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

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.