Lactate

Lactate is a three-carbon carboxylic acid (the anionic form of lactic acid) that serves as a central metabolite in cellular energy metabolism and a signaling molecule with diverse physiological functions. PMID 36633863PMID 29617642PMID 33566386

Lactate is continuously produced under fully aerobic conditions through glycolysis, not merely as a byproduct of anaerobic metabolism as historically believed. PMID 29617642PMID 33566386PMID 32113910 Its biological roles include:

Energy metabolism: Lactate functions as a major oxidative fuel through the "lactate shuttle" mechanism, where it is transported between producer (driver) and consumer (recipient) cells to fuel mitochondrial respiration. PMID 36633863PMID 29617642PMID 33566386 It also serves as the primary gluconeogenic precursor in the liver. PMID 29617642PMID 32113910

Cellular signaling: Lactate acts as a signaling molecule through multiple mechanisms, including binding to the G-protein coupled receptor HCAR1 (GPR81), modulating cellular redox state via the lactate/pyruvate ratio, and serving as a substrate for lactylation—a post-translational modification of histone and non-histone proteins that regulates gene expression. PMID 36633863PMID 37566665PMID 40073846PMID 41491598

Metabolic regulation: Lactate influences substrate partitioning by inhibiting lipolysis in adipose tissue and regulating mitochondrial fatty acid uptake, thereby controlling the balance between carbohydrate and fat oxidation. PMID 32113910

Lactate is considered both a myokine and an exerkine—molecules secreted by skeletal muscle during contraction that exert autocrine, paracrine, and endocrine effects. PMID 36633863PMID 37842902 The evidence supporting this classification includes:

Lactate concentrations increase substantially during exercise (rising more than 10-fold from resting levels) and mediate exercise-induced adaptations including mitochondrial biogenesis, angiogenesis, improved metabolic flexibility, and enhanced cognitive function. PMID 36633863PMID 33566386 As an exerkine, lactate facilitates communication between skeletal muscle and other organs, particularly the brain, where it may induce BDNF expression through SIRT1/2 and PGC-1α pathways. PMID 37842902 The intensity-dependent production of lactate during exercise, particularly from type IIb fast-twitch muscle fibers, supports its role as an exercise-derived signaling molecule. PMID 37842902

Hypertonic sodium lactate infusions have demonstrated promising therapeutic effects in several clinical settings. In traumatic brain injury, lactate treatment increases cerebral glucose availability, reduces intracranial pressure, and enhances cognitive recovery, while supporting up to 20% of cerebral energy metabolism. PMID 40440417 In cardiac applications, lactate infusion increases cardiac output, stroke volume, and ejection fraction, potentially benefiting heart failure patients. PMID 40440417

In critical care, exogenous lactate—particularly hypertonic sodium lactate (HSL)—improves hemodynamics, reduces inflammation, and enhances organ function in sepsis, acute heart failure, and brain injury. PMID 41137071 The therapeutic mechanisms extend beyond simple energy provision to include anti-inflammatory effects, improved microcirculation, and metabolic homeostasis restoration. PMID 41137071

Lactate functions as both an energy substrate and signaling molecule. It serves as a major energy source for mitochondrial respiration, the major gluconeogenic precursor, and influences gene expression through lactylation of histone proteins. PMID 29617642PMID 41491598 These dual metabolic and signaling roles underpin its therapeutic potential.

Safety data indicate that hypertonic lactate infusions are generally well tolerated, with minor electrolyte changes as the most common side effect. PMID 40440417PMID 35304646 However, large-scale randomized controlled trials are needed to establish optimal dosing, efficacy, and long-term safety profiles before widespread clinical adoption. PMID 41137071PMID 40440417

The therapeutic applications span neonatal hypoxic-ischemic encephalopathy, cerebral ischemia, inflammatory conditions, and metabolic disorders, representing a paradigm shift from viewing lactate solely as a biomarker of poor prognosis to recognizing it as a potential therapeutic agent. PMID 37268250PMID 26036941PMID 36633863PMID 40821941PMID 40075490PMID 41137071