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 O2, uptake (VO2) on-kinetics. VO2, 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 ∼60-70 % of peak ̇VO2. 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 O2 contents were measured at rest and at 5-7 s intervals during the transition. Muscle VO2, was calculated as Q multiplied by the arteriovenous O2 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 VO2 values during contraction were not significantly different between C and DCA. The time to reach 63 % of the VO2 difference between the resting baseline and the steady-state VO2 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 VO2 on-kinetics.