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Effects of dichloroacetate on O₂ and intramuscular ³¹P metabolite kinetics during high-intensity exercise in humans

St. George's Hospital Medical School, Departments of ¹Physiology, ²Biochemistry, and ³Pharmacology, London SW17 0RE; ⁴Centre for Exercise Science and Medicine, University of Glasgow, Glasgow G12 8QQ, United Kingdom; ⁵Canadian Centre for Activity and Ageing, University of Western Ontario, London, Ontario, Canada N6G 2M3; and ⁶Division of Physiology, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0623

Submitted 18 October 2002 ; accepted in final form 7 May 2003

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 (O₂) was measured breath by breath (by use of a turbine and mass spectrometer) simultaneously with intramuscular phosphocreatine (PCr) concentration ([PCr]), [P_i], [ATP], and pH (by ³¹P-MRS) and arterialized-venous blood sampling. DCA had no effect on the time constant () of either O₂ increase or PCr breakdown [O₂ 45.5 ± 7.9 vs. 44.3 ± 8.2 s (means ± SD; control vs. DCA); PCr 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 [P_i] (-1.7 ± 2.1 mM); 2) the amplitude of the fundamental components for [PCr] (-1.9 ± 1.6 mM) and O₂ (-0.1 ± 0.07 l/min, or 8%); and 3) the amplitude of the O₂ 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 O₂ or [PCr], suggesting that feedback, rather than feedforward, control mechanisms dominate during high-intensity exercise.

magnetic resonance spectroscopy; kinetics; dichloroacetate; O₂ uptake; fatigue; phosphocreatine concentration

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