The anxiolytic effect of exercise: a new role for lactate

Physical exercise is a widely recognized non-pharmacological approach to alleviating anxiety. Studies indicate that exercise restores neural circuits involved in mitigating anxiety, in humans (see here and here) and in animal models (see here and here). Several mechanisms involving various molecules have been proposed in the past, including neurotrophic factors, monoamine neurotransmitters, and neuroinflammatory cytokines. Exercise induces significant changes in several metabolites; however, the potential role of these metabolites in reducing anxiety has long been underestimated. Recent studies have suggested that some of these metabolites can reach the brain where they may have effects on mental function. Among these metabolites are kyurenine, N-lactoyl-phenylalanine (see our article on the subject), and the ketone body beta-hydroxybutyrate.

Lactate has long been considered a metabolic waste product since it is the end product of glycolysis under hypoxic conditions and its production acidifies the surrounding environment. However, recent studies have shown that lactate can not only be used as an energy source, but also participate in many signalling pathways and physiological processes. Indeed, lactate can be used directly to modify certain amino acids in several proteins. This modification, called “lactylation” of proteins, was first identified in histones (proteins that are constituents of chromosomes) and results in changes in gene expression.

Lactate has an antidepressant effect, according to a study published in 2019, but the precise mechanism by which this is achieved remains largely unknown. Recently, a group of Chinese researchers wondered whether cerebral cortex protein lactylation might be involved in the anxiolytic effect of exercise. They used an animal model and proteomic analysis to identify changes in cerebral cortex protein lactylation. The researchers had mice run on a treadmill for 1 hour per day for 14 days and tested to see if this exercise prevented anxiety-like behaviours. After this exercise regimen, lactate was elevated in the bloodstream, but also in the liver, muscle tissue, and prefrontal cortex of the brain.

The researchers then injected mice daily with lactate instead of exercising them. Behavioural tests indicated that while locomotor activity was unaffected, anxiety-like behaviours were significantly attenuated. On the other hand, injection of dichloroacetate, a compound that decreases lactate production in mice, counteracted the anxiolytic effect of exercise. Taken together, these results suggest a critical role for lactate in resilience to exercise stress.

The researchers used a proteomic approach specific to lactylated proteins to identify which proteins are induced by exercise for lactylation. The results indicate that these are synaptic proteins whose lactylation is significantly increased by exercise (or by lactate injection), in particular the synaptic protein SNAP91 (also known as AP180). This protein is involved in the assembly of clathrin-coated vesicles, maintaining the homeostasis of neurotransmitter release by synapses.

The researchers then conducted a series of experiments to establish a causal link between synaptic protein lactylation and improved neuronal function. When SNAP91 lactylation was decreased by expressing a version of SNAP91 with a mutation at the lactylation site, synaptic structure and synaptic transmission function were impaired. Importantly, decreased SNAP91 lactylation significantly reduced the anxiolytic effect of exercise in the mouse model. These results strongly suggest that lactylation of the synaptic protein SNAP91 is necessary for exercise-induced anxiety reduction. The precise molecular mechanism by which SNAP91 lactylation affects synaptic function remains unknown and requires further mechanistic and structural studies.

Lactate, one of the first metabolites produced during exercise to be identified, therefore has not only a metabolic role, but also a role in the transmission of signals from muscles to the brain where it soothes anxiety via the lactylation of synaptic proteins. The benefits of exercise on physical and mental health, via the production of lactate and many other active metabolites, are currently the subject of well-conducted and innovative studies, which continue to shed light on new mechanisms.