Effects of PDH activation by dichloroacetate in human skeletal muscle during exercise in hypoxia

Abstract

During the onset of exercise in hypoxia, the increased lactate accumulation is associated with a delayed activation of pyruvate dehydrogenase (PDH; Parolin ML, Spreit LL, Hultman E, Hollidge-Horvat MG, Jones NL, and Heigenhauser GJF. Am J Physiol Endocrinol Metab 278: E522-E534, 2000). The present study investigated whether activation of PDH with dichloroacetate (DCA) before exercise would reduce lactate accumulation during exercise in acute hypoxia by increasing oxidative phosphorylation. Six subjects cycled on two occasions for 15 min at 55% of their normoxic maximal oxygen uptake after a saline (control) or DCA infusion while breathing 11% O(2). Muscle biopsies of the vastus lateralis were taken at rest and after 1 and 15 min of exercise. DCA increased PDH activity at rest and at 1 min of exercise, resulting in increased acetyl-CoA concentration and acetylcarnitine concentration at rest and at 1 min. In the first minute of exercise, there was a trend toward a lower phosphocreatine (PCr) breakdown with DCA compared with control. Glycogenolysis was lower with DCA, resulting in reduced lactate concentration ([lactate]), despite similar phosphorylase a mole fractions and posttransformational regulators. During the subsequent 14 min of exercise, PDH activity was similar, whereas PCr breakdown and muscle [lactate] were reduced with DCA. Glycogenolysis was lower with DCA, despite similar mole fractions of phosphorylase a, and was due to reduced posttransformational regulators. The results from the present study support the hypothesis that lactate production is due in part to metabolic inertia and cannot solely be explained by an oxygen limitation, even under conditions of acute hypoxia.

Prior heavy exercise elevates pyruvate dehydrogenase activity and muscle oxygenation and speeds O2uptake kinetics during moderate exercise in older adults

“…Faster V O 2p kinetics, reflecting faster activation of mitochondrial oxidative phosphorylation and muscle O 2 utilization (2, 21, 38) is expected to reduce the requirement for substratelevel phosphorylation (and nonoxidative ATP synthesis), thereby lowering PCr breakdown and lactate accumulation during the exercise transition (7,31,40,46,53). In the present study, PCr breakdown was reduced in Mod 2 compared with Mod 1 (Fig.…”

“…However, the role of PDH activation in constraining the increase in oxidative metabolism, and therefore muscle O 2 utilization and V O 2p kinetics, is controversial. Several studies have demonstrated a decrease in substrate-level phosphoryla- tion consistent with faster adjustment of oxidative phosphorylation during exercise following pharmacological activation of PDH by dichloroacetate (DCA) (31,40,53), but other studies failed to demonstrate faster V O 2p kinetics following administration of DCA (34b, 37, 47). While these latter results are not consistent with PDH activation playing a significant role in constraining V O 2p kinetics, it is noteworthy that in these studies, PDH activation was not measured, and the studies were conducted on young healthy adults having relatively fast V O 2p kinetics, where a delay to fully activate PDH has not been observed under control conditions.…”

Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer

“…Several studies treated patients with DCA and directly measured PDH activity in muscle biopsies. Dichloroacetate administered at 35 -50 mg kg À1 decreases lactate levels by more than 60% and directly activates PDH by 3 -6 fold (Howlett et al, 1999;Parolin et al, 2000).…”

No effect of glutamine supplementation and hyperoxia on oxidative metabolism and performance during high-intensity exercise

“…However, Gibala, MacLean, Graham & Saltin, (1998) Dichloroacetate infusion results in near-maximal activation of the pyruvate dehydrogenase complex and stockpiling of acetyl-units. During the transition to subsequent moderate intensity exercise, dichloroacetate infusion has consistently been shown to enhance the rate of increase of oxidative metabolism as indicated by a reduction in phosphocreatine degradation and lactate accumulation (Timmons et al 1996;Timmons, Poucher, Constantin-Teodosiu, Macdonald & Greenhaff, 1997;Timmons et al 1998aTimmons, Gustafsson, Sundberg, Jansson & Greenhaff, 1998bHowlett, Heigenhauser, Hultman, Hollidge-Horvat & Spriet, 1999a;Parolin et al 2000;Roberts, Loxham, Poucher, Constantin-Teodosiu & Greenhaff, 2002).…”