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.
Similar content being viewed by others
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
References
Abbrescia DI, La Piana G, Lofrumento NE (2012) Malate-aspartate shuttle and exogenous NADH/cytochrome c electron transport pathway as two independent cytosolic reducing equivalent transfer systems. Arch Biochem Biophys 518(2):157–163. https://doi.org/10.1016/j.abb.2011.12.021
Agnati LF, Zoli M, Strömberg I, Fuxe K (1995) Intercellular communication in the brain: wiring versus volume transmission. Neurosci 69(3):711–726
Ahlborg G, Wahren J (1972) Brain substrate utilization during prolonged exercise. Scand J Clin Lab Invest 29(4):397–402
Ahmed K, Tunaru S, Tang C, Müller M, Gille A, Sassmann A, Hanson J, Offermanns S (2010) An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab 11(4):311–319. https://doi.org/10.1016/j.cmet.2010.02.012
Akerboom TPM, Tager JM, Van der Meer R (1979) Techniques for the investigation of intracellular compartmentation. In: Komberg H, Metcalfe J, Northcote D (eds) In: Techniques in the life sciences. Biochemistry, techniques in metabolic research. Elsevier (North-Holland), Amsterdam
Allchin D (2002) To Err and Win a Nobel Prize: Paul Boyer, ATP synthase and the emergence of bioenergetics. J Hist Biol 35(1):149–172
Allen DG, Lamb GD, Westerblad H (2008) Skeletal muscle fatigue: cellular mechanisms. Physiol Rev 88(1):287–332
Andrews MA, Godt RE, Nosek TM (1996) Influence of physiological L (+)-lactate concentrations on contractility of skinned striated muscle fibers of rabbit. J Appl Physiol 80(6):2060–2065
Armstrong RB (1988) Muscle fiber recruitment patterns and their metabolic correlates. In: Horton E, Terjung R (eds) Exercise, nutrition and energy metabolism. MacMillan Publishing Co., New York, pp 9–26
Ashford CA, Holmes EG (1929) Contributions to the study of brain metabolism. V. Role of phosphates in lactic acid production. Biochem J 23:748–759
Atlante A, Gagliardi S, Marra E, Calissano P, Passarella S (1999) Glutamate neurotoxicity in rat cerebellar granule cells involves cytochrome c release from mitochondria and mitochondrial shuttle impairment. J Neurochem 73(1):237–246. https://doi.org/10.1046/j.1471-4159.1999.0730237.x
Atlante A, de Bari L, Bobba A, Marra E, Passarella S (2007) Transport and metabolism of l-lactate occur in mitochondria from cerebellar granule cells and are modified in cells undergoing low potassium dependent apoptosis. Biochim Biophys Acta Bioenerg 1767(11):1285–1299. https://doi.org/10.1016/j.bbabio.2007.08.003
Attwell D (2000) Brain uptake of glutamate: food for thought. J Nutr 130(4):1023S-1025S
Aykin-Burns N, Ahmad Iman M, Zhu Y, Oberley Larry W, Spitz Douglas R (2009) Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem J 418(1):29–37
Baba N, Sharma HM (1971) Histochemistry of lactic dehydrogenase in heart and pectoralis muscles of rat. J Cell Biol 51(3):621–635
Bagger JP, Thomassen A, Nielsen TT (2000) Cardiac energy metabolism in patients with chest pain and normal coronary angiograms. Am J Cardiol 85(3):315–320
Bangsbo J, Juel C (2006) Counterpoint: Lactic acid accumulation is a disadvantage during muscle activity. J Appl Physiol 100(4):1410–1414
Barnard RJ, Holloszy JO (2003) The metabolic systems: aerobic metabolism and substrate utilization in Exercising skeletal muscle. In: Tipton CM (ed) Exercise physiology: people and ideas. Springer, New York, pp 292–321. https://doi.org/10.1007/978-1-4614-7543-9_7
Barnett JA (2003) A history of research on yeasts 5: the fermentation pathway. Yeast 20(6):509–543
Barnett JA, Entian KD (2005) A history of research on yeasts 9: regulation of sugar metabolism. Yeast 22(11):835–894
Beaver WL, Wasserman K, Whipp BJ (1986) A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 60(6):2020–2027
Bélanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14(6):724–738
Benedict CR, Grahame-Smith DG (1978) Plasma noradrenaline and adrenaline concentrations and dopamine-β-hydroxylase activity in patients with shock due to septicaemia, trauma and haemorrhage. QJM: Int J Med 47(1):1–20. https://doi.org/10.1093/oxfordjournals.qjmed.a067525
Beneke R, von Duvillard SP (1996) Determination of maximal lactate steady state response in selected sports events. Med Sci Sports Exerc 28(2):241–246
Benninga H (1990) A history of lactic acid making: a chapter in the history of biotechnology, vol 11. Kluwer Academic Publishers, Boston
Bergersen LH (2007) Is lactate food for neurons? Comparison of monocarboxylate transporter subtypes in brain and muscle. Neuroscience 145(1):11–19
Bergersen LH, Gjedde A (2012) Is lactate a volume transmitter of metabolic states of the brain? Front Neuroenergetics 4(5). https://doi.org/10.3389/fnene.2012.00005
Bergersen LH, Johannsson E, Veruki ML, Nagelhus EA, Halestrap A, Sejersted OM, Ottersen OP (1999) Cellular and subcellular expression of monocarboxylate transporters in the pigment epithelium and retina of the rat. Neuroscience 90(1):319–331
Bergman BC, Wolfel EE, Butterfield GE, Lopaschuk GD, Casazza GA, Horning MA, Brooks GA (1999) Active muscle and whole body lactate kinetics after endurance training in men. J Appl Physiol 87(5):1684–1696
Bergman BC, Horning MA, Casazza GA, Wolfel EE, Butterfield GE, Brooks GA (2000) Endurance training increases gluconeogenesis during rest and exercise in men. Am J Physiol Endocrinol Metab 278(2):E244–E251
Berlinerblau M (1887) Über das Vorkommen der Milchsäure im Blute und ihre Entstehung im Organismus. Naunyn-Schmiedeberg’s Arch Pharmacol 23(5):333–346
Bernard C (1855) Lecons de physiologie experimentale appliquee a la medecine, faites au College de France par M. Claude Bernard: Cours du semestre d’hiver 1854–1855, vol 1. Baillière, Paris
Bernard C (1877) De la matière glycogène considerée comme condition de developpement de certains tissus, chez le foetus, avant l’apparition de la function glycogénique du foie: In Leçons sur le diabète. Extrait de Compt rend des séances de l’Acad des Sci 48, 1859. Baillière, Paris
Bernardi P, Azzone GF (1981) Cytochrome c as an electron shuttle between the outer and inner mitochondrial membranes. J Biol Chem 256(14):7187–7192
Berzelius JJ (1848) Jahres-bericht über die fortschritte der chemie und mineralogie, vol 3. Laupp’ sche Buchhandlung, Tübingen
Bickham DC, Bentley DJ, Le Rossignol PF, Cameron-Smith D (2006) The effects of short-term sprint training on MCT expression in moderately endurance-trained runners. Eur J Appl Physiol 96(6):636–643
Billat VL, Richard R, Binsse VM, Koralsztein JP, Haouzi P (1998) The V̇O2 slow component for severe exercise depends on type of exercise and is not correlated with time to fatigue. J Appl Physiol 85(6):2118–2124
Bishop DJ, Jenkins DG, Mackinnon LT (1998) The relationship between plasma lactate parameters, Wpeak and 1-h cycling performance in women. Med Sci Sports Exerc 30(8):1270–1275
Bishop DJ, Edge J, Thomas C, Mercier J (2007) High-intensity exercise acutely decreases the membrane content of MCT1 and MCT4 and buffer capacity in human skeletal muscle. J Appl Physiol 102(2):616–621
Bittar PG, Charnay Y, Pellerin L, Bouras C, Magistretti PJ (1996) Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain. J Cereb Blood Flow Metab 16(6):1079–1089
Bodrova ME, Dedukhova VI, Mokhova EN, Skulachev VP (1998) Membrane potential generation coupled to oxidation of external NADH in liver mitochondria. FEBS Lett 435(2–3):269–274
Bonen A (2001) The expression of lactate transporters (MCT1 and MCT4) in heart and muscle. Eur J Appl Physiol 86(1):6–11
Böning D, Maassen N (2008a) Point: counterpoint: lactic acid is/is not the only physicochemical contributor to the acidosis of exercise. J Appl Physiol 105(1):358–359
Böning D, Maassen N (2008b) Point: lactic acid is the only physiochemical contributor to the acidosis of exercise. Rebuttal J Appl Physiol 105(1):368
Boumezbeur F, Petersen KF, Cline GW, Mason GF, Behar KL, Shulman GI, Rothman DL (2010) The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy. J Neurosci 30(42):13983–13991
Brandt RB, Laux JE, Spainhour SE, Kline ES (1987) Lactate dehydrogenase in rat mitochondria. Arch Biochem Biophys 259(2):412–422. https://doi.org/10.1016/0003-9861(87)90507-8
Bransford DR, Howley ET (1977) Oxygen cost of running in trained and untrained men and women. Med Sci Sports 9(1):41–44
Brin M (1965) The synthesis and metabolism of lactic acid isomers. Ann N Y Acad Sci 119(1):942–956
Bröer S, Schneider H-P, Bröer A, Rahman B, Hamprecht B, Deitmer JW (1998) Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH. Biochem J 333(1):167–174
Brooks GA (1985a) Anaerobic threshold: review of the concept and directions for future research. Med Sci Sports Exerc 17(1):22–34
Brooks GA (1985b) Lactate: Glycolytic end-product and oxidative substrate during sustained exercise in mammals—the “Lactate Shuttle”. In: Gilles R (ed) Circulation, respiration, and metabolism: current comparative approaches. Springer, Berlin, pp 208–218. https://doi.org/10.1007/978-3-642-70610-3_15
Brooks GA (1998) Mammalian fuel utilization during sustained exercise. Comp Biochem Physiol B Biochem Mol Biol 120(1):89–107
Brooks GA (2000) Intra-and extra-cellular lactate shuttles. Med Sci Sports Exerc 32(4):790–799
Brooks GA (2002) Lactate shuttles in nature. Biochem Soc Trans 30(2):258–264
Brooks GA (2007) Lactate: link between glycolytic and oxidative metabolism. Sports Med 37(4–5):341–343
Brooks GA (2009) Cell–cell and intracellular lactate shuttles. J Physiol 587(23):5591–5600
Brooks GA (2012) Bioenergetics of exercising humans. Compr Physiol (2):537–562
Brooks GA (2016) Energy flux, lactate shuttling, mitochondrial dynamics, and hypoxia. In: Roach RC, Hackett PH, Wagner PD (eds) Hypoxia: translation in progress. Springer US, Boston, pp 439–455. https://doi.org/10.1007/978-1-4899-7678-9_29
Brooks GA, Gladden LB (2003) The metabolic systems: anaerobic metabolism (glycolytic and phosphagen). In: Tipton CE (ed) Exercise physiology. people and ideas. Oxford University Press, New York, pp 322–360
