Lactate: a potential brain‐targeting exerkine

Physical activity and exercise are known to be beneficial with comprehensive physiological benefits for the whole body, though in some conditions such as acute untreated injuries, they may worsen the condition. Even when the mechanisms underlying most disease-causing pathophysiologies were poorly understood, exercise was prescribed as a medical remedy for its physiological, disease-preventive and -modifying, and health-promoting effects. In contrast, physical inactivity or lack of exercise is irrefutably associated with chronic and degenerative diseases, including, but not limited to, type 2 diabetes mellitus, cancer and neurological disorders. It is thought that a major reason for exercise's beneficial effects across multiple organ systems is due to the release of signalling molecules from various tissues in response to acute and/or chronic exercise that exert autocrine, paracrine and endocrine effects, collectively termed 'exerkines' (Chow et al., 2022). Discussion of brain-targeting exerkines and their role in enhancing learning and memory through the upregulation of neurotrophins such as brain-derived neurotrophic factor (BDNF) often focuses on proteins like irisin/FNDC5, cathepsin B and IL6 (Chow et al., 2022). Unfortunately, despite the discovery of lactate secretion from skeletal muscle over 100 years ago, lactate remains underappreciated as a brain-targeting exerkine. This oversight can partly be attributed to the long-standing perception of lactate as a metabolic waste product. It accumulates in muscles during high-intensity exercise when oxygen levels are insufficient for aerobic metabolism, leading to assumptions that it is responsible for muscle fatigue and pain. Additionally, while lactate is continuously released even during the resting state, and its release into the circulation substantially increases with exercise, it is also rapidly cleared from the bloodstream. Another reason for its neglect is that lactate, being a simple three-carbon, small, soluble organic metabolite, has been overlooked because the focus on exerkines has largely centred on proteins. However, in a recent Journal of Physiology article, Moberg et al. (2024) conducted a controlled acute forced treadmill study with mice (n = 10 per group) divided into four groups: (1) sedentary with saline injection, (2) sedentary with lactate injection but no exercise, (3) exercise with saline injection and (4) exercise with oxamate injection. They provide convincing evidence that lactate acts as an exerkine with brain-targeting effects, leading to increased α-secretase (ADAM10) activity in the brains of healthy young (age = 10 weeks) male C57BL/6 mice. Specifically, they demonstrate that (1) a single bout of exercise leads to increased ADAM10 activity in the brain; (2) peripheral injection of lactate without exercise recapitulates changes in brain ADAM10 activity; and (3) peripheral injection of oxamate, which inhibits lactate dehydrogenase from catalysing pyruvate to lactate, opposes these changes. This is the first report to link peripheral lactate release as a brain-targeting exerkine affecting ADAM10 activity. However, there were no changes in β-secretase (BACE1) brain activity due to exercise or peripheral lactate injection, which requires further investigation. To probe improvements in molecular learning and memory pathways, and explore mechanisms for the increased ADAM10 activity, the authors performed immunoblotting of prefrontal cortex (PFC) and hippocampus protein lysates for pro and mature BDNF levels but did not find any differences among the groups. This finding may be attributed to a sex-dimorphic response. Although some studies report increased brain mBDNF and proBDNF levels in response to both voluntary wheel and forced treadmill running, a previous meta-analysis showed that this increase in brain BDNF levels is stronger and more robust in female versus male exercised mice. But it is important to note that the meta-analysis included only two studies focusing on females (Barha et al., 2017). It is likely that these sex-dimorphic responses are also heavily influenced by the type of exercise, duration and intensity, the age of the animals, hormonal status (e.g. oestrogen in female mice), genetic background, environmental conditions and the time of day when the exercise is performed, among other factors, which the meta-analysis did not consider due to the scarcity of available studies. It is also possible that a longer duration of intervention might be necessary to drive significant changes in BDNF transcription and translation, irrespective of sex. The amyloid precursor protein (APP) is a transmembrane protein central to the observed amyloid β (Aβ) plaque accumulation in Alzheimer's disease (AD) due to its aberrant processing. BACE1 plays a detrimental role in this pathway by cleaving APP to produce APP-C99 and soluble APPβ (sAPPβ). APP-C99 is further cleaved and processed into Aβ peptides by γ-secretase. Conversely, ADAM10 is involved in the non-amyloidogenic processing of APP by cleaving within the Aβ domain, precluding the formation of Aβ peptides and promoting the release of neuroprotective sAPPα fragments (Moberg et al., 2024). While Moberg et