Effects of dichloroacetate on V̇o₂and intramuscular³¹P metabolite kinetics during high-intensity exercise in humans

Abstract

Traditional control theories of muscle O2 consumption are based on an "inertial" feedback system operating through features of the ATP splitting (e.g., [ADP] feedback, where brackets denote concentration). More recently, however, it has been suggested that feedforward mechanisms (with respect to ATP utilization) may play an important role by controlling the rate of substrate provision to the electron transport chain. This has been achieved by activation of the pyruvate dehydrogenase complex via dichloroacetate (DCA) infusion before exercise. To investigate these suggestions, six men performed repeated, high-intensity, constant-load quadriceps exercise in the bore of an magnetic resonance spectrometer with each of prior DCA or saline control intravenous infusions. O2 uptake (Vo2) was measured breath by breath (by use of a turbine and mass spectrometer) simultaneously with intramuscular phosphocreatine (PCr) concentration ([PCr]), [Pi], [ATP], and pH (by 31P-MRS) and arterialized-venous blood sampling. DCA had no effect on the time constant (tau) of either Vo2 increase or PCr breakdown [tauVo2 45.5 +/- 7.9 vs. 44.3 +/- 8.2 s (means +/- SD; control vs. DCA); tauPCr 44.8 +/- 6.6 vs. 46.4 +/- 7.5 s; with 95% confidence intervals averaging < +/-2 s]. DCA, however, resulted in significant (P < 0.05) reductions in 1). end-exercise [lactate] (-1.0 +/- 0.9 mM), intramuscular acidification (pH, +0.08 +/- 0.06 units), and [Pi] (-1.7 +/- 2.1 mM); 2). the amplitude of the fundamental components for [PCr] (-1.9 +/- 1.6 mM) and Vo2 (-0.1 +/- 0.07 l/min, or 8%); and 3). the amplitude of the Vo2 slow component. Thus, although the DCA infusion lessened the buildup of potential fatigue metabolites and reduced both the aerobic and anaerobic components of the energy transfer during exercise, it did not enhance either tauVo2 or tau[PCr], suggesting that feedback, rather than feedforward, control mechanisms dominate during high-intensity exercise.

Regulation of V̇o2 kinetics by O2 delivery: insights from acute hypoxia and heavy-intensity priming exercise in young men

“…Although neither leg blood flow nor cardiac output was measured in the present study, changes in HR were used to provide insights into changes in bulk (i. (20,33), and when elevated PDH activity was reported following Hvy, the correlation between PDH activity and V O 2p was nonsignificant (14); thus, evidence for a ratelimiting role of PDH in the determination of V O 2p is nonexistent. Notwithstanding the conclusions of Parolin et al, the trend for a greater [HHb]/V O 2 overshoot during Mod 1 ϩ Hypo than control in the present study suggests an exaggerated O 2 delivery limitation.…”

“…Since elevated bulk [i.e., increased heart rate (HR) following Hvy and throughout subsequent Mod] and local muscle O 2 delivery and mitochondrial PDH activity have been implicated following Hvy, isolation of the precise mechanism(s) responsible for the reduced V O 2p has proven difficult. While activation of PDH by administration of dichloroacetate, in the absence of augmented O 2 delivery, has failed to demonstrate significant reductions in V O 2p during upright cycling (20,33), this does not preclude the possibility that provision of some metabolic substrate or limitation of enzyme (other than PDH) activation may be responsible for regulation of V O 2 . As such, to investigate the independent effects of a possible metabolic substrate or enzyme activation limitation, an intervention that "primes" factors affecting metabolic substrate provision and/or enzyme activation without also priming local muscle O 2 delivery is required.…”

Effects of prior very-heavy intensity exercise on indices of aerobic function and high-intensity exercise tolerance

“…An involvement of putative intramuscular enzymatic controllers such as pyruvate dehydrogenase also seems unlikely, given the demonstration that dichloroacetate administration actually reduces the fundamental V O 2 and [PCr] amplitudes for highintensity exercise (44). Some authors have advocated a role for the recruitment of additional glycolytic muscle fibers with low oxidative capacity early in the postpriming exercise, consequent to fatigue-related influences on sarcolemmal excitation thresholds imposed by the priming bout (4, 9, 10, 48).…”

Effects of Age and Long-Term Endurance Training on V·O2 Kinetics

“…However, experiments in humans (Bangsbo et al, 2002;Jones et al, 2004;Rossiter et al, 2003) failed to demonstrate faster VO 2 kinetics following prior PDH activation by DCA supplementation. Furthermore, Grassi et al (2002) used an isolated dog gastrocnemius muscle to…”

“…Pyruvate dehydrogenase has been studied as a potential site of regulation for oxidative phosphorylation (Bangsbo et al, 2002;Grassi et al, 2002;Howlett et al, 1999;Jones et al, 2004;Rossiter et al, 2003); the mitochondrial PDH complex is responsible for regulating the entry of carbohydrate-derived substrate into the TCA cycle and the provision of reducing equivalents to the ETC. Conflicting evidence exists in the literature in both human and canine models.…”