DH) activation at rest (4.0 +/- 0.3 vs. 0.9 +/- 0.1 mmol . kg wet wt(-1) . min(-1)) and at 30 s (3.6 +/- 0.2 vs. 2.5 +/- 0.4 mmol . kg(-1) . min(-1)) of exercise. As a result, acetyl-CoA (45.9 +/- 5.9 vs. 11.3 +/- 1.5 mu mol/ kg dry wt) and acetylcarnitine (13.1 +/- 1.0 vs. 1.6 +/- 0.3 mmol/kg dry wt ) were markedly increased by DCA infusion at rest. These differences were m aintained at 30 s and 2 min for both acetyl-CoA and acetylcarnitine. Restin g muscle lactate and phosphocreatine (PCr) were not different between trial s, but DCA infusion resulted in lower lactate accumulation throughout exerc ise, especially at 2 min (21.6 +/- 3.1 vs. 44.6 +/- 8.0 mmol/kg dry art). P Cr utilization in the initial 30 s (16.9 +/- 0.4 vs. 31.7 +/- 2.6 mmol/kg d ry wt) and 2 min(27.8 +/- 4.7 vs. 45.1 +/- 2.6 mmol/kg dry wt) of exercise was decreased with DCA. This resulted in a lower accumulation of free inorg anic phosphate at 30 s (25.4 +/- 2.0 vs. 36.4 +/- 2.8 mmol/kg dry wt) and 2 min (34.6 +/- 4.7 vs. 50.5 +/- 2.2 mmol/kg dry wt) with DCA and decreased glycogenolysis over 10 min. The data from this study support the hypothesis that increased provision of substrate by DCA infusion increases oxidative metabolism during the rest-to-work transition, resulting in decreased PCr u tilization and an improved cellular energy state at the onset of exercise. The transitory improvement in energy state decreased glycogenolysis and lac tate accumulation during moderate-intensity exercise.