METABOLIC EFFECTS OF PDC ACTIVATION IN DOG GASTROCNEMIUS IN SITU

Abstract

We tested the hypothesis that the activation of the pyruvate dehydrogenase complex (PDC) by dichloracetate (DCA) would result in a faster O2 uptake (VO2) on-kinetics. VO2 on-kinetics was determined in isolated canine gastrocnemius muscles in situ (n = 6) during transitions from rest to 4 min of electrically stimulated isometric tetanic contractions, corresponding to 60–70% of (VO2) max. Two conditions were compared: 1) Control (C), 2) DCA infusion (300 mg/kg body weight, prior to contractions). Muscle blood flow (Q) was measured continuously in the popliteal vein, arterial (CaO2) and popliteal vein (CvO2) O2 contents were measured at rest and at 5s to 7s intervals during the transition. Muscle VO2 was calculated as Q·C(a-v)O2. Muscle biopsies were taken at rest and at the end of the contraction period for the determination of muscle metabolite concentrations. Muscle force was measured continuously. DCA activated PDC at rest, as shown by the significantly higher [acetylcarnitine] in DCA (15.1 ± 0.9 mmol/kgDM) vs. C (1.7 ± 0.2) (P < 0.0001). PCr degradation was ≈30% lower in DCA (19.7 ± 2.9 mmol/kgDM) vs. C (27.9 ± 4.2) (P = 0.14). Net muscle lactate accumulation was not significantly different in DCA (6.8 ± 1.8 mmol/kgDM) vs. C (4.4 ± 3.2) (P = 0.53). DCA was associated with less muscle fatigue (fatigue index at 4 min = 0.81 ± 0.05 in DCA vs. 0.72 ± 0.03 in C, P = 0.02). Resting and steady state VO2 during contractions were not different between DCA and C. The mean response time (time delay + τ) of the VO2 on-kinetics was 24.2 ± 2.0s in DCA vs. 21.3 ± 1.0s in C (P = 0.09). In the present experimental model, prior PDC activation by DCA did not significantly affect PCr degradation, muscle lactate accumulation and VO2 on-kinetics. (NIH 1RO1AR40342, AR40155, NATO CRG 97211, Telethon Italy Grant 1161C)