Brooks GA, Martin NA (2014) Cerebral metabolism following traumatic brain injury: new discoveries with implications for treatment. Front Neurosci 8:408. https://doi.org/10.3389/fnins.2014.00408
Brooks GA, Brown MA, Butz C, Sicurello JP, Dubouchaud H (1999a) Cardiac and skeletal muscle mitochondria have a monocarboxylate transporter MCT1. J Appl Physiol 87(5):1713–1718
Brooks GA, Dubouchaud H, Brown M, Sicurello JP, Butz CE (1999b) Role of mitochondrial lactate dehydrogenase and lactate oxidation in the intracellular lactate shuttle. Proc Natl Acad Sci USA 96(3):1129–1134. https://doi.org/10.1073/pnas.96.3.1129
Bruton JD, Lännergren J, Westerblad H (1998) Effects of CO2-induced acidification on the fatigue resistance of single mouse muscle fibers at 28 C. J Appl Physiol 85(2):478–483
Cahn RS, Ingold CK, Prelog V (1956) The specification of asymmetric configuration in organic chemistry. Experientia 12(3):81–94
Cai TQ, Ren N, Jin L, Cheng K, Kash S, Chen R, Wright SD, Taggart AKP, Waters MG (2008) Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem Biophys Res Commun 377(3):987–991. https://doi.org/10.1016/j.bbrc.2008.10.088
Caiozzo VJ, Davis JA, Ellis JF, Azus JL, Vandagriff R, Prietto CA, McMaster WC (1982) A comparison of gas exchange indices used to detect the anaerobic threshold. J Appl Physiol 53(5):1184–1189
Cairns SP, Lindinger MI (2008) Do multiple ionic interactions contribute to skeletal muscle fatigue? J Physiol 586(17):4039–4054
Camici P, Marraccini P, Marzilli M, Lorenzoni R, Buzzigoli G, Puntoni R, Boni C, Bellina CR, Klassen GA, L’Abbate A (1989) Coronary hemodynamics and myocardial metabolism during and after pacing stress in normal humans. Am J Physiol Endocrinol Metab 257(3):E309–E317
Caplice E, Fitzgerald GF (1999) Food fermentations: role of microorganisms in food production and preservation. Int J Food Microbiol 50(1):131–149
Chance B, Williams GR (1956) The respiratory chain and oxidative phosphorylation. Adv Enzymol Relat Areas Mol Biol 17:65–134
Chatham JC, Des Rosiers C, Forder JR (2001) Evidence of separate pathways for lactate uptake and release by the perfused rat heart. Am J Physiol Endocrinol Metab 281(4):E794–E802
Chen Y Jr, Mahieu NG, Huang X, Singh M, Crawford PA, Johnson SL, Gross RW, Schaefer J, Patti GJ (2016) Lactate metabolism is associated with mammalian mitochondria. Nat Chem Biol 12(11):937–943. https://doi.org/10.1038/nchembio.2172
Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A (2001) Regulation of glut1 mRNA by hypoxia-inducible factor-1 Interaction between H-ras and hypoxia. J Biol Chem 276(12):9519–9525
Chen C-M, Chen S-M, Chien P-J, Yu H-Y (2015) Development of an enzymatic assay system of d-lactate using d-lactate dehydrogenase and a UV-LED fluorescent spectrometer. J Pharm Biomed Anal 116:150–155
Cheng B, Kuipers H, Snyder AC, Keizer HA, Jeukendrup A, Hesselink M (1992) A new approach for the determination of ventilatory and lactate thresholds. Int J Sports Med 13(07):518–522
Chih C-P, Roberts EL Jr (2003) Energy substrates for neurons during neural activity: a critical review of the astrocyte-neuron lactate shuttle hypothesis. J Cereb Blood Flow Metab 23(11):1263–1281
Chih C-P, Lipton P, Roberts EL (2001) Do active cerebral neurons really use lactate rather than glucose? Trends Neurosci 24(10):573–578
Choo AY, Kim SG, Vander Heiden MG, Mahoney SJ, Vu H, Yoon S-O, Cantley LC, Blenis J (2010) Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol Cell 38(4):487–499. https://doi.org/10.1016/j.molcel.2010.05.007
Chung Y, Molé PA, Sailasuta N, Tran TK, Hurd R, Jue T (2005) Control of respiration and bioenergetics during muscle contraction. Am J Physiol Cell Physiol 288(3):C730–C738. https://doi.org/10.1152/ajpcell.00138.2004
Clanton T, Hogan M, Gladden L (2013) Regulation of cellular gas exchange, oxygen sensing, and metabolic control. Compr Physiol 3(3):1135–1190
Claridge JA, Crabtree TD, Pelletier SJ, Butler K, Sawyer RG, Young JS (2000) Persistent occult hypoperfusion is associated with a significant increase in infection rate and mortality in major trauma patients. J Trauma Acute Care Surg 48(1):8–14
Clutter WE, Bier DM, Shah SD, Cryer PE (1980) Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. J Clin Invest 66(1):94
Colcombe SJ, Erickson KI, Raz N, Webb AG, Cohen NJ, McAuley E, Kramer AF (2003) Aerobic fitness reduces brain tissue loss in aging humans. J Gerentol A Biol Sci Med Sci 58(2):M176–M180
Coles L, Litt J, Hatta H, Bonen A (2004) Exercise rapidly increases expression of the monocarboxylate transporters MCT1 and MCT4 in rat muscle. J Physiol 561(1):253–261
Connett RJ, Gayeski TEJ, Honig CR (1983) Lactate production in a pure red muscle in absence of anoxia mechanisms and significance. In: Bicher HI, Bruley DF (eds) Oxygen transport to tissue—IV. Advances in experimental medicine and biology, vol 159. Springer, Boston, MA, pp 327–335
Connett RJ, Gayeski TEJ, Honig CR (1984) Lactate accumulation in fully aerobic, working, dog gracilis muscle. Am J Physiol Heart Circ Physiol 246(1):H120–H128
Connett RJ, Gayeski TEJ, Honig CR (1986) Lactate efflux is unrelated to intracellular PO2 in a working red muscle in situ. J Appl Physiol 61(2):402–408
Connett RJ, Honig CR, Gayeski TEJ, Brooks GA (1990) Defining hypoxia: a systems view of V̇O2, glycolysis, energetics, and intracellular PO2. J Appl Physiol 68(3):833–842
Connor H, Woods HF (1982) Quantitative aspects of L (+)-lactate metabolism in human beings. In: Porter R, Lawrenson G (eds) Metabolic acidosis (Ciba Foundation Symposium 87). Pitman Books Ltd, London, pp 214–234
Cori CF, Cori GT (1925) The carbohydrate metabolism of tumors II. Changes in the sugar, lactic acid, and CO2—combining Power of Blood Passing through a tumor. J Biol Chem 65(2):397–405
Dalsgaard MK, Quistorff B, Danielsen ER, Selmer C, Vogelsang T, Secher NH (2004) A reduced cerebral metabolic ratio in exercise reflects metabolism and not accumulation of lactate within the human brain. J Physiol 554(2):571–578
Daniel AM, Pierce CH, MacLean LD, Shizgal HM (1976a) Lactate metabolism in the dog during shock from hemorrhage, cardiac tamponade or endotoxin. Surg Gynecol Obstet 143(4):581–586
Daniel AM, Shizgal HM, MacLean LD (1976b) Endogenous fuels in experimental shock. Surg Forum 27(62):32–33
Daniel AM, Shizgal HM, MacLean LD (1978) The anatomic and metabolic source of lactate in shock. Surg Gynecol Obstet 147(5):697–700
Davis JA, Caiozzo VJ, Lamarra N, Ellis JF, Vandagriff R, Prietto CA, McMaster WC (1983) Does the gas exchange anaerobic threshold occur at a fixed blood lactate concentration of 2 or 4 mM? Int J Sports Med 4(2):89–93
De Bari L, Atlante A, Valenti D, Passarella S (2004) Partial reconstruction of in vitro gluconeogenesis arising from mitochondrial l-lactate uptake/metabolism and oxaloacetate export via novel l-lactate translocators. Biochem J 380(1):231–242. https://doi.org/10.1042/BJ20031981
De Paoli FV, Overgaard K, Pedersen TH, Nielsen OB (2007) Additive protective effects of the addition of lactic acid and adrenaline on excitability and force in isolated rat skeletal muscle depressed by elevated extracellular K+. J Physiol 581(2):829–839
De Bari L, Chieppa G, Marra E, Passarella S (2010) l-lactate metabolism can occur in normal and cancer prostate cells via the novel mitochondrial l-lactate dehydrogenase. Int J Oncol 37(6):1607–1620. https://doi.org/10.3892/ijo-00000815
Debold EP, Fitts RH, Sundberg C, Nosek TM (2016) Muscle fatigue from the perspective of a single crossbridge. Med Sci Sports Exerc 48(11):2270–2280
Degroot M, Massie BM, Boska M, Gober J, Miller RG, Weiner MW (1993) Dissociation of [H+] from fatigue in human muscle detected by high time resolution 31P-NMR. Muscle Nerve 16(1):91–98
Deuticke B (1982) Monocarboxylate transport in erythrocytes. J Membr Biol 70(2):89–103
Elustondo PA, White AE, Hughes ME, Brebner K, Pavlov E, Kane DA (2013) Physical and functional association of lactate dehydrogenase (LDH) with skeletal muscle mitochondria. J Biol Chem 288(35):25309–25317
Engelhardt H (1848) Ueber die Verschiedenheit der durch Gährung aus dem Zucker erzeugten und der in der Fleischflüssigkeit enthaltenen Milchsäure. Eur J Org Chem 65(3):359–367
Everse J, Kaplan NO (1973) Lactate dehydrogenases: structure and function. Adv Enzymol Relat Areas Mol Biol 37:61–133
Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9(6):425–434
Faude O, Kindermann W, Meyer T (2009) Lactate threshold concepts. Sports Med 39(6):469–490
Favero TG, Zable AC, Bowman MB, Thompson A, Abramson JJ (1995) Metabolic end products inhibit sarcoplasmic reticulum Ca2+ release and [3H] ryanodine binding. J Appl Physiol 78(5):1665–1672
Filiz AI, Aladag H, Akin ML, Sucullu I, Kurt Y, Yucel E, Uluutku AH (2010) The role of d-lactate in differential diagnosis of acute appendicitis. J Invest Surg 23(4):218–223
Fitts RH (1994) Cellular mechanisms of muscle fatigue. Physiol Rev 74(1):49–94
Fitts RH (2016) The role of acidosis in fatigue: pro perspective. Med Sci Sports Exerc 48(11):2335–2338
Fletcher WM, Hopkins FG (1907) Lactic acid in amphibian muscle. J Physiol 35(4):247–309
Folwarczny C (1863) Handbuch der physiologischen Chemie mit Rücksicht auf pathologische Chemie und analytische Methoden: Mit vier Tabellen. Exemplar anf holland. Papier. Sallmayr and Comp, Vienna
Fortney SM, Nadel ER, Wenger CB, Bove JR (1981) Effect of blood volume on sweating rate and body fluids in exercising humans. J Appl Physiol 51(6):1594–1600
Fuxe K, Dahlström AB, Jonsson G, Marcellino D, Guescini M, Dam M, Manger P, Agnati L (2010) The discovery of central monoamine neurons gave volume transmission to the wired brain. Prog Neurobiol 90(2):82–100
Gaesser GA, Brooks GA (1975) Muscular efficiency during steady-rate exercise: effects of speed and work rate. J Appl Physiol 38(6):1132–1139
