The roles of exerkines, factors released from tissues during exercise, in promoting health and longevity were recently addressed in the Review by Chow and colleagues (Chow, L. S. et al. Exerkines in health, resilience and disease. Nat. Rev. Endocrinol. 18, 273–289 (2022)1). However, their timely Review did not adequately describe the major and diverse roles of lactate in regulating metabolism and physiology. Here, we highlight important functions of lactate as an exerkine.
The inevitable product of glycolysis under fully aerobic conditions is lactate2. It is exchanged among intracellular compartments, it is exported from sites of production, it fluxes within the muscular interstitium, and it is distributed to organs and tissues via the systemic circulation. Hence, lactate is a myokine and an exerkine with major signalling attributes.
Glycolysis affects the ratio of lactate to pyruvate, which rises two orders of magnitude or more during exercise. The resulting ratio of NAD+ to NADH, and hence redox change, affects metabolic regulation at the sites of lactate production and disposal. Redox changes have numerous effects on metabolic regulation, including activation of sirtuin 1 and sirtuin 3 (ref.2).
Allosteric binding and inhibition of lipolysis
Activation of the lactate receptor HCAR1 inhibits lipolysis in adipose tissues of rodents, and in humans, lactataemia inhibits lipolysis during exercise and following carbohydrate consumption. Hence, in humans, plasma concentrations of free fatty acids fall during hard exercise (here meaning exercise that results in lactataemia) because of the inhibition of lipolysis by lactate in the circulation2.
Mitochondrial energy substrate utilization
Muscle glycolysis results in the production of malonyl-CoA, which inhibits carnitine palmitoyl transferase 1 (CPT1). Moreover, lactate downregulates CPT2 (ref.2); hence lactate limits mitochondrial fatty acid uptake and oxidation.
Vascular, cardiac and pulmonary regulation
The angiogenesis that occurs with exercise training is mediated by factors such as vascular endothelial growth factor, which is upregulated by lactate5. During exercise, lactate has a dominant role in fuelling the heart2. Importantly, in muscle lactate activates the metaboreflex, thereby participating in regulation of cardiac output during exercise2. And, as seen in mice, lactate upregulates breathing by stimulating the carotid body olfactory receptor OLFR78 (ref.6).
Ghrelin, hunger and appetite
Hunger is regulated in the arcuate nucleus of the hypothalamus. Among the signals affecting the arcuate nucleus is ghrelin; its secretion is attenuated by the effect of lactate on the growth hormone secretagogue receptor 1α in the gastrointestinal tract. In rodents and humans, lactataemia inhibits hunger via an effect on lactate-reduced ghrelin signalling10.
Identifying the roles of myokines and exerkines in promoting metabolic and physiological health is important. Therefore, we offer this commentary as an addition to complement the Review of Chow et al.1. Lactate is the greatest myokine in terms of concentration and dynamic range, and the most diverse in terms of metabolic and physiological regulation.
There is a reply to this letter by Chow, L.S. et al. Nat. Rev. Endocrinol. https://doi.org/10.1038/s41574-022-00726-y (2022).
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The authors declare no competing interests.
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Brooks, G.A., Osmond, A.D., Arevalo, J.A. et al. Lactate as a major myokine and exerkine. Nat Rev Endocrinol (2022). https://doi.org/10.1038/s41574-022-00724-0
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