Date of Award

3-2000

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. G.J.F. Heigenhauser

Abstract

The studies described in this thesis were undertaken to examine the mechanism of lactate production in exercise from a standpoint of enzymatic control and investigate the two rate-limiting enzymes which regulate glycogen breakdown and oxidation, glycogen phosphorylase and pyruvate dehydrogenase (PDH). The purpose was to establish the theory that it is the differential rate of flux through these enzymes which determines the extent of lactate accumulation in situations where significant lactate production occurs such as during 30-s bouts of maximal intermittent exercise and during exercise in hypoxia. In the first study, at the onset of maximal exercise, the transformation of PDH was delayed relative to phosphorylase accounting for a greater lactate accumulation. PDH was maximally transformed after 15s and remained elevated until 30s, whereas the transformation of phosphorylase remained elevated at 15s and reverted to resting levels after 30s. Before the third bout of exercise, PDH was nearly 50% transformed and was fully transformed after only 6s, whereas phosphorylase remained at resting levels. The regulation of these enzymes at the last 15s of the first bout and throughout the third bout is consistent with a reduction in glycogenolysis and increased pyruvate oxidation leading to less lactate accumulation. In the second study, at the onset of exercise in hypoxia, there was a delayed transformation of PDH relative to normoxia, accounting for the greater lactate accumulation typically observed in hypoxia. The results from these first two studies suggested that the metabolic inertia of PDH activation may be a factor in the mechanism of lactate production in both maximal exercise and in hypoxia. The third study sought to remove the metabolic inertia of PDH activation during exercise in hypoxia with the infusion of dichloroacetate (DCA). DCA fully transformed PDH at rest and at the onset of exercise in hypoxia. By removing the metabolic inertia of PDH activation with DCA or with prior exercise as in the third bout of maximal exercise in the first study, lactate production was significantly reduced. The findings from these studies demonstrate that the mechanism of lactate production is the result of a mismatch between the rates of pyruvate production and pyruvate oxidation due to the differential catalytic rates between glycogen phosphorylase and PDH under conditions where oxygen is presumed to be limiting such as maximal exercise and exercise in hypoxia. These results contradict the theory that an O2 limitation is the main cause for lactate production ("anaerobic metabolism") and suggest that the metabolic inertia of enzyme activation also plays a role. The data are indicative of a central role for PDH and phosphorylase in the mechanism of lactate production and further question whether O2 is limiting during exercise in healthy humans.

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