Gaesser GA, Poole DC (1996) The slow component of oxygen uptake kinetics in humans. Exerc Sport Sci Rev 24(1):35–70
Gaglio G (1866) Die Milchsäure des Blutes und ihre Ursprungsstatten. Arch Anat Physiol Abt 10:400–414
Gallagher CN, Carpenter KLH, Grice P, Howe DJ, Mason A, Timofeev I, Menon DK, Kirkpatrick PJ, Pickard JD, Sutherland GR, Hutchinson PJ (2009) The human brain utilizes lactate via the tricarboxylic acid cycle: A 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study. Brain 132(10):2839–2849. https://doi.org/10.1093/brain/awp202
Garcia-Alvarez M, Marik P, Bellomo R (2014) Stress hyperlactataemia: present understanding and controversy. Lancet Diabetes Endocrinol 2(4):339–347. https://doi.org/10.1016/S2213-8587(13)70154-2
Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899
Ge H, Weiszmann J, Reagan JD, Gupte J, Baribault H, Gyuris T, Chen J-l, Tian H, Li Y (2008) Elucidation of signaling and functional activities of an orphan GPCR, GPR81. J Lipid Res 49(4):797–803. https://doi.org/10.1194/jlr.M700513-JLR200
Gertz EW, Wisneski JA, Stanley WC, Neese RA (1988) Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Invest 82(6):2017–2025
Gillies RJ, Gatenby RA (2007) Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? J Bioenerg Biomembr 39(3):251–257
Gjedde A, Léger GC, Cumming P, Yasuhara Y, Evans AC, Guttman M, Kuwabara H (1993) Striatal l-DOPA decarboxylase activity in Parkinson’s disease in vivo: implications for the regulation of dopamine synthesis. J Neurochem 61(4):1538–1541
Gladden LB (1989) Lactate uptake by skeletal muscle. Exerc Sport Sci Rev 17:115–155
Gladden LB (1991) Net lactate uptake during progressive steady-level contractions in canine skeletal muscle. J Appl Physiol 71(2):514–520
Gladden LB (1996) Lactate transport and exchange during exercise. In: Rowell LB, Shepherd JT (eds) Handbook of physiology, Section 12—Exercise: regulation and integration of multiple systems. Oxford University Press, New York, pp 614–648
Gladden LB (2004a) Lactate metabolism during exercise. In: Poortmans JR (ed) Principles of exercise biochemistry, vol 46. Karger Publishers, Basel, pp 152–196
Gladden LB (2004b) Lactate metabolism: a new paradigm for the third millennium. J Physiol 558(1):5–30
Gladden LB (2008a) 200th anniversary of lactate research in muscle. Exerc Sport Sci Rev 36(3):109–115
Gladden LB (2008b) A lactatic perspective on metabolism. Med Sci Sports Exerc 40(3):477–485
Gladden LB (2008c) Cause and effect? J Appl Physiol 105(1):364
Gladden LB (2016) The basic science of exercise fatigue. Med Sci Sports Exerc 48(11):2222–2223
Gladden L, Hogan M (2006) Point: counterpoint: commentaries on ‘Lactic acid accumulation is an advantage/disadvantage during muscle activity’. J Appl Physiol 100(4):2100–2101
Gladden LB, Welch HG (1978) Efficiency of anaerobic work. J Appl Physiol 44(4):564–570
Gladden LB, Yates JW (1983) Lactic acid infusion in dogs: effects of varying infusate pH. J Appl Physiol 54(5):1254–1260
Gladden LB, Yates JW, Stremel RW, Stamford BA (1985) Gas exchange and lactate anaerobic thresholds: inter-and intraevaluator agreement. J Appl Physiol 58(6):2082–2089
Gladden LB, Crawford RE, Webster MJ (1992) Effect of blood flow on net lactate uptake during steady-level contractions in canine skeletal muscle. J Appl Physiol 72(5):1826–1830
Gladden LB, Crawford RE, Webster MJ (1994) Effect of lactate concentration and metabolic rate on net lactate uptake by canine skeletal muscle. Am J Physiol Regul Integr Comp Physiol 266(4):R1095–R1101
Gladden LB, Goodwin ML, McDonald JR, Nijsten MWN (2011) Fuel for cancer cells? Cell Cycle 10(15):2422–2422. https://doi.org/10.4161/cc.10.15.16387
Glancy B, Hartnell LM, Malide D, Yu Z-X, Combs CA, Connelly PS, Subramaniam S, Balaban RS (2015) Mitochondrial reticulum for cellular energy distribution in muscle. Nature 523(7562):617
Gnaiger E (2001) Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply. Respir Physiol 128(3):277–297
Gnaiger E, Kuznetsov AV (2002) Mitochondrial respiration at low levels of oxygen and cytochrome c. Biochem Soc Trans 30(2):252–258
Gnaiger E, Steinlechner-Maran R, Méndez G, Eberl T, Margreiter R (1995) Control of mitochondrial and cellular respiration by oxygen. J Bioenerg Biomembr 27(6):583–596
Gold M, Miller HI, Issekutz B, Spitzer JJ (1963) Effect of exercise and lactic acid infusion on individual free fatty acids of plasma. Am J Physiol 205(5):902–904
Gollnick PD, Hermansen L (1973) Biochemical adaptations to exercise anaerobic metabolism. Exerc Sport Sci Rev 1(1):1–44
Gollnick PD, Bayly WM, Hodgson DR (1986) Exercise intensity, training, diet, and lactate concentration in muscle and blood. Med Sci Sports Exerc 18(3):334–340
Goodwin ML, Rothberg DL (2014) Lactate metabolism in trauma. J Trauma Acute Care Surg 77(1):182–183
Goodwin ML, Jin H, Straessler K, Smith-Fry K, Zhu J, Monument MJ, Grossmann AH, Randall RL, Capecchi MR, Jones KB (2014) Modeling alveolar soft part sarcomagenesis in the mouse: A role for lactate in the tumor microenvironment. Cancer Cell 26(6):851–862
Goodwin ML, Gladden LB, Nijsten, MWN, Jones KB (2015) Lactate and Cancer: Revisiting the Warburg Effect in an Era of Lactate Shuttling. Front Nutr 1:27. https://doi.org/10.3389/fnut.2014.00027
Gore DC, Honeycutt D, Jahoor F, Barrow RE, Wolfe RR, Herndon DN (1991) Propranolol diminishes extremity blood flow in burned patients. Ann Surg 213(6):568–574
Graham NA, Tahmasian M, Kohli B, Komisopoulou E, Zhu M, Vivanco I, Teitell MA, Wu H, Ribas A, Lo RS, Mellinghoff IK, Mischel PS, Graeber TG (2012) Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death. Mol Syst Biol 8:589. https://doi.org/10.1038/msb.2012.20
Granchi C, Bertini S, Macchia M, Minutolo F (2010) Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials. Curr Med Chem 17(7):672–697
Green HJ, Hughson RL, Orr GW, Ranney DA (1983) Anaerobic threshold, blood lactate, and muscle metabolites in progressive exercise. J Appl Physiol 54(4):1032–1038
Green HJ, Halestrap A, Mockett C, O’Toole D, Grant S, Ouyang J (2002) Increases in muscle MCT are associated with reductions in muscle lactate after a single exercise session in humans. Am J Physiol Endocrinol Metab 282(1):E154–E160
Green HJ, Duhamel TA, Holloway GP, Moule JW, Ranney DW, Tupling AR, Ouyang J (2008) Rapid upregulation of GLUT-4 and MCT-4 expression during 16 h of heavy intermittent cycle exercise. Am J Physiol Regul Integr Comp Physiol 294(2):R594–R600
Grimaux E (1890) Une lettre inédite de Scheele à Lavoisier [An unpublished letter from Scheele to Lavoisier]. Revue générale des sciences pures et appliqués, vol 1, pp 1–2
Halestrap AP (1976) Transport of pyruvate and lactate into human erythrocytes. Evidence for the involvement of the chloride carrier and a chloride-independent carrier. Biochem J 156(2):193–207
Halestrap AP (2012) The monocarboxylate transporter family—structure and functional characterization. IUBMB Life 64(1):1–9
Halestrap AP (2013) Monocarboxylic acid transport. Compr Physiol 3:1611–1643
Halestrap AP, Denton RM (1974) Specific inhibition of pyruvate transport in rat liver mitochondria and human erythrocytes by α-cyano-4-hydroxycinnamate. Biochem J 138(2):313–316
Halestrap AP, Meredith D (2004) The SLC16 gene family—from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflügers Archiv 447(5):619–628
Halestrap AP, Wilson MC (2012) The monocarboxylate transporter family—role and regulation. IUBMB Life 64(2):101–109
Hamann JJ, Kelley KM, Gladden LB (2001) Effect of epinephrine on net lactate uptake by contracting skeletal muscle. J Appl Physiol 91(6):2635–2641
Hamann S, Kiilgaard JF, la Cour M, Prause JU, Zeuthen T (2003) Cotransport of H+, lactate, and H2O in porcine retinal pigment epithelial cells. Exp Eye Res 76(4):493–504
Hanahan D, Weinberg Robert A (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013
Harrison TR, Pilcher C (1930a) Studies in congestive heart failure: I. The effect of edema on oxygen utilization. J Clin Invest 8(2):259–290
Harrison TR, Pilcher C (1930b) Studies in congestive heart failure: II. The respiratory exchange during and after exercise. J Clin Invest 8(3):291–315
Hasegawa H, Fukushima T, Lee J-A, Tsukamoto K, Moriya K, Ono Y, Imai K (2003) Determination of serum d-lactic and l-lactic acids in normal subjects and diabetic patients by column-switching HPLC with pre-column fluorescence derivatization. Anal Bioanal Chem 377(5):886–891
Haseler LJ, Richardson RS, Videen JS, Hogan MC (1998) Phosphocreatine hydrolysis during submaximal exercise: the effect of FIO2. J Appl Physiol 85(4):1457–1463
Hashimoto T, Brooks GA (2008) Mitochondrial lactate oxidation complex and an adaptive role for lactate production. Med Sci Sports Exerc 40(3):486–494
Hashimoto T, Hussien R, Brooks G (2006) Colocalization of MCT1, CD147, and LDH in mitochondrial inner membrane of L6 muscle cells: evidence of a mitochondrial lactate oxidation complex. Am J Physiol Endocrinol Metab 290(6):E1237–E1244. https://doi.org/10.1152/ajpendo.00594.2005
Hashimoto T, Hussien R, Oommen S, Gohil K, Brooks GA (2007) Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis. FASEB J 21(10):2602–2612
Hashimoto T, Hussien R, Cho H-S, Kaufer D, Brooks GA (2008) Evidence for the mitochondrial lactate oxidation complex in rat neurons: demonstration of an essential component of brain lactate shuttles. PLoS One 3(8):e2915
Hashimoto T, Tsukamoto H, Takenaka S, Olesen ND, Petersen LG, Sørensen H, Nielsen HB, Secher NH, Ogoh S (2017) Maintained exercise-enhanced brain executive function related to cerebral lactate metabolism in men. FASEB J. https://doi.org/10.1096/fj.201700381RR
Heck H, Mader A, Hess G, Mücke S, Müller R, Hollmann W (1985) Justification of the 4-mmol/l lactate threshold. Int J Sports Med 6(3):117–130
Heino A, Hartikainen J, Merasto ME, Koski EMJ, Alhava E, Takala J (1997) Systemic and regional effects of experimental gradual splanchnic ischemia. J Crit Care 12(2):92–98
Helmholtz HV (1845) Ueber den Stoffverbrauch bei der Muskelaktion. Arch Anat Physiol (72):72–83
