title: Skeletal muscle metabolic gene expression is not affected by dichloroacetate-mediated modulation of substrate utilisation.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Biomedical Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK. mbxpt1@nottingham.ac.uk
authors.forename: Paul B
authors.initials: PB
authors.lastname: Tisdale
authors.forename: Nandini
authors.initials: N
authors.lastname: Seevaratnam
authors.forename: Ian A
authors.initials: IA
authors.lastname: Macdonald
authors.forename: Kostas
authors.initials: K
authors.lastname: Tsintzas
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bennett
mesh_terms: D000328:Adult; D003999:Dichloroacetic Acid / Q000008:administration & dosage*; D005215:Fasting / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood; D019344:Lactic Acid / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D007328:Insulin; D011768:Pyruvate Dehydrogenase Complex; C029131:pyruvate dehydrogenase activator; D019344:Lactic Acid; D003999:Dichloroacetic Acid; D051057:Proto-Oncogene Proteins c-akt