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

  • Brian S. Ferguson
  • Matthew J. Rogatzki
  • Matthew L. Goodwin
  • Daniel A. Kane
  • Zachary Rightmire
  • L. Bruce Gladden
Invited Review

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.

Keywords

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

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

Dmax

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

Km

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

Notes

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest.

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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.College of Applied Health SciencesUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of Health and Exercise ScienceAppalachian State UniversityBooneUSA
  3. 3.Department of OrthopaedicsUniversity of UtahSalt Lake CityUSA
  4. 4.Huntsman Cancer InstituteSalt Lake CityUSA
  5. 5.Department of Human KineticsSt. Francis Xavier UniversityAntigonishCanada
  6. 6.School of KinesiologyAuburn UniversityAuburnUSA

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