Herbst E, George M, Brebner K, Holloway G, Kane D (2017) Lactate is oxidized outside of the mitochondrial matrix in rodent brain. Appl Physiol Nutr Metab. https://doi.org/10.1139/apnm-2017-0450
Hill AV, Kupalov P (1929) Anaerobic and aerobic activity in isolated muscle. Proc Roy Soc London Series B 105(737):313–322
Hill AV, Long CNH, Lupton H (1924) Muscular exercise, lactic acid, and the supply and utilisation of oxygen. Proc R Soc Lond Series B, Contain Papers Biol Character 97(681):84–138
Hochachka PW, Mommsen TP (1983) Protons and anaerobiosis. Science 219(4591):1391–1397
Hogan MC, Cox RH, Welch HG (1983) Lactate accumulation during incremental exercise with varied inspired oxygen fractions. J Appl Physiol 55(4):1134–1140
Hogan MC, Arthur PG, Bebout DE, Hochachka PW, Wagner PD (1992a) Role of O2 in regulating tissue respiration in dog muscle working in situ. J Appl Physiol 73(2):728–736
Hogan MC, Nioka S, Brechue WF, Chance B (1992b) A 31P-NMR study of tissue respiration in working dog muscle during reduced O2 delivery conditions. J Appl Physiol 73(4):1662–1670
Hogan MC, Gladden LB, Kurdak SS, Poole DC (1995) Increased [lactate] in working dog muscle reduces tension development independent of pH. Med Sci Sports Exerc 27(3):371–377
Hollmann W (1985) Historical remarks on the development of the aerobic-anaerobic threshold up to 1966. Int J Sports Med 6(03):109–116
Holmes EG (1930) Oxidations in central and peripheral nervous tissue. Biochem J 24:914–925
Holmes BE, Holmes EG (1925a) Contributions to the study of brain metabolism. I. Carbohydrate metabolism. Preliminary paper. Biochem J 19:492–499
Holmes EG, Holmes BE (1925b) Contributions to the study of brain metabolism. II. Carbohydrate metabolism. Biochem J 19:836–839
Holmes EG, Holmes BE (1926) Contributions to the study of brain metabolism. III. Carbohydrate metabolism relationship of glycogen and lactic acid. Biochem J 20:1196–1203
Holmes EG, Holmes BE (1927) Contributions to the study of brain metabolism. IV. Carbohydrate metabolism of the brain tissue of depancreatized cats. Biochem J 21:412–418
Hoshino D, Hanawa T, TakAhashi Y, Masuda H, Kato M, Hatta H (2014) Chronic post-exercise lactate administration with endurance training increases glycogen concentration and monocarboxylate transporter 1 protein in mouse white muscle. J Nutr Sci Vitaminol 60(6):413–419
Huang X, Li X, Xie X, Ye F, Chen B, Song C, Tang H, Xie X (2016) High expressions of LDHA and AMPK as prognostic biomarkers for breast cancer. Breast 30:39–46. https://doi.org/10.1016/j.breast.2016.08.014
Huckabee WE, Judson WE (1958) The role of anaerobic metabolism in the performance of mild muscular work. I. Relationship to oxygen consumption and cardiac output, and the effect of congestive heart failure. J Clin Invest 37(11):1577–1592
Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, Esparza LA, Reya T, Yanxiang GJ, White E (2017) Glucose feeds the TCA cycle via circulating lactate. Nature 551(7678):115–118
Hultman E, Bergström J, Anderson NM (1967) Breakdown and resynthesis of phosphorylcreatine and adenosine triphosphate in connection with muscular work in man. Scand J Clin Lab Invest 19(1):56–66
Ichai C, Payen JF, Orban JC, Quintard H, Roth H, Legrand R, Francony G, Leverve X (2013) Half-molar sodium lactate to prevent intracranial hypertensive episodes in severe traumatic brain-injured patients: a randomized controlled trial. Intensive Care Med 39(8):1413–1422. https://doi.org/10.1007/s00134-013-2978-9
Ichai C, Orban J-C, Fontaine E (2014) Sodium lactate for fluid resuscitation: the preferred solution for the coming decades? Crit Care 18(4):163. https://doi.org/10.1186/cc13973
Ide K, Secher NH (2000) Cerebral blood flow and metabolism during exercise. Prog Neurobiol 61(4):397–414
Ide K, Horn A, Secher NH (1999) Cerebral metabolic response to submaximal exercise. J Appl Physiol 87(5):1604–1608
Ide K, Schmalbruch IK, Quistorff B, Horn A, Secher NH (2000) Lactate, glucose and O2 uptake in human brain during recovery from maximal exercise. J Physiol 522(1):159–164
Irving MH (1968) The sympatho-adrenal factor in haemorrhagic shock. Ann R Coll Surg Engl 42(6):367–386
Ivy JL, Withers RT, Van Handel PJ, Elger DH, Costill DL (1980) Muscle respiratory capacity and fiber type as determinants of the lactate threshold. J Appl Physiol 48(3):523–527
Jacobs RA, Meinild A-K, Nordsborg NB, Lundby C (2013) Lactate oxidation in human skeletal muscle mitochondria. Am J Physiol Endocrinol Metab 304(7):E686–E694. https://doi.org/10.1152/ajpendo.00476.2012
Jadvar H, Alavi A, Gambhir SS (2009) 18F-FDG uptake in lung, breast, and colon cancers: molecular biology correlates and disease characterization. J Nucl Med 50(11):1820–1827
James JH, Fang C-H, Schrantz SJ, Hasselgren P-O, Paul RJ, Fischer JE (1996) Linkage of aerobic glycolysis to sodium-potassium transport in rat skeletal muscle. Implications for increased muscle lactate production in sepsis. J Clin Invest 98(10):2388–2397
James JH, Luchette FA, McCarter FD, Fischer JE (1999a) Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis. Lancet 354(9177):505–508
James JH, Wagner KR, King J-K, Leffler RE, Upputuri RK, Balasubramaniam A, Friend LA, Shelly DA, Paul RJ, Fischer JE (1999b) Stimulation of both aerobic glycolysis and Na+-K+-ATPase activity in skeletal muscle by epinephrine or amylin. Am J Physiol Endocrinol Metab 277(1):E176–E186
Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J (2010) Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med 182(6):752–761
Jervell O (1928) Investigation of the concentration of lactic acid in blood and urine under physiologic and pathologic conditions. Acta Med Scand Suppl XXIV:1–135
Jöbsis FF, Stainsby WN (1968) Oxidation of NADH during contractions of circulated mammalian skeletal muscle. Respir Physiol 4(3):292–300
Jones NL (1980) Hydrogen ion balance during exercise. Clin Sci 59(2):85–91
Jones AM, Doust JH (1998) The validity of the lactate minimum test for determination of the maximal lactate steady state. Med Sci Sports Exerc 30(8):1304–1313
Jones RS, Morris ME (2016) Monocarboxylate Transporters: Therapeutic targets and prognostic factors in disease. Clin Pharmacol Ther 100(5):454–463
Jones DP, Sies H (2015) The redox code. Antiox Redox Signal 23(9):734–746
Jørgensen BM, Rasmussen HN, Rasmussen UF (1985) Ubiquinone reduction pattern in pigeon heart mitochondria. Identification of three distinct ubiquinone pools. Biochem J 229(3):621–629. https://doi.org/10.1042/bj2290621
Juel C (2001) Current aspects of lactate exchange: lactate/H+ transport in human skeletal muscle. Eur J Appl Physiol 86(1):12–16
Juel C, Halestrap AP (1999) Lactate transport in skeletal muscle—role and regulation of the monocarboxylate transporter. J Physiol 517(3):633–642
Juel C, Honig A, Pilegaard H (1991) Muscle lactate transport studied in sarcolemmal giant vesicles: dependence on fibre type and age. Acta Physiol 143(4):361–366
Kane DA (2014) Lactate oxidation at the mitochondria: a lactate-malate-aspartate shuttle at work. Front Neurosci 8:366. https://doi.org/10.3389/fnins.2014.00366
Karlsson J, Bonde-Petersen F, Henriksson J, Knuttgen HG (1975) Effects of previous exercise with arms or legs on metabolism and performance in exhaustive exercise. J Appl Physiol 38(5):763–767
Katz A, Sahlin K (1988) Regulation of lactic acid production during exercise. J Appl Physiol 65(2):509–518
Keir DA, Fontana FY, Robertson TC, Murias JM, Paterson DH, Kowalchuk JM, Pogliaghi S (2015) Exercise intensity thresholds: identifying the boundaries of sustainable performance. Med Sci Sports Exerc 47(9):1932–1940
Kelley KM, Hamann JJ, Navarre C, Gladden LB (2002) Lactate metabolism in resting and contracting canine skeletal muscle with elevated lactate concentration. J Appl Physiol 93(3):865–872
Kellum JA, Elbers PWG (eds) (2009) Stewart’s textbook of acid-base. AcidBase.org, Amsterdam
Kennedy KM, Dewhirst MW (2010) Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation. Future Oncol 6(1):127–148
Kim J-W, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3(3):177–185
Kindermann W, Simon G, Keul J (1979) The significance of the aerobic-anaerobic transition for the determination of work load intensities during endurance training. Eur J Appl Physiol Occup Physiol 42(1):25–34
Kitaoka Y, Takeda K, Tamura Y, Hatta H (2016) Lactate administration increases mRNA expression of PGC-1α and UCP3 in mouse skeletal muscle. Appl Physiol Nutr Metab 41(6):695–698
Klausen K, Knuttgen HG, Forster HV (1972) Effect of pre-existing high blood lactate concentration on maximal exercise performance. Scand J Clin Lab Invest 30(4):415–419
Kline JA, Thornton LR, Lopaschuk GD, Barbee WR, Watts JA (2000) Lactate improves cardiac efficiency after hemorrhagic shock. Shock 14(2):215–221
Knuth ST, Dave H, Peters JR, Fitts RH (2006) Low cell pH depresses peak power in rat skeletal muscle fibres at both 30 C and 15 C: implications for muscle fatigue. J Physiol 575(3):887–899
Kompanje E, Jansen T, van der Hoven B, Bakker J (2007) The first demonstration of lactic acid in human blood in shock by Johann Joseph Scherer (1814–1869) in January 1843. Intensive Care Med 33(11):1967–1971
Krebs HA (1972) The Pasteur effect and the relations between respiration and fermentation. Essays Biochem 8:1–34
Kuei C, Yu J, Zhu J, Wu J, Zhang L, Shih A, Mirzadegan T, Lovenberg T, Liu C (2011) Study of GPR81, the lactate receptor, from distant species identifies residues and motifs critical for GPR81 functions. Mol Pharmacol 80(5):848–858
Kunkel M, Reichert TE, Benz P, Lehr HA, Jeong JH, Wieand S, Bartenstein P, Wagner W, Whiteside TL (2003) Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer 97(4):1015–1024
Kushmerick J (1983) Energetics of muscle contraction. In: Peachey LD (ed) Handbook of physiology, skeletal muscle. American Physiological Society, Bethesda, MD, pp 189–236
Lamb GD, Stephenson DG (2006) Point: Lactic acid accumulation is an advantage during muscle activity. J Appl Physiol 100(4):1410–1412
