Lactate metabolism: historical context, prior misinterpretations, and current understanding

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.

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