Table 1 Historical timeline of lactate metabolism thought and discoveries.

1907–1924: The Lactic Acid Era. Archibald Vivian (A.V.) Hill and the Cambridge School of Physiologists believed that the “processes of muscle contraction are due to the liberation of lactic acid from some precursor”^22,23,24,176. Otto Meyerhof quantifies the relationship between glycogen and lactic acid formation in isolated, nonperfused frog hemicorpus preparations^25,26,27. A.V. Hill develops the O₂ Debt concept in human studies^65,66,67,177. August Krogh and Johannes Lindhard¹⁷⁸ provide evidence supporting Zuntz’s assertion that both fat and carbohydrate are substrates for energy during exercise in humans¹⁷⁹, but those studies were outside the prevailing theory of the Cambridge School of A.V. Hill and associates.

1925: Contrary to the oxygen-limited, O₂ Debt Ideas of the Cambridge school, contemporaneously in Germany, Otto Warburg describes aerobic glycolysis in tumor cells; subsequently the phenomenon became known as the “Warburg Effect”^64,180. Later, it became obvious that lactate production occurs in the soma of healthy individuals while resting or exercising or after carbohydrate nutrition¹⁸¹ as well as in the gut microbiome³.

1929: Carl Ferdinand Cori and Gerty Theresa Cori propose and describe a metabolic pathway in which L-lactate produced by anaerobic glycolysis in the muscles moves to the liver where it is oxidized to pyruvate to glucose, which then returns to the muscles and is metabolized¹⁸². This was the first expression of a Lactate Shuttle mechanism involving the vascular exchange of precursor from a driver cell or tissue (muscle) and receipt by a recipient cell or tissue (liver), and return.

1933: Rodolfo Margaria, Harold T. Edwards and David Bruce Dill of the Harvard Fatigue Laboratory apply the new knowledge of the phosphagens to O₂ Debt theory in humans and segment the phenomenon into “lactacid” and “alactacid” components¹⁸³.

1936: Ole Bang challenged the established lactacid O₂ debt concepts¹⁸⁴. But, his results are ignored, WW II intervenes and oxygen debt ideas became entrenched.

1937, 1938 Data of Hans Krebs and William Johnson¹⁸⁵ and Krebs et al.¹⁸⁶ indicate that the carbohydrate derivative to enter the Tricarboxylic Acid Cycle (TCA) is pyruvate. The role of mitochondrial lactate dehydrogenase (mLDH) is unknown and unsuspected.

1940: After the elucidation of the glycolytic pathway (known as the Embden–Meyerhof–Parnas Pathway) that assumed pyruvate to be its end product under aerobic conditions, together with conclusions of Krebs and associates that pyruvate is the molecule that enters the TCA, most of the research into energy metabolism would continue unabated using the basic paradigm established by the principal players of the first half of the 20th century.

1951: Mario Umberto Dianzani shows that rat liver mitochondria oxidize lactate⁷⁸.

1955 & 1956: Douglas S. Drury, Arne N. Wick and Toshiko Morita use ¹⁴C-lactate tracers to show extra-hepatic oxidative disposal of lactate in rabbits^97,187.

1964: Karlman Wasserman and Malcolm B. McIlroy assume the Meyerhof-Hill O₂-Debt theory of oxygen-limited lactate production and coin the term “anaerobic threshold”, which purported to describe the “onset of anaerobic metabolism during exercise”¹⁸⁸.

1966–1968: Wendell Stainsby and Hugh Welch demonstrate the transient nature of muscle lactic acid output in canine muscle in situ and present evidence that argues for the O₂ independence of lactic acid formation during muscle contractions^105,106. This phenomenon is to be observed in exercising humans; in 1998, Brooks and colleagues observe the same phenomenon in humans and name it the “Stainsby Effect”¹⁸⁹.

1968 Franz F. Jöbsis and Wendell Stainsby demonstrate oxidation of Complex 1 in the mitochondrial electron transport chain of dog gastrocnemius muscles contracting in situ at an intensity sufficient to produce and release lactate¹⁹⁰.

1969: Florent Depocas and colleagues use radioactive tracers to study lactate turnover and oxidation in resting and exercising dogs. Fundamental discoveries of Depocas et al. showing active lactate turnover in resting and exercising individuals have been replicated on numerous species, including humans⁶⁹.

