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Lactate metabolism: historical context, prior misinterpretations, and current understanding

Abstract

Lactate (La) has long been at the center of controversy in research, clinical, and athletic settings. Since its discovery in 1780, La has often been erroneously viewed as simply a hypoxic waste product with multiple deleterious effects. Not until the 1980s, with the introduction of the cell-to-cell lactate shuttle did a paradigm shift in our understanding of the role of La in metabolism begin. The evidence for La as a major player in the coordination of whole-body metabolism has since grown rapidly. La is a readily combusted fuel that is shuttled throughout the body, and it is a potent signal for angiogenesis irrespective of oxygen tension. Despite this, many fundamental discoveries about La are still working their way into mainstream research, clinical care, and practice. The purpose of this review is to synthesize current understanding of La metabolism via an appraisal of its robust experimental history, particularly in exercise physiology. That La production increases during dysoxia is beyond debate, but this condition is the exception rather than the rule. Fluctuations in blood [La] in health and disease are not typically due to low oxygen tension, a principle first demonstrated with exercise and now understood to varying degrees across disciplines. From its role in coordinating whole-body metabolism as a fuel to its role as a signaling molecule in tumors, the study of La metabolism continues to expand and holds potential for multiple clinical applications. This review highlights La’s central role in metabolism and amplifies our understanding of past research.

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Reprinted with permission from Gladden (2004a) Lactate metabolism during exercise. In Principles of Exercise Biochemistry, 3rd edn, ed. Poortmans JR, pp. 152–196. Karger, Basel

Fig. 5

Reprinted with permission from Gladden (2004a) Lactate metabolism during exercise. In Principles of Exercise Biochemistry, 3rd edn, ed. Poortmans JR, pp. 152–196. Karger, Basel

Fig. 6

Redrawn with permission from Welch and Stainsby (1967)

Fig. 7

Reprinted with permission from Clanton et al. (2013)

Fig. 8

Reprinted with permission from Clanton et al. (2013)

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Abbreviations

ADP:

Adenosine diphosphate

ANLS:

Astrocyte–neuron lactate shuttle

ATP:

Adenosine triphosphate

C :

Cytochrome c

CD147:

Chaperone protein for MCT1

cLDH:

Cytosolic l-lactate dehydrogenase

CO2 :

Carbon dioxide

CoA:

Coenzyme A;

COXIV:

Cytochrome oxidase complex IV

D max :

Method for determination of lactate threshold

EAATs:

Excitatory amino acid transporters

GET:

Gas exchange threshold

GLUT:

Glucose transporter

GPR81:

HCA1 G-protein coupled receptor 81

GS:

Gastrocnemius-superficial digital flexor muscle complex

H+ :

Hydrogen ion, proton

1H-MRS:

Proton magnetic resonance spectroscopy

H13CO3 :

Isotopic bicarbonate

HIF-1:

Hypoxia-inducible factor-1

I:

Complex I/NADH oxidoreductase of the mitochondrial electron system

III:

Complex III of the mitochondrial electron transport system

IV/COX:

Complex IV/cytochrome c oxidase

K m :

Michaelis–Menten constant for concentration of substrate at half-maximal speed of a reaction or transport process

La :

Lactate anion

[La]:

Lactate anion concentration

LDH:

Lactate dehydrogenase

LPH:

Lactate-protected hypoglycemia

LT:

Lactate threshold

LTD :

Lactate threshold as determined by the Dmax method

MAS:

Malate–aspartate shuttle

MCT:

Monocarboxylate transporter

mLDH:

Mitochondrial lactate dehydrogenase

MLSS:

Maximal lactate steady state

MPC:

Mitochondrial pyruvate carrier

NAD+ :

Oxidized nicotinamide adenine dinucleotide

NADH:

Reduced nicotinamide adenine dinucleotide

NADPH:

Reduced nicotinamide adenine dinucleotide phosphate

O2 :

Oxygen

OBLA:

Onset of blood lactate accumulation

PDH:

Pyruvate dehydrogenase

PDK1:

Pyruvate dehydrogenase kinase 1

PGC-1:

αPeroxisome proliferator activated receptor gamma coactivator-1α

Pi:

Inorganic phosphate

PiO2 :

Intracellular partial pressure of oxygen

Pyr :

Pyruvate

Q :

Quinone

SLC16:

Solute Carrier Family 16 proteins

TCA:

Tricarboxylic acid cycle

UCP3:

Uncoupling protein 3

V :

Complex V/ATP synthase

\(\dot {V}\)CO2 :

Carbon dioxide output per minute

\(\dot {V}\)O2 :

Oxygen uptake per minute

\(\dot {V}\)O2LT :

Oxygen uptake per minute at the lactate threshold

\(\dot {V}\)O2max :

Maximum oxygen uptake per minute

\(\dot {V}\)O2peak :

Peak oxygen uptake per minute

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Correspondence to L. Bruce Gladden.

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Communicated by Michael Lindinger.

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Ferguson, B.S., Rogatzki, M.J., Goodwin, M.L. et al. Lactate metabolism: historical context, prior misinterpretations, and current understanding. Eur J Appl Physiol 118, 691–728 (2018). https://doi.org/10.1007/s00421-017-3795-6

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  • DOI: https://doi.org/10.1007/s00421-017-3795-6

Keywords

  • Lactate metabolism
  • Lactate shuttle
  • Hypoxia
  • Glycolysis
  • Cancer metabolism
  • Astrocyte–neuron lactate shuttle
  • Lactate threshold
  • Mitochondria
  • Fatigue and lactic acidosis
  • Cytosolic redox