DOI QR코드

DOI QR Code

Lactate: a multifunctional signaling molecule

  • Lee, Tae-Yoon (Department of Microbiology, Yeungnam University College of Medicine)
  • Received : 2020.12.22
  • Accepted : 2021.01.25
  • Published : 2021.07.31

Abstract

Since its discovery in 1780, lactate has long been misunderstood as a waste by-product of anaerobic glycolysis with multiple deleterious effects. Owing to the lactate shuttle concept introduced in the early 1980s, a paradigm shift began to occur. Increasing evidence indicates that lactate is a coordinator of whole-body metabolism. Lactate is not only a readily accessible fuel that is shuttled throughout the body but also a metabolic buffer that bridges glycolysis and oxidative phosphorylation between cells and intracellular compartments. Lactate also acts as a multifunctional signaling molecule through receptors expressed in various cells and tissues, resulting in diverse biological consequences including decreased lipolysis, immune regulation, anti-inflammation, wound healing, and enhanced exercise performance in association with the gut microbiome. Furthermore, lactate contributes to epigenetic gene regulation by lactylating lysine residues of histones, accounting for its key role in immune modulation and maintenance of homeostasis.

Keywords

References

  1. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell 2008;134:703-7. https://doi.org/10.1016/j.cell.2008.08.021
  2. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009;324:1029-33. https://doi.org/10.1126/science.1160809
  3. Warburg O, Minami S. Versuche an uberlebendem carcinom-gewebe. Klin Wochenschr 1923;2:776-7. https://doi.org/10.1007/BF01712130
  4. Warburg O. On the origin of cancer cells. Science 1956;123: 309-14. https://doi.org/10.1126/science.123.3191.309
  5. Ferguson BS, Rogatzki MJ, Goodwin ML, Kane DA, Rightmire Z, Gladden LB. Lactate metabolism: historical context, prior misinterpretations, and current understanding. Eur J Appl Physiol 2018;118:691-728. https://doi.org/10.1007/s00421-017-3795-6
  6. Hasegawa H, Fukushima T, Lee JA, Tsukamoto K, Moriya K, Ono Y, et al. 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 2003;377:886-91. https://doi.org/10.1007/s00216-003-2108-6
  7. Connor H, Woods HF. Quantitative aspects of L(+)-lactate metabolism in human beings. Ciba Found Symp 1982;87:214-34.
  8. Gladden LB. Lactate metabolism: a new paradigm for the third millennium. J Physiol 2004;558:5-30. https://doi.org/10.1113/jphysiol.2003.058701
  9. de la Cruz-Lopez KG, Castro-Munoz LJ, Reyes-Hernandez DO, Garcia-Carranca A, Manzo-Merino J. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front Oncol 2019;9:1143. https://doi.org/10.3389/fonc.2019.01143
  10. Valvona CJ, Fillmore HL, Nunn PB, Pilkington GJ. The regulation and function of lactate dehydrogenase a: therapeutic potential in brain tumor. Brain Pathol 2016;26:3-17. https://doi.org/10.1111/bpa.12299
  11. Fletcher WM. Lactic acid in amphibian muscle. J Physiol 1907; 35:247-309. https://doi.org/10.1113/jphysiol.1907.sp001194
  12. Hill AV, Long CN, Lupton H. Muscular exercise, lactic acid, and the supply and utilisation of oxygen. Proc R Soc Lond B Contain Pap Biol Character 1924;97:84-138.
  13. Meyerhof O. The chemistry of muscular contraction. Lancet 1930;216:1415-22. https://doi.org/10.1016/S0140-6736(00)90497-5
  14. Wasserman K. The anaerobic threshold measurement to evaluate exercise performance. Am Rev Respir Dis 1984;129(2 Pt 2):S35-40. https://doi.org/10.1164/arrd.1984.129.2P2.S35
  15. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care 2014;18:503. https://doi.org/10.1186/s13054-014-0503-3
  16. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med 2014;371: 2309-19. https://doi.org/10.1056/NEJMra1309483
