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.

Effects of decreased lactate accumulation after dichloroacetate administration on exercise training-induced mitochondrial adaptations in mouse skeletal muscle

“…Therefore, the DCA-treated exercised group was affected by DCA itself stronger than the DCA-treated sedentary group. However, in human skeletal muscle, 180 min infusion of DCA did not change gene expressions involved with substrate metabolism compared with the preinfusion state (Tisdale et al 2011). Second, there are chronic effects of DCA administration.…”

“…However, in human skeletal muscle, 180 min infusion of DCA did not change gene expressions involved with substrate metabolism compared with the preinfusion state (Tisdale et al. 2011). Second, there are chronic effects of DCA administration.…”