Lambeth MJ, Kushmerick MJ (2002) A computational model for glycogenolysis in skeletal muscle. Ann Biomed Eng 30(6):808–827
Lauritzen KH, Morland C, Puchades M, Holm-Hansen S, Hagelin EM, Lauritzen F, Attramadal H, Storm-Mathisen J, Gjedde A, Bergersen LH (2013) Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb Cortex 24(10):2784–2795
Lauritzen KH, Morland C, Puchades M, Holm-Hansen S, Hagelin EM, Lauritzen F, Attramadal H, Storm-Mathisen J, Gjedde A, Bergersen LH (2014) Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb Cortex 24(10):2784–2795. https://doi.org/10.1093/cercor/bht136
Lavoisier A-L (1789) Traité élémentaire de chimie. Chez Cuchet, Paris
Lehninger AL (1951) Phosphorylation coupled to oxidation of dihydrodiphosphopyridine nucleotide. J Biol Chem 190(1):345–359
Leite TC, Da Silva D, Coelho RG, Zancan P, Sola-Penna M (2007) Lactate favours the dissociation of skeletal muscle 6-phosphofructo-1-kinase tetramers down-regulating the enzyme and muscle glycolysis. Biochem J 408(1):123–130
Leite TC, Coelho RG, Da Silva D, Coelho WS, Marinho-Carvalho MM, Sola-Penna M (2011) Lactate downregulates the glycolytic enzymes hexokinase and phosphofructokinase in diverse tissues from mice. FEBS Lett 585(1):92–98
Lemire J, Mailloux RJ, Appanna VD (2008) Mitochondrial lactate dehydrogenase is involved in oxidative-energy metabolism in human astrocytoma cells (CCF-STTG1). PLoS ONE, 3(2):e1550. https://doi.org/10.1371/journal.pone.0001550
Levinovitz AW, Ringertz N (2001) The nobel prize: the first 100 Years. Imperial College Press, London
Li S, Kim E, Bonanno JA (2016) Fluid transport by the cornea endothelium is dependent on buffering lactic acid efflux. Am J Physiol Cell Physiol 311(1):C116–C126
Liang X, Liu L, Fu T, Zhou Q, Zhou D, Xiao L, Liu J, Kong Y, Xie H, Yi F (2016) Exercise inducible lactate dehydrogenase B regulates mitochondrial function in skeletal muscle. J Biol Chem 291(49):25306–25318
Liddell MJ, Daniel AM, MacLean LD, Shizgal HM (1979) The role of stress hormones in the catabolic metabolism of shock. Surg Gynecol Obstet 149(6):822–830
Lindinger MI, Spriet LL, Hultman E, Putman T, McKelvie RS, Lands LC, Jones NL, Heigenhauser GJ (1994) Plasma volume and ion regulation during exercise after low- and high-carbohydrate diets. Am J Physiol 266(6 Pt 2):R1896–R1906
Lindinger M, Heigenhauser G (2008a) Counterpoint: lactic acid is not the only physicochemical contributor to the acidosis of exercise-Rebuttal. J Appl Physiol 105(1):359–361
Lindinger M, Heigenhauser G (2008b) Counterpoint: lactic acid is not the only physicochemical contributor to the acidosis of exercise. Rebuttal J Appl Physiol 105(1):361–362
Lindinger MI, Leung M, Trajcevski KE, Hawke TJ (2011) Volume regulation in mammalian skeletal muscle: the role of sodium-potassium-chloride cotransporters during exposure to hypertonic solutions. J Physiol 589(Pt 11):2887–2899
Lindinger MI, Leung MJ, Hawke TJ (2013) Inward flux of lactate- through monocarboxylate transporters contributes to regulatory volume increase in mouse muscle fibers. PLoS ONE 8(12):e84451. https://doi.org/10.1371/journal.pone.0084451
Liu C, Wu J, Zhu J, Kuei C, Yu J, Shelton J, Sutton SW, Li X, Su JY, Mirzadegan T, Mazur C, Kamme F, Lovenberg TW (2009) Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J Biol Chem 284(5):2811–2822. https://doi.org/10.1074/jbc.M806409200
Lockwood LB, Yoder DE, Zienty M (1965) Lactic acid. Ann N Y Acad Sci 119(1):854–867
Lopaschuk GD, Ussher JR, Folmes CDL, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90(1):207–258
Luchette FA, Jenkins WA, Friend LA, Su C, Fischer JE, James JH (2002) Hypoxia is not the sole cause of lactate production during shock. J Trauma Acute Care Surg 52(3):415–419
Lundberg GD (2011) Medical Publishing for an N of One-New technologies and mind-sets required for information delivery in the age of genomics. Scientist 25(4):31
Lundgren A (2014) Carl Wilhelm Scheele. Encyclopaedia Britannica, Inc. https://www.britannica.com/biography/Carl-Wilhelm-Scheele. Accessed 2 Aug 2017
Lundin G, Ström G (1947) The concentration of blood lactic acid in man during muscular work in relation to the partial pressure of oxygen of the inspired air. Acta Physiol 13(3):253–266
Lunt SY, Vander Heiden MG (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 27(1):441–464. https://doi.org/10.1146/annurev-cellbio-092910-154237
Lytovchenko O, Kunji ERS (2017) Expression and putative role of mitochondrial transport proteins in cancer. Biochim Biophys Acta Bioenerg 1858(8):641–654. https://doi.org/10.1016/j.bbabio.2017.03.006
Mack GW (2012) The body fluid and hemopoietic systems. In: Farrell PA, Joyner MJ, Caiozzo VJ (eds) ACSM’s advanced exercise physiology, 2nd edition. Lippincott Williams & Wilkins, New York, pp 535–536
Magistretti PJ, Pellerin L (1996) Cellular bases of brain energy metabolism and their relevance to functional brain imaging: evidence for a prominent role of astrocytes. Cereb Cortex 6(1):50–61
Marcinek DJ, Kushmerick MJ, Conley KE (2010) Lactic acidosis in vivo: testing the link between lactate generation and H + accumulation in ischemic mouse muscle. J Appl Physiol 108(6):1479–1486
Martinez-Outschoorn UE, Peiris-Pages M, Pestell RG, Sotgia F, Lisanti MP (2017) Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 14(1):11–31. https://doi.org/10.1038/nrclinonc.2016.60
Martin-Requero A, Ayuso MS, Parilla R (1986) Rate-limiting steps for hepatic gluconeogenesis. Mechanisms of oxamate inhibition of mitochondrial pyruvate metabolism. J Biol Chem 261(30):13973–13978
Mason S (2017) Lactate shuttles in neuroenergetics—homeostasis, allostasis and beyond. Front Neurosci 11:43
Mazzeo RS, Reeves JT (2003) Adrenergic contribution during acclimatization to high altitude: perspectives from Pikes Peak. Exerc Sport Sci Rev 31(1):13–18
Mazzeo RS, Brooks GA, Schoeller DA, Budinger TF (1986) Disposal of blood [1–13C] lactate in humans during rest and exercise. J Appl Physiol 60(1):232–241
Mazzeo RS, Bender PR, Brooks GA, Butterfield GE, Groves BM, Sutton JR, Wolfel EE, Reeves JT (1991) Arterial catecholamine responses during exercise with acute and chronic high-altitude exposure. Am J Physiol Endocrinol Metab 261(4):E419–E424
Merezhinskaya N, Fishbein WN (2009) Monocarboxylate transporters: Past, present, and future. Histol Histopathol 24(2):243–264
Meyerhof O (1930a) Die chemischen Vorgänge im Zusammenhang mit der Wärmebildung. Die chemischen Vorgänge im Muskel und ihr Zusammenhang mit Arbeitsleistung und Wärmebildung. Springer, Berlin, Heidelberg
Meyerhof O (1930b) The chemistry of muscular contraction. Lancet 216(5600):1415–1422
Meyerhof O (1942) Intermediary carbohydrate metabolism. In: A symposium on respiratory enzymes. The University of Wisconsin Press, Madison, pp 3–15
Miller BF, Fattor Ja J, Ka H, Ma Navazio F, Lindinger MI, Brooks Ga (2002a) Lactate and glucose interactions during rest and exercise in men: effect of exogenous lactate infusion. J Physiol 544 (3):963–975. https://doi.org/10.1113/jphysiol.2002.027128
Miller BF, Fattor JA, Jacobs KA, Horning MA, Suh S-H, Navazio F, Brooks GA (2002b) Metabolic and cardiorespiratory responses to “the lactate clamp”. Am J Physiol Endocrinol Metab 283(5):E889–E898
Mobasheri A, Richardson S, Mobasheri R, Shakibaei M, Hoyland JA (2005) Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes. Histol Histopathol 20(4):1327–1338
Molé PA, Chung Y, Tran TK, Sailasuta N, Hurd R, Jue T (1999) Myoglobin desaturation with exercise intensity in human gastrocnemius muscle. Am J Physiol Regul Integr Comp Physiol 277(1):R173–R180
Moreno-Sánchez R, Rodríguez-Enríquez S, Marín-Hernández A, Saavedra E (2007) Energy metabolism in tumor cells. FEBS J 274(6):1393–1418
Morland C, Lauritzen KH, Puchades M, Holm-Hansen S, Andersson K, Gjedde A, Attramadal H, Storm-Mathisen J, Bergersen LH (2015) The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: Expression and action in brain. J Neurosci Res 93(7):1045–1055
Mosler F, Körner W (1862) Zur Blut- und Harnanalyse bei Leukämie. Virchows Arch 25(1):142–150. https://doi.org/10.1007/BF01879718
Murray B, Wilson DJ (2001) A study of metabolites as intermediate effectors in angiogenesis. Angiogenesis 4(1):71–77
Nalbandian M, Takeda M (2016) Lactate as a signaling molecule that regulates exercise-induced adaptations. Biology 5(4):38. https://doi.org/10.3390/biology5040038
Nalos M, Leverve XM, Huang SJ, Weisbrodt L, Parkin R, Seppelt IM, Ting I, McLean AS (2014) Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomised controlled clinical trial. Crit Care 18(2):R48. https://doi.org/10.1186/cc13793
Nasse OJF (1877) Bemerkungen zur Physiologie der Kohlehydrate. Pflügers Archiv Euro J Physiol 14(1):473–484
Nasse OJF (1879) Chemie und Stoffwechsel der Muskeln, vol 1. In: [Hermann’s] Handbuch der Physiologie. Der Bewegungsapparate, FCW Vogel, Leipzig
Needham DM (1971) Machina carnis: the biochemistry of muscular contraction in its historical development. Cambridge University Press, Cambridge
Nelson CR, Debold EP, Fitts RH (2014) Phosphate and acidosis act synergistically to depress peak power in rat muscle fibers. Am J Physiol Cell Physiol 307(10):C939–C950
Nichol AD, Egi M, Pettila V, Bellomo R, French C, Hart G, Davies A, Stachowski E, Reade MC, Bailey M (2010) Relative hyperlactatemia and hospital mortality in critically ill patients: a retrospective multi-centre study. Crit Care 14(1):R25. https://doi.org/10.1186/cc8888
Nicholls DG, Ferguson SJ (2013) Bioenergetics. 4th edn. Academic Press, London
Nicholson RM, Sleivert GG (2001) Indices of lactate threshold and their relationship with 10-km running velocity. Med Sci Sports Exerc 33(2):339–342
Nielsen OB, Paoli F, Overgaard K (2001) Protective effects of lactic acid on force production in rat skeletal muscle. J Physiol 536(1):161–166
Nielsen HB, Clemmesen JO, Skak C, Ott P, Secher NH (2002) Attenuated hepatosplanchnic uptake of lactate during intense exercise in humans. J Appl Physiol 92(4):1677–1683