  17. Robergs RA, Ghiasvand F, Parker D. Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Regul Integr Comp Physiol 2004;287:R502-16. https://doi.org/10.1152/ajpregu.00114.2004
  18. Feher JJ. Quantitative human physiology: an introduction. 2.9 - ATP production I: glycolysis. 2nd ed. International: Elsevier Science Publishing; 2016. p. 171-9.
  19. Argiles A, Mourad G, Mion C, Atkins RC, Haiech J. Kidney, proteins and drugs. In: Bianchi C, Bocci V, Carone FA, Rabkin R, editors. 6th International Symposium on Nephrology, Montecatini Terme. Basel: Karger; 1990. p. 1-8.
  20. Levraut J, Ciebiera JP, Jambou P, Ichai C, Labib Y, Grimaud D. Effect of continuous venovenous hemofiltration with dialysis on lactate clearance in critically ill patients. Crit Care Med 1997; 25:58-62. https://doi.org/10.1097/00003246-199701000-00013
  21. Cori CF, Cori GT. The carbohydrate metabolism of tumors. J Biol Chem 1925;65:397-405. https://doi.org/10.1016/S0021-9258(18)84849-9
  22. Consoli A, Nurjhan N, Reilly JJ Jr, Bier DM, Gerich JE. Contribution of liver and skeletal muscle to alanine and lactate metabolism in humans. Am J Physiol 1990;259:E677-84.
  23. Miller BF, Fattor JA, Jacobs KA, Horning MA, Navazio F, Lindinger MI, et al. Lactate and glucose interactions during rest and exercise in men: effect of exogenous lactate infusion. J Physiol 2002;544:963-75. https://doi.org/10.1113/jphysiol.2002.027128
  24. Brooks GA. Lactate: glycolytic end product and oxidative substrate during sustained exercise in mammals - the "lactate shuttle". In: Gilles R, editor. Comparative physiology and biochemistry: current topics and trends. Vol. A. Respiration-metabolism-circulation. Berlin: Springer-Verlag; 1985. p. 208-18.
  25. Brooks GA. Anaerobic threshold: review of the concept and directions for future research. Med Sci Sports Exerc 1985;17:22-34.
  26. Brooks GA. Lactate production under fully aerobic conditions: the lactate shuttle during rest and exercise. Fed Proc 1986;45: 2924-9.
  27. Brooks GA. Lactate shuttles in nature. Biochem Soc Trans 2002;30:258-64. https://doi.org/10.1042/bst0300258
  28. Boussouar F, Benahmed M. Lactate and energy metabolism in male germ cells. Trends Endocrinol Metab 2004;15:345-50. https://doi.org/10.1016/j.tem.2004.07.003
  29. Ahmed K, Tunaru S, Tang C, Muller M, Gille A, Sassmann A, et al. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab 2010;11:311-9. https://doi.org/10.1016/j.cmet.2010.02.012
  30. Liu L, MacKenzie KR, Putluri N, Maletic-Savatic M, Bellen HJ. The glia-neuron lactate shuttle and elevated ROS promote lipid synthesis in neurons and lipid droplet accumulation in glia via APOE/D. Cell Metab 2017;26:719-37. https://doi.org/10.1016/j.cmet.2017.08.024
  31. Johnson ML, Hussien R, Horning MA, Brooks GA. Transpulmonary pyruvate kinetics. Am J Physiol Regul Integr Comp Physiol 2011;301:R769-74. https://doi.org/10.1152/ajpregu.00206.2011
  32. Brooks GA. The science and translation of lactate shuttle theory. Cell Metab 2018;27:757-85. https://doi.org/10.1016/j.cmet.2018.03.008
  33. Brooks GA. Lactate as a fulcrum of metabolism. Redox Biol 2020;35:101454. https://doi.org/10.1016/j.redox.2020.101454
  34. Mazzeo RS, Brooks GA, Schoeller DA, Budinger TF. Disposal of blood [1-13C]lactate in humans during rest and exercise. J Appl Physiol (1985) 1986;60:232-41. https://doi.org/10.1152/jappl.1986.60.1.232
  35. Hashimoto T, Hussien R, Brooks GA. 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 2006;290:E1237-44. https://doi.org/10.1152/ajpendo.00594.2005
  36. Stanley WC. Myocardial lactate metabolism during exercise. Med Sci Sports Exerc 1991;23:920-4. https://doi.org/10.1249/00005768-199108000-00006
  37. van Hall G. Lactate kinetics in human tissues at rest and during exercise. Acta Physiol (Oxf) 2010;199:499-508. https://doi.org/10.1111/j.1748-1716.2010.02122.x
