Skeletal Muscle Metabolic Gene Expression Is Not Affected by Dichloroacetate-Mediated Modulation of Substrate Utilisation

Abstract

Aim: This study investigated whether changing fuel use, by increasing pyruvate dehydrogenase complex (PDC) flux, independently of plasma substrate availability and insulin signalling, would alter metabolic gene expression. Methods: The PDC activator, dichloroacetate (DCA), was administered as an intravenous infusion in healthy male subjects at a rate of 50 mg kg^–1 min^–1, for 90 min. Saline was infused as a control (CON) on a separate occasion in a randomised sequence. Muscle biopsies were taken from the vastus lateralis at 0 and 30 min into the infusion and 90 min after infusion. Gene expression was quantified using RT-qPCR, and immunoblotting was used to confirm that there were no changes in insulin signalling via the PI3K/Akt pathway. Results: Blood glucose concentrations fell during both trials but 3 h after the start of the infusion they were lower in DCA (p < 0.05) than CON. Blood lactate concentrations also declined in both trials (p < 0.01), however, this decrease was also more pronounced in DCA than CON (p < 0.001). Carbohydrate oxidation was increased by DCA, 0.037 ± 0.017 g min^–1 (p < 0.05) at 3 h with no change observed in CON. UCP3 and PGC1α mRNA expression were induced in CON (as a response to continued fasting) but this was attenuated by DCA. Akt phosphorylation and the expression of other metabolic genes and transcription factors were unchanged throughout the intervention. Conclusion: It is concluded that PDC flux can be increased independently of plasma substrate availability, without causing downstream alterations to metabolic gene expression in the short term.