1970: Albert Lehninger publishes the textbook Biochemistry⁴¹. Concepts of glycolysis and fermentation are confused. Ideas that glycolysis leading to pyruvate under aerobic conditions and that lactate is produced due to oxygen lack were enshrined in the latter part of the 20th century. Only recently has a contemporary understanding of distinctions between fermentation and glycolysis, and the role of oxygen, or rather the lack thereof, in determining the end product of glycolysis which is lactate have started to emerge in contemporary basic biology textbooks ⁴⁰.

1971: Nobuhisa Baba and Hari M. Sharma visualize mitochondrial LDH using electron microscopy. They were the first to postulate a “Lactate Shuttle”, but did not follow up on their observation⁵³.

1973: George A. Brooks and associates give ¹⁴C-lactate to rats after exhausting exercise and find, contrary to classic “O₂ Debt” theory, little incorporation of lactate into glycogen but major disposal as ¹⁴CO₂. This is the first challenge to the classic Hill-Meyerhof concept of a 1/5 – 4/5 lactate-to-lactate conversion to glycogen ratio, which is converse of what happens in a mammalian system after exercise¹⁹¹.

1980: Glenn A. Gaesser and George A. Brooks use bolus injections of [U-¹⁴C]glucose and -lactate tracers, indirect calorimetry, and two-dimensional chromatography to trace the paths of lactate and glucose disposal during recovery from exhausting exercise. Again, they find little incorporation of lactate-derived carbon into glycogen but major disposal as ¹⁴CO₂. In mammals, oxidation, not reconversion to glycogen, is the major fate of lactate after exercise^116,117.

1983: Casey M. Donovan and George A. Brooks use primed continuous infusions of [U-¹⁴C]glucose and -lactate tracers, indirect calorimetry, and two-dimensional chromatography to determine the flux, oxidation, and conversion rates of lactate to glucose in endurance-trained and untrained rats during exercise. Training results in the classic finding of lowered arterial [lactate] that is due to increased clearance via oxidation and gluconeogenesis^71,124. This seminal study on lab rats and the resulting paper was subsequently reproduced using stable, nonradioactive tracers on human subjects^{35,112,113,114,192,193}.

1984: Richard Connett, Tom Gayeski, and Carl Honig observe lactate production in canine muscle in situ when intramuscular PO₂ is apparently above the critical value for mitochondrial oxidative phosphorylation³⁰.

1984: Lactate Shuttle Hypothesis Articulated: Based on tracer-measured glucose and lactate fluxes and biochemical evidence from the Kenneth M. Baldwin Lab^194,195, George Brooks proposes the Lactate Shuttle in a meeting of comparative physiology in Liege, Belgium. Meeting proceedings are published the following year¹²⁵.

1984: Daniel Foster presents at the annual Banting Lecture, revealing the importance of lactate to hepatic glycogen synthesis (the ‘Indirect Pathway’) following carbohydrate nutrition¹⁹⁶. In retrospect, Foster’s work anticipated the Postprandial Lactate Shuttle¹⁸¹.

1984: George A. Brooks and Thomas D. Fahey publish the first edition of EXERCISE PHYSIOLOGY: HUMAN BIOENERGETICS AND ITS APPLICATIONS¹¹⁸. Contemporary ideas of lactate metabolism appear in a textbook. In two volumes, the work is now in its fifth edition^46,197. Textbook versions of the Oxygen Debt and Anaerobic Threshold were fundamentally changed.

1988: Peter W. Watt and Peter A. MacLennan¹³⁴ describe the characteristics of muscle lactate exchange kinetics, pH dependence, and competitive inhibition and saturation of lactate exchange in perfused rat skeletal muscle preparations.

1988: For the first time, Avital Schurr and colleagues described the ability of lactate to support synaptic function of hippocampal neurons in vitro as the sole source of energy substrate¹⁹⁸.

1990: David Roth and George Brooks describe the characteristics of sarcolemmal lactic acid transport^132,133. Concentration and pH dependence, competitive inhibition, and saturation kinetics were demonstrated, as predicted from Watt and MacLennan¹³⁴.

