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; Parolin ML, Spreit LL, Hultman E, Hollidge-Horvat MG, Jones NL, and Heigenhauser GJF. Am J Physiol Endocrinol Metab 278: E522-E534, 2000). The present study investigated whether activation of PDH with dichloroacetate (DCA) before exercise would reduce lactate accumulation during exercise in acute hypoxia by increasing oxidative phosphorylation. Six subjects cycled on two occasions for 15 min at 55% of their normoxic maximal oxygen uptake after a saline (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 rest 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. Glycogenolysis was lower with DCA, resulting in reduced lactate concentration ([lactate]), despite similar phosphorylase a mole fractions and posttransformational regulators. During the subsequent 14 min of exercise, PDH activity 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. The results from the present study support the hypothesis that lactate production is due in part to metabolic inertia and cannot solely be explained by an oxygen limitation, even under conditions of acute hypoxia.
Parolin
M L
ML
Department of Medicine, McMaster University, Hamilton, Ontario L8N 3Z5.
Spriet
L L
LL
Hultman
E
E
Matsos
M P
MP
Hollidge-Horvat
M G
MG
Jones
N L
NL
Heigenhauser
G J
GJ
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D001786:Blood Glucose; D001794:Blood Pressure; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D019344:Lactic Acid / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology; D010101:Oxygen Consumption / Q000187:drug effects; D010725:Phosphocreatine / Q000378:metabolism; D006005:Phosphorylases / Q000378:metabolism; D005082:Physical Exertion / Q000187:drug effects* / Q000502:physiology; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D012129:Respiratory Function Tests
D001786:Blood Glucose; D011768:Pyruvate Dehydrogenase Complex; D010725:Phosphocreatine; D019344:Lactic Acid; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000105:Acetyl Coenzyme A; D000255:Adenosine Triphosphate; D006003:Glycogen; D003999:Dichloroacetic Acid; D006005:Phosphorylases