  38. Pellerin L, Pellegri G, Bittar PG, Charnay Y, Bouras C, Martin JL, et al. Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev Neurosci 1998;20: 291-9. https://doi.org/10.1159/000017324
  39. Sun S, Li H, Chen J, Qian Q. Lactic acid: no longer an inert and end-product of glycolysis. Physiology (Bethesda) 2017;32: 453-63. https://doi.org/10.1152/physiol.00016.2017
  40. Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 1999;343 Pt 2:281-99. https://doi.org/10.1042/bj3430281
  41. Srinivas SR, Gopal E, Zhuang L, Itagaki S, Martin PM, Fei YJ, et al. Cloning and functional identification of slc5a12 as a sodium-coupled low-affinity transporter for monocarboxylates (SMCT2). Biochem J 2005;392:655-64. https://doi.org/10.1042/BJ20050927
  42. Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D'Acquisto F, et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol 2015;13:e1002202. https://doi.org/10.1371/journal.pbio.1002202
  43. Liu C, Kuei C, Zhu J, Yu J, Zhang L, Shih A, et al. 3,5-Dihydroxybenzoic acid, a specific agonist for hydroxycarboxylic acid 1, inhibits lipolysis in adipocytes. J Pharmacol Exp Ther 2012; 341:794-801. https://doi.org/10.1124/jpet.112.192799
  44. de Castro Abrantes H, Briquet M, Schmuziger C, Restivo L, Puyal J, Rosenberg N, et al. The lactate receptor HCAR1 modulates neuronal network activity through the activation of Gα and Gβγ subunits. J Neurosci 2019;39:4422-33. https://doi.org/10.1523/JNEUROSCI.2092-18.2019
  45. Ohno Y, Oyama A, Kaneko H, Egawa T, Yokoyama S, Sugiura T, et al. Lactate increases myotube diameter via activation of MEK/ERK pathway in C2C12 cells. Acta Physiol (Oxf) 2018;223:e13042. https://doi.org/10.1111/apha.13042
  46. Roland CL, Arumugam T, Deng D, Liu SH, Philip B, Gomez S, et al. Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Res 2014;74:5301-10. https://doi.org/10.1158/0008-5472.CAN-14-0319
  47. Harun-Or-Rashid M, Inman DM. Reduced AMPK activation and increased HCAR activation drive anti-inflammatory response and neuroprotection in glaucoma. J Neuroinflammation 2018;15:313. https://doi.org/10.1186/s12974-018-1346-7
  48. Hoque R, Farooq A, Ghani A, Gorelick F, Mehal WZ. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology 2014;146: 1763-74. https://doi.org/10.1053/j.gastro.2014.03.014
  49. Brown TP, Ganapathy V. Lactate/GPR81 signaling and proton motive force in cancer: role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther 2020; 206:107451. https://doi.org/10.1016/j.pharmthera.2019.107451
  50. Langin D. Adipose tissue lipolysis revisited (again!): lactate involvement in insulin antilipolytic action. Cell Metab 2010;11: 242-3. https://doi.org/10.1016/j.cmet.2010.03.003
  51. Liu C, Wu J, Zhu J, Kuei C, Yu J, Shelton J, et al. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J Biol Chem 2009;284:2811-22. https://doi.org/10.1074/jbc.M806409200
  52. Khatib-Massalha E, Bhattacharya S, Massalha H, Biram A, Golan K, Kollet O, et al. Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling. Nat Commun 2020;11:3547. https://doi.org/10.1038/s41467-020-17402-2
  53. Hu J, Cai M, Liu Y, Liu B, Xue X, Ji R, et al. The roles of GRP81 as a metabolic sensor and inflammatory mediator. J Cell Physiol 2020;235:8938-50. https://doi.org/10.1002/jcp.29739
  54. Otto AM. Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism. Cancer Metab 2016;4:5. https://doi.org/10.1186/s40170-016-0145-9
  55. Racker E. Bioenergetics and the problem of tumor growth. Am Sci 1972;60:56-63.
  56. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 2007;11:37-51. https://doi.org/10.1016/j.ccr.2006.10.020
  57. DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab 2020;2:127-9. https://doi.org/10.1038/s42255-020-0172-2
  58. Semenza GL, Wang GL. 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 1992;12:5447-54. https://doi.org/10.1128/MCB.12.12.5447
  59. Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 2009;8:3984-4001. https://doi.org/10.4161/cc.8.23.10238