Nijsten MWN, van Dam GM (2009) Hypothesis: using the Warburg effect against cancer by reducing glucose and providing lactate. Med Hypotheses 73(1):48–51
Nohl H (1987) Demonstration of the existence of an organo-specific NADH dehydrogenase in heart mitochondria. Eur J Biochem 169(3):585–591. https://doi.org/10.1111/j.1432-1033.1987.tb13649.x
Odom SR, Howell MD, Silva GS, Nielsen VM, Gupta A, Shapiro NI, Talmor D (2013) Lactate clearance as a predictor of mortality in trauma patients. J Trauma Acute Care Surg 74(4):999–1004
Okubo Y, Iino M (2011) Visualization of glutamate as a volume transmitter. J Physiol 589(3):481–488
Oldenbeuving G, McDonald JR, Goodwin ML, Sayilir R, Reijngoud DJ, Gladden LB, Nijsten MWN (2014) A patient with acute liver failure and extreme hypoglycaemia with lactic acidosis who was not in coma: causes and consequences of lactate-protected hypoglycaemia. Anaesth Intensive Care 42(4):507–511
Otto AM (2016) Warburg effect(s)—a biographical sketch of Otto Warburg and his impacts on tumor metabolism. Cancer Metab 4(1):5. https://doi.org/10.1186/s40170-016-0145-9
Owles WH (1930) Alterations in the lactic acid content of the blood as a result of light exercise and associated changes in the CO2-combining power of the blood and in the alveolar CO2 pressure. J Physiol 69(2):214–237
Paddle BM (1985) A cytoplasmic component of pyridine nucleotide fluorescence in rat diaphragm: evidence from comparisons with flavoprotein fluorescence. Pflügers Archiv 404(4):326–331
Pagliassotti MJ, Donovan CM (1990) Role of cell type in net lactate removal by skeletal muscle. Am J Physiol Endocrinol Metab 258(4):E635–E642
Parolin ML, Chesley A, Matsos MP, Spriet LL, Jones NL, Heigenhauser GJF (1999) Regulation of skeletal muscle glycogen phosphorylase and PDH during maximal intermittent exercise. Am J Physiol Endocrinol Metab 277(5):E890–E900
Parsikia A, Bones K, Kaplan M, Strain J, Leung PS, Ortiz J, Joshi ART (2014) The predictive value of initial serum lactate in trauma patients. Shock 42(3):199–204
Passarella S, de Bari L, Valenti D, Pizzuto R, Paventi G, Atlante A (2008) Mitochondria and l-lactate metabolism. FEBS Lett 582(25–26):3569–3576. https://doi.org/10.1016/j.febslet.2008.09.042
Passarella S, Paventi G, Pizzuto R (2014) The mitochondrial l-lactate dehydrogenase affair. Front Neurosci 8:407. https://doi.org/10.3389/fnins.2014.00407
Pasteur L (1861) Expériences et vues nouvelles sur la nature des fermentations. Comptes Rendus Hebdomadaires des Séances de l’Académie des Sciences, Paris 53:1260–1264
Paventi G, Pizzuto R, Passarella S (2017) The occurance of l-lactate dehydrogenase in the inner mitochondrial compartment of pig liver. Biochem Biophys Res Commun 489:255–261
Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2009) The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8(23):3984–4001. https://doi.org/10.4161/cc.8.23.10238
Pedersen PK, Sj G, Juel C (2001) Plasma acid-base status and hyperventilation during cycling at MAXLASS in low and high lactate responders. Med Sci Sports Exerc 33(5):S314
Pedersen TH, Nielsen OB, Lamb GD, Stephenson DG (2004) Intracellular acidosis enhances the excitability of working muscle. Science 305(5687):1144–1147
Pellerin L (2003) Lactate as a pivotal element in neuron–glia metabolic cooperation. Neurochem 43(4):331–338
Pellerin L (2010) Food for thought: the importance of glucose and other energy substrates for sustaining brain function under varying levels of activity. Diabetes Metab 36:S59–S63
Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci 91(22):10625–10629
Pellerin L, Magistretti PJ (2003) How to balance the brain energy budget while spending glucose differently. J Physiol 546(2):325–325
Pellerin L, Magistretti PJ (2011) Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32(7):1152–1166
Pellerin L, Pellegri G, Bittar PG, Charnay Y, Bouras C, Martin JL, Stella N, Magistretti PJ (1998) Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev Neurosci 20(4–5):291–299
Pértega-Gomes N, Vizcaíno JR, Miranda-Gonçalves V, Pinheiro C, Silva J, Pereira H, Monteiro P, Henrique RM, Reis RM, Lopes C, Baltazar F (2011) Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer. BMC Cancer 11(1):312. https://doi.org/10.1186/1471-2407-11-312
Philp NJ, Yoon H, Lombardi L (2001) Mouse MCT3 gene is expressed preferentially in retinal pigment and choroid plexus epithelia. Am J Physiol Cell Physiol 280(5):C1319–C1326
Pizzuto R, Paventi G, Porcile C, Sarnataro D, Daniele A, Passarella S (2012) l-Lactate metabolism in HEP G2 cell mitochondria due to the l-lactate dehydrogenase determines the occurrence of the lactate/pyruvate shuttle and the appearance of oxaloacetate, malate and citrate outside mitochondria. Biochim Biophys Acta Bioenerg 1817(9):1679–1690
Plato PA, McNulty M, Crunk SM, Ergun AT (2008) Predicting lactate threshold using ventilatory threshold. Int J Sports Med 29(09):732–737
Pölönen P, Ruokonen E, Hippeläinen M, Pöyhönen M, Takala J (2000) A prospective, randomized study of goal-oriented hemodynamic therapy in cardiac surgical patients. Anesth Analg 90(5):1052–1059
Ponsot E, Zoll J, N’Guessan B, Ribera F, Lampert E, Richard R, Veksler V, Ventura-Clapier R, Mettauer B (2005) Mitochondrial tissue specificity of substrates utilization in rat cardiac and skeletal muscles. J Cell Physiol 203(3):479–486. https://doi.org/10.1002/jcp.20245
Poole RC, Halestrap AP (1992) Identification and partial purification of the erythrocyte l-lactate transporter. Biochem J 283(3):855–862
Poole RC, Halestrap AP (1993) Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am J Physiol Cell Physiol 264(4):C761–C782
Poole DC, Gladden LB, Kurdak S, Hogan MC (1994) l-(+)-lactate infusion into working dog gastrocnemius: no evidence lactate per se mediates V̇O2 slow component. J Appl Physiol 76(2):787–792
Posterino GS, Dutka TL, Lamb GD (2001) L (+)-lactate does not affect twitch and tetanic responses in mechanically skinned mammalian muscle fibres. Pflügers Arch 442(2):197–203
Potter VR (1958) The biochemical approach to the cancer problem. Fed Proc 17(2):691–697
Potter M, Newport E, Morten KJ (2016) The Warburg effect: 80 years on. Biochem Soc Trans 44(5):1499–1505
Prebble JN (2010) The discovery of oxidative phosphorylation: a conceptual off-shoot from the study of glycolysis. Stud Hist Philos Biol Biomed Sci 41(3):253–262
Pringle JS, Jones AM (2002) Maximal lactate steady state, critical power and EMG during cycling. Eur J Appl Physiol 88(3):214–226. https://doi.org/10.1007/s00421-002-0703-4
ProCESS (2014) A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014(370):1683–1693
Proia P, Di Liegro CM, Schiera G, Fricano A, Di Liegro I (2016) Lactate as a Metabolite and a Regulator in the Central Nervous System. Int J Mol Sci 17(9):1450–1470
Quintard H, Patet C, Zerlauth J-B, Suys T, Bouzat P, Pellerin L, Meuli R, Magistretti PJ, Oddo M (2016) Improvement of neuroenergetics by hypertonic lactate therapy in patients with traumatic brain injury is dependent on baseline cerebral lactate/pyruvate ratio. J Neurotrauma 33(7):681–687
Quistorff B, Secher NH, Van Lieshout JJ (2008) Lactate fuels the human brain during exercise. FASEB J 22(10):3443–3449
Racker E (1972) Bioenergetics and the problem of tumor growth: an understanding of the mechanism of the generation and control of biological energy may shed light on the problem of tumor growth. Am Sci 60(1):56–63
Racker E (1974) History of the Pasteur effect and its pathobiology. Mol Cell Biochem 5(1–2):17–23
Rasmussen UF (1969) The oxidation of added NADH by intact heart mitochondria. FEBS Lett 2(3):157–162
Rasmussen UF, Rasmussen HN (1985) The NADH oxidase system (external) of muscle mitochondria and its role in the oxidation of cytoplasmic NADH. Biochem J 229(3):631–641
Rasmussen UF, Krustrup P, Bangsbo J, Rasmussen HN (2001) The effect of high-intensity exhaustive exercise studied in isolated mitochondria from human skeletal muscle. Pflügers Archiv 443(2):180–187. https://doi.org/10.1007/s004240100689
Rasmussen HN, van Hall G, Rasmussen UF (2002) Lactate dehydrogenase is not a mitochondrial enzyme in human and mouse vastus lateralis muscle. J Physiol 541(2):575–580. https://doi.org/10.1113/jphysiol.2002.019216
Rasmussen UF, Krustrup P, Kjaer M, Rasmussen HN (2003a) Human skeletal muscle mitochondrial metabolism in youth and senescence: no signs of functional changes in ATP formation and mitochondrial oxidative capacity. Pflügers Archiv 446:270–278
Rasmussen UF, Krustrup P, Kjær M, Rasmussen HN (2003b) Experimental evidence against the mitochondrial theory of aging. A study of isolated human skeletal muscle mitochondria. Exp Gerontol 38(8):877–886. https://doi.org/10.1016/S0531-5565(03)00092-5
Rej R (1979) Measurement of aspartate aminotransferase activity: Effects of oxamate. Clin Chem 25(4):555–559
Richardson R, Noyszewski E, Kendrick K, Leigh J, Wagner P (1995) Myoglobin O2 desaturation during exercise. Evidence of limited O2 transport. J Clin Invest 96(4):1916–1926
Richardson RS, Noyszewski EA, Leigh JS, Wagner PD (1998) Lactate efflux from exercising human skeletal muscle: role of intracellular PO2. J Appl Physiol 85(2):627–634
Richardson RS, Leigh JS, Wagner PD, Noyszewski EA (1999) Cellular PO2 as a determinant of maximal mitochondrial O2 consumption in trained human skeletal muscle. J Appl Physiol 87(1):325–331
Richardson RS, Newcomer SC, Noyszewski EA (2001) Skeletal muscle intracellular PO2 assessed by myoglobin desaturation: response to graded exercise. J Appl Physiol 91(6):2679–2685
Richardson RS, Noyszewski EA, Saltin B, Gonzalez-Alonso J (2002) Effect of mild carboxy-hemoglobin on exercising skeletal muscle: intravascular and intracellular evidence. Am J Physiol Regul Integr Comp Physiol 283(5):R1131–R1139
Richardson RS, Duteil S, Wary C, Wray DW, Hoff J, Carlier PG (2006) Human skeletal muscle intracellular oxygenation: the impact of ambient oxygen availability. J Physiol 571(2):415–424
