Lactate as a fulcrum of metabolism
Open accessAbstract
Mistakenly thought to be the consequence of oxygen lack in contracting skeletal muscle we now know that the L-enantiomer of the lactate anion is formed under fully aerobic conditions and is utilized continuously in diverse cells, tissues, organs and at the whole-body level. By shuttling between producer (driver) and consumer (recipient) cells lactate fulfills at least three purposes: 1] a major energy source for mitochondrial respiration; 2] the major gluconeogenic precursor; and 3] a signaling molecule. Working by mass action, cell redox regulation, allosteric binding, and reprogramming of chromatin by lactylation of lysine residues on histones, lactate has major influences in energy substrate partitioning. The physiological range of tissue [lactate] is 0.5-20 mM and the cellular Lactate/Pyruvate ratio (L/P) can range from 10 to >500; these changes during exercise and other stress-strain responses dwarf other metabolic signals in magnitude and span. Hence, lactate dynamics have rapid and major short- and long-term effects on cell redox and other control systems. By inhibiting lipolysis in adipose via HCAR-1, and muscle mitochondrial fatty acid uptake via malonyl-CoA and CPT1, lactate controls energy substrate partitioning. Repeated lactate exposure from regular exercise results in major effects on the expression of regulatory enzymes of glycolysis and mitochondrial respiration. Lactate is the fulcrum of metabolic regulation in vivo.
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During acute hard exercise, elevated blood lactate induces suppression of adipose lipolysis through adipocyte receptor binding.
“During acute hard exercise, elevated blood lactate induces suppression of adipose lipolysis through adipocyte receptor binding [14].”
During acute hard exercise (RQ ≥ 1.0), significant elevation of blood lactate inhibits lipolysis through HCAR1 binding.
“During acute hard exercise (RQ ≥ 1.0), significant elevation of blood lactate inhibits lipolysis through the hydroxycarboxylic acid receptor 1 (HCAR1, also called GPR81, a lactate-specific G protein-coupled receptor) binding [14].”
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Coady, M. J., Chang, M., Charron, F. M., Plata, C., Wallendorff, B., Sah, J. F., Markowitz, S. D., Romero, M. F., & Lapointe, J. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2004.063859 · Cited by 166 · see citing works
Systemic lactate kinetics during graded exercise in man
Stanley, W. C., Gertz, E. W., Wisneski, J. A., Morris, D. L., Neese, R. A., & Brooks, G. A. (1985) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1985.249.6.e595 · Cited by 163 · see citing works
Self-citationRenal substrate exchange and gluconeogenesis in normal postabsorptive humans
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Maintained exercise‐enhanced brain executive function related to cerebral lactate metabolism in men
Hashimoto, T., Tsukamoto, H., Takenaka, S., Olesen, N. D., Petersen, L. G., Sørensen, H., Nielsen, H. B., Secher, N. H., & Ogoh, S. (2018) · The FASEB Journal · doi:10.1096/fj.201700381rr · Cited by 156 · see citing works
Endurance training increases gluconeogenesis during rest and exercise in men
Bergman, B. C., Horning, M. A., Casazza, G. A., Wolfel, E. E., Butterfield, G. E., & Brooks, G. A. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.278.2.e244 · Cited by 153 · see citing works
Self-citationVersuche an Überlebendem Carcinomgewebe
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Decreased reliance on lactate during exercise after acclimatization to 4,300 m
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Self-citationContribution of liver and skeletal muscle to alanine and lactate metabolism in humans
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Self-citationLactate administration attenuates cognitive deficits following traumatic brain injury
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Gluconeogenesis and hepatic glycogenolysis during exercise at the lactate threshold
Emhoff, C.-A. W., Messonnier, L. A., Horning, M. A., Fattor, J. A., Carlson, T. J., & Brooks, G. A. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01202.2012 · Cited by 139 · see citing works
Self-citationSchurr, A., & Payne, R. S. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.05.002 · Cited by 138 · see citing works
Pathways for glucose disposal after meal ingestion in humans
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Training-induced alterations of glucose flux in men
Friedlander, A. L., Casazza, G. A., Horning, M. A., Huie, M. J., & Brooks, G. A. (1997) · Journal of Applied Physiology · doi:10.1152/jappl.1997.82.4.1360 · Cited by 130 · see citing works
Self-citationElucidation of signaling and functional activities of an orphan GPCR, GPR81
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Lactate, pyruvate, and lactate-to-pyruvate ratio during exercise and recovery
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Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system?
McClelland, G. B., Khanna, S., Gonzalez, G. F., Butz, C. E., & Brooks, G. A. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)00550-3 · Cited by 118 · see citing works
Self-citationEndurance training increases fatty acid turnover, but not fat oxidation, in young men
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Self-citationIntermittent increases in cytosolic Ca2+ stimulate mitochondrial biogenesis in muscle cells.