1990: Szczesna-Kaczmarek demonstrates L-Lactate oxidation by skeletal muscle mitochondria¹⁹.

1991: George Brooks proposes the Intracellular Lactate Shuttle based on measured muscle lactate exchange and oxidation in vivo¹⁹⁹.

1992: Szczesna-Kaczmarek demonstrates control of mitochondrial L-Lactate oxidation by LDH¹⁹.

1994: Christine Kim Garcia, Michael S. Brown, Joseph L. Goldstein, and colleagues sequence and clone the gene encoding for a muscle cell membrane monocarboxylate transport protein (MCT)¹³⁵.

1995: Garcia and colleagues identify a second isoform, MCT2, located mainly in the liver¹³⁷.

1997: Avital Schurr and associates demonstrated that brain lactate, not glucose, fuels the recovery of synaptic function from hypoxia upon reoxygenation in vitro²⁰⁰.

1998: Russ Richardson, Peter Wagner, and colleagues use magnetic resonance spectroscopy (MRS) to show lactate production and net release from fully aerobic, working human skeletal muscle³².

1998: Andrew Halestrap and colleagues clone and sequence four new MCT isoforms and describe tissue variability in MCT isoform expression¹⁴².

1998: An Astrocyte-Neuron Lactate Shuttle was proposed by Pierre Magistretti, Luc Pellerin^139,201, and colleagues.

1999: Paul Molé and colleagues³¹ use MRS to confirm results of Richardson et al.³² showing lactate production and net release from fully aerobic, working human skeletal muscle.

1999: Henriette Pilegaard, Andrew Halestrap and Carsten Juel show MCT1 and MCT4 distribution in human skeletal muscle^202,203.

1999: Brooks, Marcy Brown, Hervé Dubouchaud, and colleagues show LDH and MCT1 in muscle mitochondria of rats^13,50.

2000: Hervé Dubouchaud and colleagues in the Brooks Lab confirm the presence of mLDH and mMCT1 in human skeletal muscle mitochondria¹⁵.

1999 & 2000: Bryan Bergman, Eugene Wolfel, Gail Butterfield, Gretchen Casazza, Michael Horning, Hervé Dubouchaud, George Brooks, and colleagues show that endurance training improves lactate clearance by intramuscular oxidation and gluconeogenesis in humans^{35,113,193,204}. These results confirm and extend the 1983 studies on lab rats^71,124.

2001: Avital Schurr et al. showed that blockade of lactate transport via MCT1 exacerbates neuronal damage in a rat model of cerebral ischemia²⁰⁵.

2002: Recognition of lactate as a signaling molecule, a lactormone”⁸⁹.

2002: Benjamin Miller, George Brooks, and colleagues use exogenous lactate infusion (“Lactate Clamp”) and stable isotope tracer technology to test lactate clearance mechanisms and show preferential lactate over glucose oxidation in exercising men^206,207.

2002: Daniela Valenti, Lidia De Bari, Anna Atlante*, and Salvatore Passarella publish “L-Lactate transport into rat heart mitochondria and reconstruction of the L-lactate/pyruvate shuttle”²⁰⁸.

2003: Anne Karine Bouzier-Sore et al. showed lactate to be the preferential energy substrate over glucose for neurons in culture²⁰⁹.

2003: Diarmuid Smith and colleagues demonstrate that lactate is a preferred fuel for human brain metabolism in vivo²¹⁰.

2004: Robert A. Robergs and colleagues illustrate that lactate anions, not lactic acid (pKa = 3.86), are formed during exercise.

2004: C. Eric Butz and Grant McClelland reconfirm the presence of mLDH and mMCT1 in skeletal muscle mitochondria⁶⁸.

2006: Takeshi Hashimoto and George A. Brooks and colleagues provide evidence of a mitochondrial lactate oxidation Complex (mLOC) comprised minimally of mLDH, mMCT1, basigin (CD147), and cytochrome oxidase (COx) in rodent skeletal muscle¹⁵³.

2006: Avital Schurr hypothesizes that lactate is the ultimate cerebral oxidative energy substrate¹⁴⁷.

