The pyruvate dehydrogenase complex (PDC) is the rate limiting step in the entry of glucose derived pyruvate into the tricarboxylic acid (TCA) cycle. As such it plays an important role in the control of the use of carbohydrate as the source of oxidative energy for skeletal muscle contraction. The first experimental chapter investigates the effect of dichloroacetate pre-treatment during low-intensity (<60% VO2max) exercise, below which it is suggested that increasing PDC activation and resting acetyl group availability via dichloroacetate (DCA) pre-treatment will be ineffective at reducing non-oxidative ATP production and improving contractile function. Despite a significant increase in both PDC activation (p<0.01) and acetylcarnitine availability (p<0.01) prior to the onset of exercise following DCA infusion, there was no difference in substrate level phosphorylation detected during exercise. The following experimental chapter examines the link between blood lactate concentration and the onset of the ventilatory threshold. Infusion of DCA (50mg.kg-1) prior to the onset of incremental exercise lead to a significant reduction in resting blood lactate (p<0.05), but this was not preserved during the following bout of incremental cycling exercise commencing at 50% VO2max. There was also no alteration in the onset of the ventilatory threshold detected after DCA pre-treatment. The final experimental chapter has investigated the effect of DCA infusion (50 mg.kg-1) upon high-fat diet induced PDC inhibition during exercise. During moderate cycling exercise (75% VO2max) DCA infusion reversed the high-fat induced inhibition of PDC activation. DCA infusion reduced the metabolic inertia present at the onset of contraction, through both PDC activation and pooling of acetyl groups prior to contraction. This thesis has highlighted the role of the PDC as an important site of regulation of human skeletal muscle fuel metabolism, which may provide a novel target for the treatment of the metabolic syndrome.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:559512 |
| Date | January 2009 |
| Creators | Laithwaite, David |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/10992/ |
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