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Myocardial glucose and lactate metabolism during rest and atrial pacing in humans
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Rates of formation and oxidation of lactic acid in dogs at rest and during moderate exercise
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Muscle net glucose uptake and glucose kinetics after endurance training in men
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Self-citationEffects of physiological hyperinsulinemia on systemic, renal, and hepatic substrate metabolism
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Effect of lactate therapy upon cognitive deficits after traumatic brain injury in the rat
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Glucose and lactate interrelations during moderate-intensity exercise in humans
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Self-citationHISTOCHEMISTRY OF LACTIC DEHYDROGENASE IN HEART AND PECTORALIS MUSCLES OF RAT
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San-Millán, I., Julian, C. G., Matarazzo, C. J., Martinez, J. L., & Brooks, G. A. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01536 · Cited by 93 · see citing works
Self-citationMCT1 confirmed in rat striated muscle mitochondria
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Plasma free fatty acids in exercise
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No evidence of an intracellular lactate shuttle in rat skeletal muscle
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Metabolic and cardiorespiratory responses to “the lactate clamp”
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Self-citationEffects of endurance training on a mitochondrial reticulum in limb skeletal muscle
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Lactate oxidation in human skeletal muscle mitochondria
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Successive bouts of cycling stimulates genes associated with mitochondrial biogenesis
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Lactate dehydrogenase is not a mitochondrial enzyme in human and mouse vastus lateralis muscle
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The mitochondrial L-lactate dehydrogenase affair
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Lactate Stimulates a Potential for Hypertrophy and Regeneration of Mouse Skeletal Muscle
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Localization of l-lactate dehydrogenase in mitochondria
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Direct and indirect lactate oxidation in trained and untrained men
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Self-citationThe Epigenetics of Stem Cell Aging Comes of Age
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The importance of redox shuttles to pancreatic β-cell energy metabolism and function
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Pyruvate shuttling during rest and exercise before and after endurance training in men
Henderson, G. C., Horning, M. A., Lehman, S. L., Wolfel, E. E., Bergman, B. C., & Brooks, G. A. (2004) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01367.2003 · Cited by 56 · see citing works
Self-citationGlenn, T. C., Martin, N. A., McArthur, D. L., Hovda, D. A., Vespa, P. M., Johnson, M. L., Horning, M. A., & Brooks, G. A. (2014) · Journal of Neurotrauma · doi:10.1089/neu.2014.3482 · Cited by 56 · see citing works
Self-citationPGC-1 Coactivators and the Regulation of Skeletal Muscle Fiber-Type Determination
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Effect of lactic acid on plasma free fatty acids in pancreatectomized dogs
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Hyperpolarized 13C NMR observation of lactate kinetics in skeletal muscle
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Lactate: a major and crucial player in normal function of both muscle and brain
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Energy Flux, Lactate Shuttling, Mitochondrial Dynamics, and Hypoxia
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Self-citationEffect of exercise and lactic acid infusion on individual free fatty acids of plasma
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Glycemic control in critically ill patients: What to do post NICE-SUGAR?
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Investigating the role of Sirtuins in cell reprogramming
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Gluconeogenesis in the burned patient.
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History of Exercise Physiology
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Metabolic Systems: The Formation and Utilization of Lactate
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Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- [24]Brooks G.A. Brown M.A. Butz C.E. Sicurello J.P. Dubouchaud H. Cardiac and skeletal muscle mitochondria have a monocarboxylate transporter MCT1 J. Appl. Physiol. 87 1999 1713 1718 10562613
- [77]Hashimoto T. Tsukamoto H. Takenaka S. Olesen N.D. Petersen L.G. Sorensen H. Nielsen H.B. Secher N.H. Ogoh S. Maintained exercise-enhanced brain executive function related to cerebral lactate metabolism in men Faseb. J. 32 2018 1417 1427 29127193
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- Authors
- Brooks, G. A.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Brooks, George A.
- ORCID
- Brooks, George A.
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 35
- Pages
- 101454
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC7284908
- OpenAlex
- W3005469631
- Cited by
- 724
- References
- 172
- Citations by year
- 2026: 112 · 2025: 168 · 2024: 158 · 2023: 99 · 2022: 102 · 2021: 61 · 2020: 22 · 2019: 1
- FWCI
- 7.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (1 R01 AG059715-01, 3-02-Brooks-17)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- lactate, L-lactate, lactate shuttle, gluconeogenesis, lactate signaling, histone lactylation, redox regulation, mitochondrial respiration, glycolysis, lipolysis, malonyl-CoA, carnitine palmitoyltransferase 1, physical activity, skeletal muscle, adipose tissue
- MeSH terms
- Energy Metabolism, Glycolysis, Mitochondria, Oxidation-Reduction, Muscle, Skeletal, Lactic Acid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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