Effects of dichloroacetate infusion on human skeletal muscle metabolism at the onset of exercise

• Published in: American journal of physiology: endocrinology and metabolism 1999-07, Vol.277 (1), p.E18-E25
• Main Authors: Howlett, Richard A, Heigenhauser, George J. F, Hultman, Eric, Hollidge-Horvat, Melanie G, Spriet, Lawrence L
• Format: Article
• Language: English
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.1999.277.1.e18

Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1; Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5; and Department of Clinical Chemistry, Huddinge University Hospital, Karolinska Institute, S-141 86 Huddinge, Sweden This study investigated whether dichloroacetate (DCA) decreases the reliance on substrate level phosphorylation during the transition from rest to moderate-intensity exercise in humans. Nine subjects cycled at ~65% of maximal oxygen uptake ( O 2 max ) 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 (PDH) 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 µmol/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 maintained at 30 s and 2 min for both acetyl-CoA and acetylcarnitine. Resting muscle lactate and phosphocreatine (PCr) were not different between trials, but DCA infusion resulted in lower lactate accumulation throughout exercise, especially at 2 min (21.6 ± 3.1 vs. 44.6 ± 8.0 mmol/kg dry wt). PCr utilization in the initial 30 s (16.9 ± 0.4 vs. 31.7 ± 2.6   mmol/kg dry 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 inorganic 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 utilization and an improved cellular energy state at the onset of exercise. The transitory improvement in energy state decreased glycogenolysis and lactate accumulation during moderate-intensity exercise. glycogenolysis; lactate; phosphocreatine; inorganic phosphate; oxidative metabolism; pyruvate dehydrogenase activity; acetyl-coenzyme A; acetylcarnitine