The acetyl-group deficit limits mitochondrial ATP production at the onset of exercise

Abstract

The 'Cell-cell Lactate Shuttle' hypothesis posited that together with blood glucose, glycogen reserves in diverse tissues are mobilized to provide lactate, a metabolic intermediate that is either used within cells of formation or transported to adjacent and anatomically distributed cells for utilization. Hence, lactate was conceived to be a quantitatively important oxidizable substrate and gluconeogenic recursor. First with rats and 14C-tracers, then with humans and P3C-tracers we showed rapid lactate turnover during exercise with oxidation accounting for 75-80% of disposal. Further, the predominant site of lactate removal and oxidation in men is working muscle. During exercise, lactate contributes significantly to glucose production, but gluconeogenesis accounts for only about 20-25% of lactate disposal. We and others have shown that myocyte lactate exchange is mediated by lactate/pyruvate (monocarboxylate) transporters. More recently, we posited a role for the 'Intracellular Lactate Shuttle' in regulation of redox when lactate is exchanged for, or converted to its more oxidized analog, pyruvate. Thus, during exercise and other conditions lactate may become a pseudo hormone, a "lactonone." Beyond human exercise examples of lactate shuttles are found in yeast, sperm, glutamate-mediated synaptic transmission in brain, and within cellular organelles such as mitochondria and peroxisomes. Rather than a dead-end metabolite formed as the result of cell O2 insufficiency, lactate production, exchange and oxidation fulfills important functions in maintaining energy substrate supply and in coordinating metabolic pathways.c7 Adipose tissue, the immune system and exercise fatigue: how activated lymphocytes compete for lipids c J 5 J h c -

Oxygen Uptake Dynamics: From Muscle to Mouth—An Introduction to the Symposium

“…Of these, significant research attention has been paid to the pyruvate dehydrogenase complex (PDC), which irreversibly commits acetyl groups to the tricarboxylic acid cycle for oxidation. It has been demonstrated that preexercise activation of the PDC with dichloroacetate (DCA) can reduce substrate-level phosphorylation (SLP) (i.e., PCr hydrolysis and anaerobic glycolysis) early in exercise, and this has led to suggestions that oxidative metabolism must be greater in this condition (20). However, although there is evidence for a speeding of PiO 2 kinetics with DCA in the frog single-fiber model (22), no studies to date have been able to discern any effect of (1,17,24,35,53).…”

Effects of hyperventilation on phosphocreatine kinetics and muscle deoxygenation during moderate-intensity plantar flexion exercise

“…Control of oxidative phosphorylation during moderate-intensity exercise has been linked in some way to the creatine kinase reaction {e.g., cytosolic free [ADP] (5), phosphorylation potential ([ATP]/[ADP][P i ]) (59), or Gibbs free energy of ATP hydrolysis (⌬G ATP ) (45)}, and this is supported by the tight coupling of PCr breakdown and the phase II kinetics of pulmonary O 2 uptake (V O 2 ), reflecting muscle O 2 consumption (44,49). However, other factors, including O 2 availability (56) and activation of enzymes [e.g., pyruvate dehydrogenase (PDH)] and provision of substrates (16), have been also implicated to control oxidative phosphorylation at the onset of exercise.…”

Prior heavy exercise elevates pyruvate dehydrogenase activity and speeds O2 uptake kinetics during subsequent moderate‐intensity exercise in healthy young adults

“…J Physiol 577.3 mitochondrial pyruvate dehydrogenase complex (PDH; Howlett et al 1999;Greenhaff et al 2002;Rossiter et al 2003;Howlett & Hogan, 2003). PDH has been proposed as a possible site of metabolic inertia as it controls the entry of carbohydrate-derived substrate into the tricarboxylic acid (TCA) cycle, and thus the provision of reducing equivalents (in the form of NADH and FADH 2 ) to the electron transport chain.…”