European Journal of Applied Physiology

, Volume 118, Issue 4, pp 691–728 | Cite as

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


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.


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



Adenosine diphosphate


Astrocyte–neuron lactate shuttle


Adenosine triphosphate


Cytochrome c


Chaperone protein for MCT1


Cytosolic l-lactate dehydrogenase


Carbon dioxide


Coenzyme A;


Cytochrome oxidase complex IV


Method for determination of lactate threshold


Excitatory amino acid transporters


Gas exchange threshold


Glucose transporter


HCA1 G-protein coupled receptor 81


Gastrocnemius-superficial digital flexor muscle complex


Hydrogen ion, proton


Proton magnetic resonance spectroscopy


Isotopic bicarbonate


Hypoxia-inducible factor-1


Complex I/NADH oxidoreductase of the mitochondrial electron system


Complex III of the mitochondrial electron transport system


Complex IV/cytochrome c oxidase


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


Lactate anion


Lactate anion concentration


Lactate dehydrogenase


Lactate-protected hypoglycemia


Lactate threshold


Lactate threshold as determined by the Dmax method


Malate–aspartate shuttle


Monocarboxylate transporter


Mitochondrial lactate dehydrogenase


Maximal lactate steady state


Mitochondrial pyruvate carrier


Oxidized nicotinamide adenine dinucleotide


Reduced nicotinamide adenine dinucleotide


Reduced nicotinamide adenine dinucleotide phosphate




Onset of blood lactate accumulation


Pyruvate dehydrogenase


Pyruvate dehydrogenase kinase 1


αPeroxisome proliferator activated receptor gamma coactivator-1α


Inorganic phosphate


Intracellular partial pressure of oxygen






Solute Carrier Family 16 proteins


Tricarboxylic acid cycle


Uncoupling protein 3


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


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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