  60. De Saedeleer CJ, Copetti T, Porporato PE, Verrax J, Feron O, Sonveaux P. Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One 2012;7:e46571. https://doi.org/10.1371/journal.pone.0046571
  61. Ali MA, Konishi T. Enhancement of hydroxyl radical generation in the Fenton reaction by alpha-hydroxy acid. Biochem Mol Biol Int 1998;46:137-45.
  62. Kozlov AM, Lone A, Betts DH, Cumming RC. Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts. Sci Rep 2020;10:8388. https://doi.org/10.1038/s41598-020-65193-9
  63. Luo W, Semenza GL. Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget 2011;2:551-6. https://doi.org/10.18632/oncotarget.299
  64. Hayashi Y, Yokota A, Harada H, Huang G. Hypoxia/pseudohypoxia-mediated activation of hypoxia-inducible factor-1α in cancer. Cancer Sci 2019;110:1510-7. https://doi.org/10.1111/cas.13990
  65. Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O'Sullivan D, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013;153:1239-51. https://doi.org/10.1016/j.cell.2013.05.016
  66. Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 2016;354:481-4. https://doi.org/10.1126/science.aaf6284
  67. Nolt B, Tu F, Wang X, Ha T, Winter R, Williams DL, et al. Lactate and Immunosuppression in Sepsis. Shock 2018;49:120-5. https://doi.org/10.1097/SHK.0000000000000958
  68. Pucino V, Bombardieri M, Pitzalis C, Mauro C. Lactate at the crossroads of metabolism, inflammation, and autoimmunity. Eur J Immunol 2017;47:14-21. https://doi.org/10.1002/eji.201646477
  69. Hirschhaeuser F, Sattler UG, Mueller-Klieser W. Lactate: a metabolic key player in cancer. Cancer Res 2011;71:6921-5. https://doi.org/10.1158/0008-5472.CAN-11-1457
  70. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013;13:862-74. https://doi.org/10.1038/nri3552
  71. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 2013;13:260-8. https://doi.org/10.1016/S1473-3099(13)70001-X
  72. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007;109:3812-9. https://doi.org/10.1182/blood-2006-07-035972
  73. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 2011;186:3299-303. https://doi.org/10.4049/jimmunol.1003613
  74. Wenes M, Shang M, Di Matteo M, Goveia J, Martin-Perez R, Serneels J, et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab 2016;24: 701-15. https://doi.org/10.1016/j.cmet.2016.09.008
  75. Certo M, Tsai CH, Pucino V, Ho PC, Mauro C. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat Rev Immunol 2021;21:151-61. https://doi.org/10.1038/s41577-020-0406-2
  76. Nasi A, Rethi B. Disarmed by density: a glycolytic break for immunostimulatory dendritic cells? Oncoimmunology 2013; 2:e26744. https://doi.org/10.4161/onci.26744
  77. Gottfried E, Kunz-Schughart LA, Ebner S, Mueller-Klieser W, Hoves S, Andreesen R, et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 2006;107:2013-21. https://doi.org/10.1182/blood-2005-05-1795
  78. Kelly B, O'Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 2015;25:771-84. https://doi.org/10.1038/cr.2015.68
  79. Schlee M, Hartmann G. Discriminating self from non-self in nucleic acid sensing. Nat Rev Immunol 2016;16:566-80. https://doi.org/10.1038/nri.2016.78
  80. Ivashkiv LB. The hypoxia-lactate axis tempers inflammation. Nat Rev Immunol 2020;20:85-6. https://doi.org/10.1038/s41577-019-0259-8
  81. Yasukawa K, Kinoshita D, Yaku K, Nakagawa T, Koshiba T. The microRNAs miR-302b and miR-372 regulate mitochondrial metabolism via the SLC25A12 transporter, which controls MAVS-mediated antiviral innate immunity. J Biol Chem 2020;295:444-57. https://doi.org/10.1074/jbc.RA119.010511
  82. Zhang W, Wang G, Xu ZG, Tu H, Hu F, Dai J, et al. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 2019;178:176-89. https://doi.org/10.1016/j.cell.2019.05.003