Richter EA, Kiens B, Saltin B, Christensen NJ, Savard G (1988) Skeletal muscle glucose uptake during dynamic exercise in humans: role of muscle mass. Am J Physiol Endocrinol Metab 254(5):E555–E561
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345(19):1368–1377
Robergs RA (2008) Science vs. personal bias in acid-base physiology. J Appl Physiol 105(1):363
Robergs RA, Ghiasvand F, Parker D (2004) Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Regul Integr Comp Physiol 287(3):R502–R516
Robergs RA, Ghiasvand F, Parker D (2005) Lingering construct of lactic acidosis. Am J Physiol Regul Integr Comp Physiol 289(3):R904–R910
Robergs RA, Ghiasvand F, Parker D (2006) Reply: the wandering argument favoring a lactic acidosis. Am J Physiol Regul Integr Comp Physiol 291(1):R238–R239
Roef MJ, De Meer K, Kalhan SC, Straver H, Berger R, Reijngoud D-J (2003) Gluconeogenesis in humans with induced hyperlactatemia during low-intensity exercise. Am J Physiol Endocrinol Metab 284(6):E1162–E1171
Rogatzki MJ, Ferguson BS, Goodwin ML, Gladden LB (2015) Lactate is always the end product of glycolysis. Front Neurosci 9:22. https://doi.org/10.3389/fnins.2015.00022
Rooney K, Trayhurn P (2011) Lactate and the GPR81 receptor in metabolic regulation: implications for adipose tissue function and fatty acid utilisation by muscle during exercise. Br J Nutr 106(9):1310–1316. https://doi.org/10.1017/S0007114511004673
Roos A (1975) Intracellular pH and distribution of weak acids across cell membranes. A study of d-and l-lactate and of DMO in rat diaphragm. J Physiol 249(1):1–25
Roth DA, Brooks GA (1990a) Lactate and pyruvate transport is dominated by a pH gradient-sensitive carrier in rat skeletal muscle sarcolemmal vesicles. Arch Biochem Biophys 279(2):386–394. https://doi.org/10.1016/0003-9861(90)90506-T
Roth DA, Brooks GA (1990b) Lactate transport is mediated by a membrane-bound carrier in rat skeletal muscle sarcolemmal vesicles. Arch Biochem Biophys 279(2):377–385
Sahlin K, Ren JM (1989) Relationship of contraction capacity to metabolic changes during recovery from a fatiguing contraction. J Appl Physiol 67(2):648–654
Sahlin K, Harris R, Nylind B, Hultman E (1976) Lactate content and pH in muscle samples obtained after dynamic exercise. Pflügers Archiv 367(2):143–149
Sahlin K, Fernström M, Svensson M, Tonkonogi M (2002) No evidence of an intracellular lactate shuttle in rat skeletal muscle. J Physiol 541(2):569–574. https://doi.org/10.1113/jphysiol.2002.016683
Sakagami H, Makino Y, Mizumoto K, Isoe T, Takeda Y, Watanabe J, Fujita Y, Takiyama Y, Abiko A, Haneda M (2014) Loss of HIF-1α impairs GLUT4 translocation and glucose uptake by the skeletal muscle cells. Am J Physiol Endocrinol Metab 306(9):E1065–E1076
Samaja M, Allibardi S, Milano G, Neri G, Grassi B, Gladden LB, Hogan MC (1999) Differential depression of myocardial function and metabolism by lactate and H+. Am J Physiol Heart Circ Physiol 276(1):H3–H8
San-Millán I, Brooks GA (2017) Reexamining cancer metabolism: Lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect. Carcinogenesis 38(2):119–133. https://doi.org/10.1093/carcin/bgw127
Sauer LA, Dauchy RT (1985) Regulation of lactate production and utilization in rat tumors in vivo. J Biol Chem 260(12):7496–7501
Scandurra FM, Gnaiger E (2010) Cell respiration under hypoxia: facts and artefacts in mitochondrial oxygen kinetics. In: Takahashi E, Bruley DF (eds) Oxygen Transport to Tissue XXXI, Adv Exp Med Biol, vol 662. Springer US, Boston, pp 7–25. https://doi.org/10.1007/978-1-4419-1241-1_2
Scheele CW, Bergman T (1777) Chemische Abhandlung von der Luft und dem Feuer: nebst einem Vorbericht. Verlegt von Magnus Swederus. SL Crusius, Upsalla, Leipzig
Scheele CW, Forster JR, Priestley J, Kirwan R, Bergman T (1780) Chemical Observations and Experiments on Air and Fire, translated by Forster JR. Johnson, London
Scherer JJ (1843) Chemische und mikroskopische Untersuchungen zur Pathologie: angestellt an den Kliniken des Julius-Hospitales zu Würzburg. Kessinger Legacy Reprints Publishing, Whitefish
Scherer JJ (1851) Eine Untersuchung des Blutes bei Leukämie. Verhandlungen der Physikalisch-Medicinischen Gesellschaft im Würzburg 2:321–325
Schurr A (2006) Lactate: the ultimate cerebral oxidative energy substrate? J Cereb Blood Flow Metab 26(1):142–152
Schurr A (2014) Cerebral glycolysis: a century of persistent misunderstanding and misconception. Front Neurosci 8 (360). https://doi.org/10.3389/fnins.2014.00360
Schurr A (2017) Lactate, Not Pyruvate, Is the End Product of Glucose Metabolism via Glycolysis. In: Caliskan M, Kavakli HI, Oz GC (eds) Biochem Genet Mol Biol. InTech, Rijeka, p 2. https://doi.org/10.5772/66699
Schurr A, Payne RS (2007) Lactate, not pyruvate, is neuronal aerobic glycolysis end product: An in vitro electrophysiological study. Neuroscience 147(3):613–619. https://doi.org/10.1016/j.neuroscience.2007.05.002
Schurr A, West CA, Rigor BM (1988) Lactate-supported synaptic function in the rat hippocampal slice preparation. Science 240(4857):1326–1328
Schurr A, Payne RS, Miller JJ, Rigor BM (1997a) Brain lactate is an obligatory aerobic energy substrate for functional recovery after hypoxia: further in vitro validation. J Neurochem 69(1):423–426
Schurr A, Payne RS, Miller JJ, Rigor BM (1997b) Brain lactate, not glucose, fuels the recovery of synaptic function from hypoxia upon reoxygenation: an in vitro study. Brain Res 744(1):105–111
Schurr A, Payne RS, Miller JJ, Rigor BM (1997c) Glia are the main source of lactate utilized by neurons for recovery of function posthypoxia. Brain Res 774(1):221–224
Semenza GL (2001) HIF-1, O2, and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell 107(1):1–3
Semenza GL (2004) Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiol 19(4):176–182
Semenza GL (2008) Tumor metabolism: cancer cells give and take lactate. J Clin Invest 118(12):3835–3837
Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12(12):5447–5454
Semenza GL, Jiang B-H, Leung SW, Passantino R, Concordet J-P, Maire P, Giallongo A (1996) Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271(51):32529–32537
Severinghaus JW (2006) The breathless quest for the gas supporting combustion. Phys Today 59(8):51. https://doi.org/10.1063/1.2349733
Severinghaus JW (2016) Eight sages over five centuries share oxygens discovery. Adv Physiol Edu 40(3):370–376
Sheng SL, Liu JJ, Dai YH, Sun XG, Xiong XP, Huang G (2012) Knockdown of lactate dehydrogenase A suppresses tumor growth and metastasis of human hepatocellular carcinoma. FEBS J 279(20):3898–3910
Shi M, Cui J, Du J, Wei D, Jia Z, Zhang J, Zhu Z, Gao Y, Xie K (2014) A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer. Clin Cancer Res 20(16):4370–4380
Siegler JC, Marshall PWM, Bishop D, Shaw G, Green S (2016) Mechanistic insights into the efficacy of sodium bicarbonate supplementation to improve athletic performance. Sports Med Open 2(1):41
Simon J, Young JL, Gutin B, Blood DK, Case RB (1983) Lactate accumulation relative to the anaerobic and respiratory compensation thresholds. J Appl Physiol 54(1):13–17
Siskind SJ, Sonnenblick EH, Forman R, Scheuer J, Lejemtel TH (1981) Acute substantial benefit of inotropic therapy with amrinone on exercise hemodynamics and metabolism in severe congestive heart failure. Circulation 64(5):966–973
Skelton MS, Kremer DE, Smith EW, Gladden LB (1995) Lactate influx into red blood cells of athletic and nonathletic species. Am J Physiol Regul Integr Comp Physiol 268(5):R1121–R1128
Skelton MS, Kremer DE, Smith EW, Gladden LB (1998) Lactate influx into red blood cells from trained and untrained human subjects. Med Sci Sports Exerc 30(4):536–542
Smith D, Pernet A, Hallett WA, Bingham E, Marsden PK, Amiel SA (2003) Lactate: a preferred fuel for human brain metabolism in vivo. J Cereb Blood Flow Metab 23(6):658–664
Sokoloff L (1989) Circulation and energy metabolism of the brain. Basic Neurochem 2:338–413
Sonveaux P, Végran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118(12):3930–3942
Spangenburg EE, Ward CW, Williams JH (1998) Effects of lactate on force production by mouse EDL muscle: implications for the development of fatigue. Can J Physiol Pharmacol 76(6):642–648
Stacpoole PW, Wright EC, Baumgartner TG, Bersin RM, Buchalter S, Curry SH, Duncan CA, Harman EM, Henderson GN, Jenkinson S, Lachin JM, Lorenz A, Schneider SH, Siegel JH, Summer WR, Thompson D, Wolfe CL, Zorovich B (1992) A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. N Engl J Med 327(22):1564–1569. https://doi.org/10.1056/NEJM199211263272204
Stainsby WN, Brooks GA (1990) Control of lactic acid metabolism in contracting muscles and during exercise. Exerc Sport Sci Rev 18(1):29–64
Stainsby WN, Welch HG (1966) Lactate metabolism of contracting dog skeletal muscle in situ. Am J Physiol 211(1):177–183
Stainsby WN, Sumners C, Eitzman PD (1987) Effects of adrenergic agonists and antagonists on muscle O2 uptake and lactate metabolism. J Appl Physiol 62(5):1845–1851
Stanley WC (1991) Myocardial lactate metabolism during exercise. Med Sci Sports Exerc 23(8):920–924
Stanley WC, Gertz EW, Wisneski JA, Neese RA, Morris DL, Brooks GA (1986) Lactate extraction during net lactate release in legs of humans during exercise. J Appl Physiol 60(4):1116–1120
Stegmann H, Kindermann W, Schnabel A (1981) Lactate kinetics and individual anaerobic threshold. Int J Sports Med 2(3):160–165
Stewart PA (1981) How to understand acid-base: a quantitative acid-base primer for biology and medicine. Elsevier, New York
Stickland MK, Lindinger MI, Olfert IM, Heigenhauser GJF, Hopkins SR (2013) Pulmonary gas exchange and acid-base balance during exercise. Compr Physiol (3):693–739
Szczesna-Kaczmarek A, Litwinska D, Popinigis J (1984) Oxidation of NADH via an “external” pathway in skeletal -muscle mitochondria and its possible role in the repayment of lactacid oxygen debt. Int J Biochem 16(12):1231–1235
