The blood lactate/pyruvate equilibrium affair

Abstract

The Lactate Shuttle hypothesis is supported by a variety of techniques including mass spectrometry analytics following infusion of carbon-labeled isotopic tracers. However, there has been controversy over whether lactate tracers measure lactate (L) or pyruvate (P) turnover. Here, we review the analytical errors, use of inappropriate tissue and animal models, failure to consider L and P pool sizes in modeling results, inappropriate tracer and blood sampling sites, and failure to anticipate roles of heart and lung parenchyma on L⇔P interactions. With support from magnetic resonance spectroscopy (MRS) and immunocytochemistry, we conclude that carbon-labeled lactate tracers can be used to quantitate lactate fluxes.

Keywords: energy-substrate partitioning; exercise; glycolysis; isotope tracers; oxidative metabolism.

Figure 1.

Lactate-to-pyruvate (L/P) concentration ratio in femoral venous (A) and arterial blood (B) of men during rest and exercise before and after 2-mo of supervised endurance training. Values are means ± SE; n = 7–9 men. Exercise conditions are: Pre, before training; Post, after training; 45% Pre, 45% pretraining peak oxygen consumption (V̇o_2peak); 65% Pre, 65% pretraining V̇o_2peak; 65% Old (ABT), 65% old V̇o_2peak peak post-training; 65% New (RLT), 65% post-training V̇o_2peak. *Significantly different from 45% Pre, P < 0.05; +significantly different from 65% Pre, P < 0.05, #significantly different from 65% Old (ABT), P < 0.05; ¶significantly different from 65% New (RLT), P < 0.05. From Ref. .

Figure 2.

Isotopic enrichment (IE) in mole percent excess (MPE) of [3-¹³C]pyruvate in arterial blood of men during rest and exercise; data obtained simultaneously with those in Fig. 1. Values are means ± SE; n = 8 or 9. Exercise conditions are described in the legend to Fig. 1. From Ref. .

Figure 3.

Illustration of the relationships between whole body glucose rate of disappearance (R_d) and lactate appearance (R_a) in 10 men during rest, exercise at 40% V̇o_2max (59), and lactate threshold (≈65% V̇o_2max; 6 men) (38). Symbols: for rest glucose † and lactate †† fluxes significantly different from each other; for 40% V̇o_2max exercise, glucose ⋆ and lactate ⋆⋆ fluxes not significantly different from each other, but increased from corresponding values at rest; for exercise at the LT glucose flux * significantly greater than that at rest and 40% V̇o_2max, and lactate flux ** significantly greater than corresponding values at rest, 40% V̇o_2max and the corresponding glucose flux. Lactate flux in excess of glucose flux is attributable to the contribution of glycogenolysis to glycolytic carbon flux (18).

Figure 4.

Lactate-to-pyruvate concentration ratio (L/P) in central mixed venous ($\overline{\upsilon }$) and arterial blood (a), of anesthetized rats studied under control (Con), exogenous lactate infusion (lactate clamp, LC) and epinephrine infusion (Epi). Values are expressed as means ± SD. Metabolic activity of the lung parenchyma in converting pyruvate to lactate is apparent under all conditions studied. ^Significantly different than the corresponding trial $\overline{\upsilon }$, P < 0.05. From Ref. . Mixed venous and arterial lactate/pyruvate ratios are different clearly indicating roles of heart and lung parenchyma.

Figure 5.

A: relationship between mixed central venous lactate and pyruvate isotopic enrichment expressed as molar percent excess (MPE) in rat blood during control (Con), exogenous unlabeled lactate infusion, lactate clamp (LC), and epinephrine infusion (Epi) conditions, respectively. B: relationship between arterial lactate and pyruvate MPE in rat blood during Con, LC, and Epi conditions, respectively. Lactate and pyruvate enrichments following [U-¹³C]lactate infusion are correlated, but not equivalent, n = 7 each condition. From Ref. .