  83. Prakash K, Fournier D. Evidence for the implication of the histone code in building the genome structure. Biosystems 2018; 164:49-59. https://doi.org/10.1016/j.biosystems.2017.11.005
  84. Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature 2019;574:575-80. https://doi.org/10.1038/s41586-019-1678-1
  85. Hunt TK, Conolly WB, Aronson SB, Goldstein P. Anaerobic metabolism and wound healing: an hypothesis for the initiation and cessation of collagen synthesis in wounds. Am J Surg 1978;135:328-32. https://doi.org/10.1016/0002-9610(78)90061-2
  86. Constant JS, Feng JJ, Zabel DD, Yuan H, Suh DY, Scheuenstuhl H, et al. Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia. Wound Repair Regen 2000;8:353-60. https://doi.org/10.1111/j.1524-475X.2000.00353.x
  87. Hunt TK, Aslam RS, Beckert S, Wagner S, Ghani QP, Hussain MZ, et al. Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxid Redox Signal 2007;9:1115-24. https://doi.org/10.1089/ars.2007.1674
  88. Porporato PE, Payen VL, De Saedeleer CJ, Preat V, Thissen JP, Feron O, et al. Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice. Angiogenesis 2012;15:581-92. https://doi.org/10.1007/s10456-012-9282-0
  89. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature 2007; 449:804-10. https://doi.org/10.1038/nature06244
  90. Iraporda C, Errea A, Romanin DE, Cayet D, Pereyra E, Pignataro O, et al. Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells. Immunobiology 2015;220:1161-9. https://doi.org/10.1016/j.imbio.2015.06.004
  91. Iraporda C, Romanin DE, Rumbo M, Garrote GL, Abraham AG. The role of lactate on the immunomodulatory properties of the nonbacterial fraction of kefir. Food Res Int 2014;62:247-53. https://doi.org/10.1016/j.foodres.2014.03.003
  92. Iraporda C, Abatemarco Junior M, Neumann E, Nunes AC, Nicoli JR, Abraham AG, et al. Biological activity of the non-microbial fraction of kefir: antagonism against intestinal pathogens. J Dairy Res 2017;84:339-45. https://doi.org/10.1017/S0022029917000358
  93. Teramae H, Yoshikawa T, Inoue R, Ushida K, Takebe K, Nio-Kobayashi J, et al. The cellular expression of SMCT2 and its comparison with other transporters for monocarboxylates in the mouse digestive tract. Biomed Res 2010;31:239-49. https://doi.org/10.2220/biomedres.31.239
  94. Clarke SF, Murphy EF, O'Sullivan O, Lucey AJ, Humphreys M, Hogan A, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut 2014;63:1913-20. https://doi.org/10.1136/gutjnl-2013-306541
  95. Petersen LM, Bautista EJ, Nguyen H, Hanson BM, Chen L, Lek SH, et al. Community characteristics of the gut microbiomes of competitive cyclists. Microbiome 2017;5:98. https://doi.org/10.1186/s40168-017-0320-4
  96. Scheiman J, Luber JM, Chavkin TA, MacDonald T, Tung A, Pham LD, et al. Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism. Nat Med 2019;25:1104-9. https://doi.org/10.1038/s41591-019-0485-4
  97. Nalos M, Leverve X, Huang S, Weisbrodt L, Parkin R, Seppelt I, et al. Half-molar sodium lactate infusion improves cardiac performance in acute heart failure: a pilot randomised controlled clinical trial. Crit Care 2014;18:R48. https://doi.org/10.1186/cc13793
  98. Tassinari ID, Andrade MKG, da Rosa LA, Hoff ML, Nunes RR, Vogt EL, et al. Lactate administration reduces brain injury and ameliorates behavioral outcomes following neonatal hypoxia-ischemia. Neuroscience 2020;448:191-205. https://doi.org/10.1016/j.neuroscience.2020.09.006
  99. Zhang J, Muri J, Fitzgerald G, Gorski T, Gianni-Barrera R, Masschelein E, et al. Endothelial lactate controls muscle regeneration from ischemia by inducing m2-like macrophage polarization. Cell Metab 2020;31:1136-53. https://doi.org/10.1016/j.cmet.2020.05.004

Cited by

  1. Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer vol.13, pp.16, 2021, https://doi.org/10.3390/cancers13164139
  2. Metabolic orchestration of the wound healing response vol.33, pp.9, 2021, https://doi.org/10.1016/j.cmet.2021.07.017