title: Dichloroacetate enhances performance and reduces blood lactate during maximal cycle exercise in chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Impaired skeletal muscle function contributes to exercise limitation in patients with chronic obstructive pulmonary disease (COPD). This is characterized by reduced mitochondrial adenosine triphosphate generation, and greater reliance on nonmitochondrial energy production. Dichloroacetate (DCA) infusion activates muscle pyruvate dehydrogenase complex (PDC) at rest, reducing inertia in mitochondrial energy delivery at the onset of exercise and diminishing anaerobic energy production.
  
  
  OBJECTIVE
  This study aimed to determine whether DCA infusion enhanced mitochondrial energy delivery during symptom-limited maximal exercise, thereby reducing exercise-induced lactate and ammonia accumulation and, consequently, improving exercise performance in patients with COPD.
  
  
  METHODS
  A randomized, double-blind crossover design was used. Eighteen subjects with COPD performed maximal cycle exercise after an intravenous infusion of DCA (50 mg/kg body mass) or saline (control). Exercise work output was determined, and blood lactate and ammonia concentrations were measured at rest, 1 and 2 minutes of exercise, peak exercise, and 2 minutes postexercise.
  
  
  RESULTS
  DCA infusion reduced peak blood lactate concentration by 20% (mean [SE]; difference, 0.48 [0.11] mmol/L, P < 0.001) and peak blood ammonia concentration by 15% (mean [SE]; difference, 14.2 [2.9] mumol/L, P < 0.001] compared with control. After DCA, peak exercise workload improved significantly by a mean (SE) of 8 (1) W (P < 0.001) and peak oxygen consumption by 1.2 (0.5) ml/kg/minute (P = 0.03) compared with control.
  
  
  CONCLUSIONS
  We have shown that a pharmacologic intervention known to activate muscle PDC can reduce blood lactate and ammonia accumulation during exercise and improve maximal exercise performance in subjects with COPD. Skeletal muscle PDC activation may be a target for pharmacologic intervention in the management of exercise intolerance in COPD.
authors.affiliation: University Hospitals of Leicester NHS Trust, Department of Respiratory Medicine, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK. lori.calvert@uhl-tr.nhs.uk
authors.forename: Lori D
authors.initials: LD
authors.lastname: Calvert
authors.forename: Rhea
authors.initials: R
authors.lastname: Shelley
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Singh
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greenhaff
authors.forename: John
authors.initials: J
authors.lastname: Bankart
authors.forename: Mike D
authors.initials: MD
authors.lastname: Morgan
authors.forename: Michael C
authors.initials: MC
authors.lastname: Steiner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000641:Ammonia / Q000378:metabolism; D018592:Cross-Over Studies; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004311:Double-Blind Method; D020536:Enzyme Activators / Q000494:pharmacology*; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011768:Pyruvate Dehydrogenase Complex / Q000187:drug effects*
chemical_list: D020536:Enzyme Activators; D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D000641:Ammonia; D003999:Dichloroacetic Acid