Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism

George A. Brooks, Adam D. Osmond, Jose A. Arevalo, Justin J. Duong, Casey C. Curl, Diana D. Moreno-Santillan, Robert G. Leija

No longer viewed as a metabolic waste product and cause of muscle fatigue, a contemporary view incorporates the roles of lactate in metabolism, sensing and signaling in normal as well as pathophysiological conditions. Lactate exists in millimolar concentrations in muscle, blood and other tissues and can rise more than an order of magnitude as the result of increased production and clearance limitations. Lactate exerts its powerful driver-like influence by mass action, redox change, allosteric binding, and other mechanisms described in this article. Depending on the condition, such as during rest and exercise, following injury, or pathology, lactate can serve as a myokine or exerkine with autocrine-, paracrine-, and endocrine-like functions that have important basic and translational implications. For instance, lactate signaling is: involved in reproductive biology, fueling the heart, muscle and brain, controlling cardiac output and breathing, growth and development, and a treatment for inflammatory conditions. Ironically, lactate can be disruptive of normal processes such as insulin secretion when insertion of lactate transporters into pancreatic Beta-cell membranes is not suppressed and in carcinogenesis. Lactate signaling is important in areas of intermediary metabolism, redox biology, mitochondrial biogenesis, cardiovascular and pulmonary regulation, genomics, neurobiology, gut physiology, appetite regulation, nutrition and overall health and vigor. The various roles of lactate as a myokine and exerkine are reviewed.