al. (2024) show that exercise and peripheral lactate administration lead to alterations in ADAM10 dynamics in the brain, APP levels were not changed. Furthermore, although the authors mention using sAPPα and sAPPβ antibodies for immunoblotting in the methods section, they did not include any data on these measurements. Regardless, the lack of changes in APP levels likely suggests that ADAM10 is acting through pathways unrelated to APP processing, implying that sAPPα and sAPPβ levels would likely remain stable. In my opinion, the absence of changes in APP concentrations is to be expected. This is because these experiments were conducted in healthy young mice, which typically do not exhibit aberrant APP processing or Aβ accumulation. Furthermore, although ADAM10 activity is often associated with APP processing, this is not always the case. ADAM10 is believed to exist in different transmembrane protein isoforms and is known to contribute to a plethora of cellular functions, such as the regulation of cell adhesion, modulation of the immune system and the shedding of membrane proteins like notch receptors and growth factors, independent of its effect on APP processing (Dorta et al., 2024). As such, it is likely that exercise- and lactate-induced improvement in ADAM10 brain activity is acting to drive other pathways that benefit the brain. What those pathways are and to what degree they are beneficial remains to be elucidated. One way to test these effects is to perform similar exercise and lactate interventions in aged or transgenic mice with an Aβ-related pathology (e.g. transgenic 5xFAD or 3xTg mice). Moreover, ADAM10 activity should ideally be measured while it remains attached to the intact phospholipid bilayer as a transmembrane protein. This method preserves the natural physiological conditions under which the enzyme operates, rather than testing it after homogenization. Lastly, it would also be interesting to see if the changes observed in ADAM10 brain activity translate to any changes in neurocognitive behaviour. Given the robust peripheral lactate-induced effects on ADAM10 brain activity, it is likely that lactate is the major direct or indirect driver of these changes. Lactate has been indeed shown to be able to cross the blood–brain barrier (BBB) through endothelial monocarboxylate transporters. However, lactate is widely believed to be rapidly cleared from the circulation, as its uptake by a myriad of cells surpasses its release as exercise intensity and duration increases. Furthermore, even if lactate crosses the BBB, it is likely to be rapidly oxidized (Moberg et al., 2024). This situation is further complicated by the ongoing debate in the field regarding the transport of these exerkines through the BBB. Therefore, cell-free lactate is unlikely to survive the long trip from the periphery to the brain to reach its targets without being taken up by cells, metabolically modified or degraded. This raises the question: how can peripheral lactate reach the brain safely? One possible mechanism involves packaging into extracellular vesicles (EVs) – small, bubble-like structures with a phospholipid membrane that cannot replicate, comprising three major types: exosomes, ectosomes and apoptotic bodies. These EVs transport proteins, lipids, carbohydrates, nucleic acids and metabolites such as lactate. They provide a protective shield, preserving the integrity of the biomolecules enclosed within, and preventing their modification or degradation. Due to their lipophilic nature, EVs can easily traverse the BBB. Additionally, exercise has been shown to increase the release and packaging of exerkines into EVs in both humans and rodents (Nederveen et al., 2020). However, there are no rodent or human studies evaluating lactate in EVs following an acute, intense exercise bout. Could lactate be preferentially packaged into EVs for delivery to the brain, and if so, from which specific cells? To explore this hypothesis, future work could isolate general EVs using methods such as ultracentrifugation and size-exclusion chromatography or cell-specific EVs by incubating general EVs with beads conjugated to specific antibodies shortly after the exercise bout or after a peripheral lactate injection. Then lactate concentration within these EVs can be quantified. In summary, Moberg et al. (2024) provide robust evidence supporting the role of lactate as a brain-targeting exerkine, demonstrating for the first time that increased lactate levels, whether due to an acute exercise bout or peripheral injection, are capable of altering ADAM10 activity in the PFC and hippocampi of healthy male C57BL/6 mice. Future research should include female mice to assess sex-dimorphic responses, examine age-related effects and determine if these changes can be replicated in longitudinal exercise models. Future efforts should also explore other pathways associated with ADAM10's increased activity, validate these findings in disease-relevant models with amyloid pathology, such as 5xFAD and 3xTg mice and investigate the mechanisms by which lactate travels to the brain, possibly involving EVs. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare no conflict of interest. H.B.T. conceptualized and wrote the manuscript. None.