2007: Takeshi Hashimoto and George Brooks and colleagues provide evidence of gene regulation by lactate. In L6 (rat muscle-derived) cells, the upregulated genes include those encoding for MCT1, mitochondrial proteins, proteins involved in ROS generation and quenching, and calcium response elements¹⁵⁵.

2007: Schurr and Payne show that lactate, not pyruvate, is the end product of glycolysis in neurons under aerobic conditions¹⁵⁰.

2007: John T. (Jack) Azevedo and colleagues demonstrate preferential lactate oxidation over glucose and fructose when co-ingested during continuous exercise¹⁷⁰.

2008: Takeshi Hashimoto and George Brooks and colleagues provide evidence of a mitochondrial lactate oxidation Complex (mLOC) comprised minimally of mLDH, mMCT1, basigin (CD147), and cytochrome oxidase (COx) in rat neurons¹³⁸.

2008: Pierre Sonveaux and colleagues find MCTs and cell–cell lactate shuttling to be prevalent among tumor cells. They used siRNAs and MCT pharmacological to kill cancer cells in vitro and in mice in vivo, thus making MCTs targets for cancer treatment¹⁴¹.

2009: Garret van Hall, Niels Secher, and colleagues show cerebral lactate uptake and oxidation in exercising humans⁸⁴.

2010: Kashan Ahmed and colleagues elucidate a lactate-mediated autocrine response through an orphan G protein (GPR81), now known as hydroxycarboxylic acid receptor-1 (HCAR-1), demonstrating the ability of lactate to downregulate levels cAMP levels and therein having an antilipolytic effect¹⁶³.

2010: Lidia de Bari, Daniela Valenti, Anna Atlante, and Salvatore Passarella provide evidence of the presence of an intermembrane lactate oxidase that generates H₂O₂ sufficient to activate the known ROS response elements signaling mitochondrial adaptation and other adaptations to exercise. This work provides a mechanism by which lactate generation in muscle exercise participates in the feedback loop by which lactate generation in exercise leads to adaptations facilitating high rates of lactate disposal in exercise¹⁴.

2011: Rajaa Hussien and George Brooks find differences in mitochondrial LDH and MCT isoform expression in normal breast cancer and breast cancer cells¹⁴⁰.

2011: Avital Schurr publishes “Lactate: the ultimate cerebral oxidative energy substrate?”¹⁴⁷.

2011: Schurr and Gozal showed that aerobic production and utilization of lactate satisfy increased energy demands upon neuronal activation in hippocampal slices and provide neuroprotection against oxidative stress¹⁴⁹.

2011: Luc Pellerin and Pierre Magistretti celebrate the 16^th year of proposing the Astrocyte-Neuron Lactate Shuttle (ANLS). Neglected was that the ANLS was proposed 14 years after the seminal lactate shuttle papers^126,127.

2013: Robert A. Jacobs and colleagues reconfirm mitochondrial lactate oxidation in mitochondrial preparations from human skeletal muscle ⁵⁶.

2014: Salvatore Passarella and colleagues publish “The mitochondrial L-lactate dehydrogenase affair“⁷.

2014: Avital Schurr publishes “Cerebral glycolysis: a century of persistent misunderstanding and misconception”⁸.

2016–2021: Results of studies showing lactate shuttling in rabbits, dogs, horses, and humans confirmed in mice^{211,212,213,214}.

2019: By the addition of exogenous lactate and U¹³-C₆-Glucose, Di Zhang and colleagues identify 28 lactylation targets on core histones, illustrating another epigenetic modification by which the genome is regulated¹⁶². Knowledge of the role of the role of lactate as a signal is extended^{3,5,89,155,215}.

2020: Adrian Young and colleagues reconfirm mitochondrial LDH and lactate oxidation in mitochondrial preparations from mouse liver, cardiac, and skeletal muscle, yet again⁵⁴.

2020: David C. Poole, Harry B. Rossiter, L. Bruce Gladden, and George A. Brooks review 50 years of controversy on the anaerobic threshold and interpret results in terms of Lactate Shuttle Theory²¹⁶.

2021 Brooks and graduate students articulate the Postprandial Lactate Shuttle¹⁸¹.

2021: Brooks and graduate students review the role of the heart in lactate shuttling¹⁰².

2021: Brooks and graduate students explain, and review false claims about use of lactate tracers to study metabolism⁶⁰.