PDH activation by dichloroacetate reduces TCA cycle intermediates at rest but not during exercise in humans

Abstract

We hypothesized that dichloroacetate (DCA), which stimulates the pyruvate dehydrogenase complex (PDH), would attenuate the increase in muscle tricarboxylic acid cycle intermediates (TCAI) during exercise by increasing the oxidative disposal of pyruvate and attenuating the flux through anaplerotic pathways. Six subjects were infused with either saline (Con) or DCA (100 mg/kg body mass) and then performed a moderate leg kicking exercise for 15 min, followed immediately by intense exercise until exhaustion (Exh; ∼4 min). Resting active fraction of PDH (PDHa) was markedly increased ( P ≤ 0.05) after DCA vs. Con (2.65 ± 0.27 vs. 0.64 ± 0.07 mmol ⋅ min−1 ⋅ kg wet wt−1); however, there were no differences between trials after 1 or 15 min of exercise or at Exh. The sum of five measured TCAI (ΣTCAI; ∼90% of total TCAI pool) was lower ( P ≤ 0.05) after DCA vs. Con at rest (0.78 ± 0.11 vs. 1.52 ± 0.23 mmol/kg dry wt, respectively). However, the net increase in muscle TCAI during the first minute of exercise was higher ( P≤ 0.05) in the DCA trial vs. Con (3.05 ± 0.45 vs. 2.44 ± 0.55 mmol ⋅ min−1 ⋅ kg dry wt−1, respectively), and consequently, the ΣTCAI was not different between trials during exercise. We conclude that DCA reduced TCAI pool size at rest by increasing the flux through PDH and diverting pyruvate away from anaplerotic pathways. The reason for the similar absolute increase in TCAI during exercise is not clear but may be related to 1) an initial mismatch between glycolytic flux and PDH flux that provided sufficient pyruvate for anaplerosis in both trials; or 2) a transient inhibition of PDH flux during the DCA trial due to an elevated resting acetyl-CoA-to-CoASH ratio, which augmented the anaplerotic flux of carbon during the rest-to-work transition.