title: Oxygen uptake on-kinetics in dog gastrocnemius in situ following activation of pyruvate dehydrogenase by dichloroacetate.
abstract: The aim of the present study was to determine whether the activation of the pyruvate dehydrogenase complex (PDC) by dichloroacetate (DCA) is associated with faster O(2) uptake (V(O2)) on-kinetics. V(O2) on-kinetics was determined in isolated canine gastrocnemius muscles in situ (n = 6) during the transition from rest to 4 min of electrically stimulated isometric tetanic contractions, corresponding to approximately 60-70 % of peak V(O2). Two conditions were compared: (1) control (saline infusion, C); and (2) DCA infusion (300 mg (kg body mass)(-1), 45 min before contraction). Muscle blood flow (Q) was measured continuously in the popliteal vein; arterial and popliteal vein O(2) contents were measured at rest and at 5-7 s intervals during the transition. Muscle V(O2) was calculated as Q multiplied by the arteriovenous O(2) content difference. Muscle biopsies were taken before and at the end of contraction for determination of muscle metabolite concentrations. DCA activated PDC at rest, as shown by the 9-fold higher acetylcarnitine concentration in DCA (vs. C; P < 0.0001). Phosphocreatine degradation and muscle lactate accumulation were not significantly different between C and DCA. DCA was associated with significantly less muscle fatigue. Resting and steady-state V(O2) values during contraction were not significantly different between C and DCA. The time to reach 63 % of the V(O2) difference between the resting baseline and the steady-state V(O2) values during contraction was 22.3 +/- 0.5 s in C and 24.5 +/- 1.4 s in DCA (n.s.). In this experimental model, activation of PDC by DCA resulted in a stockpiling of acetyl groups at rest and less muscle fatigue, but it did not affect 'anaerobic' energy provision and V(O2) on-kinetics.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biomediche, Università degli Studi di Milano, I-20090 Segrate (MI), Italy. bruno.grassi@unimi.it
authors.forename: Bruno
authors.initials: B
authors.lastname: Grassi
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hogan
authors.forename: Paul L
authors.initials: PL
authors.lastname: Greenhaff
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Hamann
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Kelley
authors.forename: William G
authors.initials: WG
authors.lastname: Aschenbach
authors.forename: Dumitru
authors.initials: D
authors.lastname: Constantin-Teodosiu
authors.forename: L Bruce
authors.initials: LB
authors.lastname: Gladden
mesh_terms: D000108:Acetylcarnitine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004285:Dogs; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006706:Homeostasis; D066298:In Vitro Techniques; D007700:Kinetics; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D010101:Oxygen Consumption / Q000502:physiology*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D000108:Acetylcarnitine; D000255:Adenosine Triphosphate; D003999:Dichloroacetic Acid