Skeletal muscle metabolic gene expression is not affected by dichloroacetate-mediated modulation of substrate utilisation

Ann Nutr Metab. 2011;58(1):19-24. doi: 10.1159/000322971. Epub 2011 Feb 8.

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.

MeSH terms

  • Adult
  • Dichloroacetic Acid / administration & dosage*
  • Fasting / metabolism
  • Gene Expression Regulation*
  • Humans
  • Immunoblotting
  • Infusions, Intravenous
  • Insulin / blood
  • Lactic Acid / blood
  • Male
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyruvate Dehydrogenase Complex / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Insulin
  • Pyruvate Dehydrogenase Complex
  • pyruvate dehydrogenase activator
  • Lactic Acid
  • Dichloroacetic Acid
  • Proto-Oncogene Proteins c-akt