Tang F, Lane S, Korsak A, Paton JFR, Gourine AV, Kasparov S, Teschemacher AG (2014) Lactate-mediated glia-neuronal signalling in the mammalian brain. Nat Commun 5:3284. https://doi.org/10.1038/ncomms4284
Taylor EB (2017) Functional properties of the mitochondrial carrier system. Trends Cell Biol 27(9):633–644
Tenhunen JJ, Jakob SM, Takala JA (2001) Gut luminal lactate release during gradual intestinal ischemia. Intensive Care Med 27(12):1916–1922
The History of Cancer (2002) https://www.cancer.org/cancer/cancer-basics/history-of-cancer.html. Accessed 9 Jan 2018
Thomas C, Bishop DJ, Lambert K, Mercier J, Brooks GA (2012) Effects of acute and chronic exercise on sarcolemmal MCT1 and MCT4 contents in human skeletal muscles: current status. Am J Physiol Integr Comp Physiol 302(1):R1–R14
Thornburg JM, Nelson KK, Clem BF, Lane AN, Arumugam S, Simmons A, Eaton JW, Telang S, Chesney J (2008) Targeting aspartate aminotransferase in breast cancer. Breast Cancer Res 10(5):R84–R84. https://doi.org/10.1186/bcr2154
Tonouchi M, Hatta H, Bonen A (2002) Muscle contraction increases lactate transport while reducing sarcolemmal MCT4, but not MCT1. Am J Physiol Endocrinol Metab 282(5):E1062–E1069
Trzeciak S, McCoy JV, Dellinger RP, Arnold RC, Rizzuto M, Abate NL, Shapiro NI, Parrillo JE, Hollenberg SM (2008) Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med 34(12):2210–2217
Tsacopoulos M (2002) Metabolic signaling between neurons and glial cells: a short review. J Physiol (Paris) 96(3):283–288
Tsai S-F, Chen P-C, Calkins MJ, Wu S-Y, Kuo Y-M (2016) Exercise counteracts aging-related memory impairment: a potential role for the astrocytic metabolic shuttle. Front Aging Neurosci 8:57. https://doi.org/10.3389/fnagi.2016.00057
Twentyman OP, Disley A, Gribbin HR, Alberti KG, Tattersfield AE (1981) Effect of beta-adrenergic blockade on respiratory and metabolic responses to exercise. J Appl Physiol 51(4):788–793
Ugrumov MV (2009) Non-dopaminergic neurons partly expressing dopaminergic phenotype: distribution in the brain, development and functional significance. J Chem Neuroanat 38(4):241–256
Ullah MS, Davies AJ, Halestrap AP (2006) The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1 α -dependent mechanism. J Biol Chem 281(14):9030–9037. https://doi.org/10.1074/jbc.M511397200
Unkefer CJ, Blazer RM, London RE (1983) In vivo determination of the pyridine nucleotide reduction charge by carbon-13 nuclear magnetic resonance spectroscopy. Science 222(4619):62–65
Valenti D, di Bari L, Atlante A, Passarella S (2002) l-Lactate transport into rat heart mitochondria and reconstruction of the l-lactate/pyruvate shuttle. Biochem J 364(1):101–104
Van Hall G (2000) Lactate as a fuel for mitochondrial respiration. Acta Physiol Scand 168(4):643–656
Van Hall G, Jensen-Urstad M, Rosdahl H, Holmberg HC, Saltin B, Calbet JAL (2003) Leg and arm lactate and substrate kinetics during exercise. Am J Physiol Endocrinol Metab 284(1):E193–E205
Vander Heiden MG (2011) Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 10(9):671–684
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 324(5930):1029–1033
Vanderthommen M, Duteil S, Wary C, Raynaud J-S, Leroy-Willig A, Crielaard J-M, Carlier PG (2003) A comparison of voluntary and electrically induced contractions by interleaved 1H- and 31P-NMRS in humans. J Appl Physiol 94(3):1012–1024
Venkatesan M, Smith RP, Balasubramanian S, Khan A, Uzoigwe CE, Coats TJ, Godsiff S (2015) Serum lactate as a marker of mortality in patients with hip fracture: a prospective study. Injury 46(11):2201–2205
Vogel JA, Gleser MA (1972) Effect of carbon monoxide on oxygen transport during exercise. J Appl Physiol 32(2):234–239
von Liebig J (1847) Recherches de chimie animale. CR Hebdom Seances Acad Sci 24:69–73
von Muralt A (1950) The development of muscle-chemistry, a lesson in neurophysiology. Biochim Biophys Acta 4:126–129
von Euler H, Myrbäck K, Karlsson S (1925) Enzymatischer Abbau und Aufbau der Kohlehydrate. I. Phosphatumsatz und Glykogenspaltung in Muskel und Hefe. Hoppe-Seyler´s Zeitschrift für physiologische Chemie 143(4–6):243–264
Voter WA, Gayeski TE (1995) Determination of myoglobin saturation of frozen specimens using a reflecting cryospectrophotometer. Am J Physiol Heart Circ Physiol 269(4):H1328–H1341
Wang J, Wang H, Liu A, Fang C, Hao J, Wang Z (2015) Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer. Oncotarget 6(23):19456–19468
Warburg O (1926) Über den Stoffwechsel der Tumoren. Arbeiten aus dem Kaiser Wilhelm-Institut für Biologie - Berlin-Dahlem Julius Springer, Berlin
Warburg O, Minami S (1923) Versuche an überlebendem carcinomgewebe. Klin Wochenschr 2(17):776–777. https://doi.org/10.1007/BF01712130
Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8(6):519–530
Wasserman K (1984) The anaerobic threshold measurement to evaluate exercise performance. Am Rev Respir Dis 129(2P2):S35–S40
Wasserman K, Koike A (1992) Is the anaerobic threshold truly anaerobic? Chest 101(5):211S–218S. https://doi.org/10.1378/chest.101.5_Supplement.211S
Wasserman K, McIlroy MB (1964) Detecting the threshold of anaerobic metabolism in cardiac patients during exercise. Am J Cardiol 14(6):844–852
Wasserman K, Van Kessel AL, Burton GG (1967) Interaction of physiological mechanisms during exercise. J Appl Physiol 22(1):71–85
Wasserman K, Whipp BJ, Koyl SN, Beaver WL (1973) Anaerobic threshold and respiratory gas exchange during exercise. J Appl Physiol 35(2):236–243
Wasserman K, Beaver WL, Whipp BJ (1986) Mechanisms and patterns of blood lactate increase during exercise in man. Med Sci Sports Exerc 18(3):344–352
Welch HG, Stainsby WN (1967) Oxygen debt in contracting dog skeletal muscle in situ. Respir Physiol 3(2):229–242. https://doi.org/10.1016/0034-5687(67)90013-8
West JB (2014) Carl Wilhelm Scheele, the discoverer of oxygen, and a very productive chemist. Am J Physiol Lung Cell Mol Physiol 307(11):L811–L816
Westerblad H (2016) Acidosis is not a significant cause of skeletal muscle fatigue. Med Sci Sports Exerc 48(11):2339–2342
Westerblad H, Allen DG (1992) Changes of intracellular pH due to repetitive stimulation of single fibres from mouse skeletal muscle. J Physiol 449(1):49–71
Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, Birbe R, Howell A, Pavlides S, Gandara R, Pestell RG, Sotgia F, Philp NJ, Lisanti MP (2011) Evidence for a stromal-epithelial “lactate shuttle” in human tumors. Cell Cycle 10(11):1772–1783. https://doi.org/10.4161/cc.10.11.15659
Williams TI, Moyer AE (1982) A biographical dictionary of scientists, 3rd edn, vol 2. Wiley, New York
Williamson DH, Lund P, Krebs Ha (1967) The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem J 103(2):514–527. https://doi.org/10.1042/bj1030514
Wilson DF (1994) Factors affecting the rate and energetics of mitochondrial oxidative phosphorylation. Med Sci Sports Exerc 26(1):37–43
Wilson DF, Owen CS, Erecińska M (1979) Quantitative dependence of mitochondrial oxidative phosphorylation on oxygen concentration: a mathematical model. Arch Biochem Biophys 195(2):494–504. https://doi.org/10.1016/0003-9861(79)90376-X
Wilson DF, Rumsey WL, Green TJ, Vanderkooi JM (1988) The oxygen dependence of mitochondrial oxidative phosphorylation measured by a new optical method for measuring oxygen concentration. J Biol Chem 263(6):2712–2718
Wislicenus J (1873) Ueber die optisch-active Milchsäure der Fleischflussigkeit, die Paramilchsäure. Justus Liebigs Ann Chem 167:302–346
Witkiewicz AK, Whitaker-Menezes D, Dasgupta A, Philp NJ, Lin Z, Gandara R, Sneddon S, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2012) Using the “reverse Warburg effect” to identify high-risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell cycle 11(6):1108–1117
Wood SM, Wiesener MS, Yeates KM, Okada N, Pugh CW, Maxwell PH, Ratcliffe PJ (1998) Selection and analysis of a mutant cell line defective in the hypoxia-inducible factor-1 α-subunit (HIF-1α) characterization of HIF-1α-dependent and independent hypoxia inducible gene expression. J Biol Chem 273(14):8360–8368
Woodson RD, Wills RE, Lenfant C (1978) Effect of acute and established anemia on O2 transport at rest, submaximal and maximal work. J Appl Physiol 44(1):36–43
Wyatt HL, Da Luz PL, Waters DD, Swan HJ, Forrester JS (1977) Contrasting influences of alterations in ventricular preload and afterload upon systemic hemodynamics, function, and metabolism of ischemic myocardium. Circulation 55(2):318–324
Yates JW, Gladden LB, Cresanta MK (1983) Effects of prior dynamic leg exercise on static effort of the elbow flexors. J Appl Physiol 55(3):891–896
Yeh MP, Gardner RM, Adams TD, Yanowitz FG, Crapo RO (1983) “Anaerobic threshold”:problems of determination and validation. J Appl Physiol 55(4):1178–1186
Ying W (2008) NAD+/NADH and NADP+/NADPH in cellular functions and cell Death: regulation and biological consequences. Antioxid Redox Signal 10(2):179–206. https://doi.org/10.1089/ars.2007.1672
Yoshida Y, Holloway GP, Ljubicic V, Hatta H, Spriet LL, Hood DA, Bonen A (2007) Negligible direct lactate oxidation in subsarcolemmal and intermyofibrillar mitochondria obtained from red and white rat skeletal muscle. J Physiol 582(Pt 3):1317–1335. https://doi.org/10.1113/jphysiol.2007.135095
Zeuthen T, Hamann S, la Cour M (1996) Cotransport of H+, lactate and H2O by membrane proteins in retinal pigment epithelium of bullfrog. J Physiol 497(1):3–17
Zoli M, Agnati LF (1996) Wiring and volume transmission in the central nervous system: the concept of closed and open synapses. Prog Neurobiol 49(4):363–380
Zuntz VN (1911) Umsatz der nahrstoffe. XI. Betrachtungen uber die beziehungen zwischen nahrstoffen und leistungen des korpers. In: Oppenheimer K (ed) Handbuch der Biochemie des Menschen und der Tiere. pp 826–855
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
There are no conflicts of interest.
Additional information
Communicated by Michael Lindinger.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00421-017-3795-6