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Title: The effect of dichloroacetate on oxygen uptake during sub-maximal and maximal exercise in humans
Author: Parker, Matthew Edward
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2006
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Objective. Pyruvate dehydrogenase (PDH) is a multienzyme complex situated on the inner mitochondrial membrane. Its principal function is to catalyze the irreversible oxidation of pyruvate to acetyl CoA. PDH is activated by a compound known as dichloroacetate (DCA). The principal metabolic effect of DCA administration is an increased availability of acetyl-CoA and acetylcarnitine for substrate phosphorylation, and a lowering of blood [lactate]. Studies using DCA during exercise have identified the availability of these acetyl groups as a major determinant of VO2 increase at the start of exercise, suggesting a functional stenosis to VO2 may reside at the level of PDH. It was the aim of these studies to further investigate whether DCA has an effect on the rate and magnitude of the VO2 response for sub-maximal and maximal work intensities. Procedures A ramped incremental exercise protocol and 2 sub-maximal constant exercise protocols were undertaken on a cycle ergometer. The constant work protocols were undertaken at work intensities above and below that corresponding to the individual blood lactate threshold. Measures of breath-by-breath VO2 and heart rate were made in conjunction with measures of muscle oxygen saturation (NIRS) and blood borne indices (Lactate, pH, Glucose, Bicarbonate). VO2 kinetics were estimated using non-linear least squares regression strategies. Results Dichloroacetate had no significant effect on submaximal oxygen uptake. This was evidenced as no change in the amplitude or time course of the kinetic response during exercise above or below the lactate threshold, and no change in the slow component response above the lactate threshold. DCA administration did promote a small but significant increase in VO2nmx. Blood [Lactate] was reduced at submaximal exercise intensities. However, no significant difference was evident during maximal exercise. DCA was shown to have chronotropic properties evident by an observed increase in heart rate at rest and during the initial stages of exercise. Conclusions The present studies clearly illustrate a haemodynamic response to DCA that has not been described previously. Control of oxygen uptake kinetics at the level of pyruvate dehydrogenase is not supported by this work.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral