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Review
. 2022 Jul 30;19(1):52.
doi: 10.1186/s12986-022-00687-z.

The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule

Xiangli Xue  1   2 , Beibei Liu  1   3 , Jingyun Hu  1 , Xuepeng Bian  1 , Shujie Lou  4   5
Affiliations
Review

The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule

Xiangli Xue et al. Nutr Metab (Lond). .

Abstract

Lactate has previously been considered a metabolic waste and is mainly involved in exercise-induced fatigue. However, recent studies have found that lactate may be a mediator of the beneficial effects of exercise on brain health. Lactate plays a dual role as an energy supply substrate and a signaling molecule in this process. On the one hand, astrocytes can uptake circulating glucose or degrade glycogen for glycolysis to produce lactate, which is released into the extracellular space. Neurons can uptake extracellular lactate as an important supplement to their energy metabolism substrates, to meet the demand for large amounts of energy when synaptic activity is enhanced. Thus, synaptic activity and energy transfer show tight metabolic coupling. On the other hand, lactate acts as a signaling molecule to activate downstream signaling transduction pathways by specific receptors, inducing the expression of immediate early genes and cerebral angiogenesis. Moderate to high-intensity exercise not only increases lactate production and accumulation in muscle and blood but also promotes the uptake of skeletal muscle-derived lactate by the brain and enhances aerobic glycolysis to increase brain-derived lactate production. Furthermore, exercise regulates the expression or activity of transporters and enzymes involved in the astrocyte-neuron lactate shuttle to maintain the efficiency of this process; exercise also activates lactate receptor HCAR1, thus affecting brain plasticity. Rethinking the role of lactate in cognitive function and the regulatory effect of exercise is the main focus and highlights of the review. This may enrich the theoretical basis of lactate-related to promote brain health during exercise, and provide new perspectives for promoting a healthy aging strategy.

Keywords: Astrocyte-neuron metabolic coupling; Cognitive function; Exercise intervention; Lactate receptor HCAR1/GPR81; Lactate shuttle.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic diagram of astrocyte-neuron lactate shuttle (ANLS). ACoA, acetyl-CoA; EAAT, Excitatory amino acid transporter; HK, Hexokinase; Gln, Glutamine; GLS, Glutaminase; GLUT, Glucose transporter; GlyP, Glycogen phosphorylase; GlyS, Glycogen synthase; GS, Glutamate synthase; LDH, Lactate dehydrogenase; MCT, Monocarboxylic acid transporters; PDH, Pyruvate dehydrogenase; PFK, Phosphofructokinase; PKM1, Pyruvate kinase M1; PKM2, Pyruvate kinase M2; TCA cycle, Tricarboxylic acid cycle
Fig. 2
Fig. 2
Putative mechanisms of lactate as a signal molecule to regulate cognition. ATP, Adenosine triphosphate; BDNF, Brain-derived neurotrophic factor; cAMP, Cyclic adenosine mono-phosphate; CREB, Cyclic AMP-responsive element-binding protein; ERK, Extracellular regulated protein kinases; Gi, Inhibitory adenylate cyclase G protein; GPR81, G protein-coupled receptor 81; HCAR1, Hydroxycarboxylic acid receptor 1; NLRP3, NLR family pyrin domain containing 3; NMDAR, N-methyl-D-aspartic acid receptor; PKA, Protein kinase A; VEGFA, Vascular Endothelial Growth Factor A; VGF, VGF nerve growth factor inducible
Fig. 3
Fig. 3
Exercise increases brain lactate levels in two ways, including central brain-derived and peripheral skeletal muscle-derived. GLUT 1, Glucose transporter 1; MCT, Monocarboxylic acid transporter
See this image and copyright information in PMC

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References

    1. Brooks GA. Lactate: glycolytic end product and oxidative substrate during sustained exercise in mammals—the ‘lactate shuttle’. In: Gilles R, editor. Circulation, Respiration, and Metabolism: Current Comparative Approaches. Berlin: Springer-Verlag Press; 1985. pp. 208–218.
    1. Brooks GA. Mammalian fuel utilization during sustained exercise. Comp Biochem Physiol. 1998;120:89–107. doi: 10.1016/S0305-0491(98)00025-X. - DOI - PubMed
    1. Todd JJ. Lactate: valuable for physical performance and maintenance of brain function during exercise. Biosci Horizons. 2014;7:hzu001–hzu001. doi: 10.1093/biohorizons/hzu001. - DOI
    1. Harris RA, Lone A, Lim H, Martinez F, Frame AK, Scholl TJ, et al. Aerobic glycolysis is required for spatial memory acquisition but not memory retrieval in mice. eNeuro. 2018 doi: 10.1523/ENEURO.0389-18.2019. - DOI - PMC - PubMed
    1. Belanger M, Allaman I, Magistretti PJ. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 2011;14:724–738. doi: 10.1016/j.cmet.2011.08.016. - DOI - PubMed

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