Lactate as a Cardiovascular Exerkine: Mechanisms, Signaling Pathways, and Clinical Implications

Lactate was traditionally considered a metabolic by-product of anaerobic glycolysis, mainly associated with tissue hypoxia and muscle fatigue. However, increasing evidence has redefined lactate as a multifunctional metabolic intermediate and signaling molecule involved in exercise-induced systemic adaptations. During physical activity, circulating lactate levels rise markedly when skeletal muscle production exceeds systemic clearance, allowing lactate to act as an exercise-responsive metabolite, or exerkine, and as a mediator of cardiometabolic adaptation. In the cardiovascular system, lactate serves not only as an efficient substrate for myocardial energy production but also as a regulator of vascular tone, endothelial function, angiogenesis, inflammation, and cardiac remodeling. These effects occur through receptor-dependent and receptor-independent mechanisms, including activation of hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), modulation of intracellular redox balance, and histone or non-histone protein lactylation. This review summarizes current evidence on lactate in cardiovascular physiology and disease, focusing on myocardial lactate metabolism, HCAR1/GPR81 signaling, protein lactylation, extracellular vesicle communication, gut microbiota interactions, and therapeutic implications in heart failure, atherosclerosis, and diabetic cardiomyopathy. Although lactate is also produced under resting, postprandial, and pathological conditions, exercise is characterized by the amplitude and kinetics of lactatemia, coordinated hormonal and hemodynamic responses, and transient high-concentration signaling. These features support exercise-derived lactate as a context-dependent cardiovascular exerkine.