Lactate: It's Not What You Think
Lactate has always been thought of as a waste product. Trash. So when it comes up again and again in ME/CFS research what are we to make of it? Lactate is a lot more important than you think. Let’s take a deeper dive.
Where Does Lactate Come From?
Lactate accumulates one of two ways: with the breakdown of glucose (glycolysis) or it is produced when there are low levels of oxygen in the cell (hypoxia). Lactate is produced more from certain types of cells and consumed by other types of cells—lactate givers and takers. There are special shuttles that move lactate to its preferred destination. Lactate is a valuable energy source for various body systems, such as the brain, heart, and skeletal muscle.
Lactate can be converted back into glucose or it can be oxidized to pyruvate which can be used to make cellular energy, ATP. It’s a two-way street. Lactate is best known for exercise. During exercise, the production of lactate helps maintain the acid-base balance of the muscle. With continued exertion, lactate can no longer keep up to maintain acid-base balance, leading to a lowering of pH in the muscle. This is experienced as immediate or next-day soreness. In those who regularly exercise, the body is better able to recycle lactate so it does not linger.
Lactate Has Many Roles
Lactate is traditionally thought of as a waste product but that couldn’t be further from the truth. Not only can it be used to generate ATP, lactate also can interact with other cells as a messenger. Lactate also plays a key role in immune cell function. The surface of immune cells even houses specialized transporters for lactate. When there is inflammation, lactate is shuttled into T cells.
In rheumatoid arthritis, lactate accumulates in the joints during acute exacerbations of joint inflammation. It also interferes with T cells in the joints, essentially trapping them in the joint where they contribute to further localize smoldering inflammation that eventually destroys the joint. Indeed lactate plays a major role in the ability of T cells to be mobile and migrate.
Lactate in the Brain
Lactate produced peripherally in the body can cross into the brain for utilization. During exercise, the uptake of lactate is enhanced. It can be used in the brain as a quick energy source.
Not only can lactate travel to the brain, it is also released by specialized nerve cells (astrocytes) where it again can be used as fuel. The transfer of lactate from astrocytes to neurons is essential for memory formation and helps nerve cells make more connections (neuroplasticity).
Lactate in Fibromyalgia
Elevated lactate levels have been found in the brain of fibromyalgia patients but also in tissue biopsies. A double-blind placebo-controlled trial showed that an anti-depressant drug (read more below) was able to reduce lactate in the brain and this correlated with reductions in pain.
Lactate in Chronic Fatigue Syndrome (ME/CFS)
A study from 2012, showed that lactate was accumulated in the brain ventricles of ME/CFS patients. This was repeated in 2017. Other studies have looked for lactate following an exercise challenge test. Albeit not every study of exercise in ME/CFS has demonstrated abnormal lactate levels. As is the case with many ME/CFS studies, the study designs and selection criteria are likely to blame for such inconclusive results.
A recent study used an even better study design to bring lactate back into the picture. A group of 18 women with ME/CFS (Canadian Consensus Criteria; so PEM was required criteria) were compared to healthy controls during a 2-day exercise bike test. Subjects were put on exercise bikes and pedaled with a gradual increase in resistance for just 8-12 minutes. Blood levels of lactate were measured at various time points. The ME/CFS group showed a spike in lactate early on during the biking. On the second day of exercise testing, they performed worse on the test and also showed large elevations in blood lactate. To compare, the healthy controls had usual elevations in lactate on the first day of exercise, and on the second day had even lower levels suggesting an adaption of improved lactate clearance.
Does Lactate Cause Post-Exertional Malaise (PEM)?
Lactate increases according to the grade of inflammation. The higher the inflammation, the higher the levels of lactate. Could this also equate to the symptom severity of PEM in ME/CFS patients? The more severe the case, the more the lactate, the worse the PEM with exertion.
“Lactate concentrations were 2.8x higher in multiple sclerosis patients than healthy controls...” Does high lactate cause post-exertional malaise? Probably not.”
Taking a step back, realize that lactate is not itself an inflammatory molecule. Instead, it is a stop brake. During inflammation, lactate is produced and has an anti-inflammatory effect. Its function is believed to be the stop brake on preventing excess inflammation.
In ME/CFS, the excess lactate produced after a 2-day exercise test, for example, maybe an attempt to stop the excess inflammatory response that occurs with this exertion. Since the demand to reduce inflammatory responses is much higher in ME/CFS than in controls, the lactate levels of those with ME/CFS go through the roof. But consider too that studies have found that lactate concentrations were 2.8x higher in multiple sclerosis patients than healthy controls. Does high lactate cause post-exertional malaise? Probably not.
Is it the Gut?
The lactate talked about thus far, is a metabolic byproduct, L-lactate. Also, consider that gut bacteria produce lactate as D-lactate. Both of these forms can be converted to pyruvate to be used for ATP production. Certain strains of bacteria are lactate producers: Streptococcus and Enterococcus. One study found these two bugs elevated in stool samples from patients with ME/CFS.
What is D-Lactate?
D-lactate can also be produced through normal metabolism as an off-shoot of glucose breakdown. Glucose is shuttled through a different path to methylglyoxal—a toxic product that is converted to D-lactate. Methylglyoxal is a highly reactive molecule that forms advanced glycation end-products (AGEs for short). These are essentially sugar-coated molecules that are associated with aging as well as diseases like diabetes and neurodegenerative diseases. Why would glucose get shuttled to this nasty pathway? Very high carbohydrate (high sugar) diets for starters!
It is unclear from the studies in ME/CFS and Fibromyalgia if measurements are of both D- and L-lactate. In general, the research methods used cannot readily differentiate these two forms.
Reducing Lactate May Reduce Symptoms of Exercise Intolerance
Despite all these factors so far, it still stands to reason that reducing lactate may in part reduce some of the symptoms that occur during post-exertional malaise. While not THE driving force of pain and fatigue, reducing lactate may relieve the excessive burden and prevent bystander effects that do in fact cause pain and fatigue.
Turning to research in exercise provides some clues on how to reduce lactate related to exertion. Magnesium has been shown to reduce lactate levels following exercise. Supplementing with citrulline and malate is also commonly used by athletes to reduce lactate and improve recovery. This combo has been utilized in clinical trials with mostly positive outcomes in lactate reduction.
Some pharmacological options may be useful as well. Milnacipran, which is FDA-approved for fibromyalgia was trialed in a 2015 study. After 8 weeks on the drug (n=37), fibro patients showed decreases in both ventricular lactate and pain compared to placebo.
A final approach could be to reduce lactate-producing bacteria in the gut through antibiotics, natural anti-microbial, diet, or pre and probiotics. Ketones may reduce lactate levels. In the gut, the ketone β-hydroxybutyrate scavenges lactate to clear it away. Ketogenic diets or exogenous ketones might help.
Putting it All Together
While it is interesting that lactate is so much higher in exercised ME/CFS patients, these findings are non-specific and have been seen in others at rest such as fibromyalgia patients, migraine, multiple sclerosis, rheumatoid arthritis, and likely others.
Lactate is not a waste product
Lactate is not pain-producing
Lactate is not inflammatory
Lactate is released in response to inflammation to put the brakes on the inflammatory process. It is akin to a defense mechanism. Increased production could mean too much inflammation that is difficult to keep in check. It could also simply mean the lactate isn’t being utilized (turned back into cellular energy) efficiently. Alternately the excess lactate could be coming from where we least suspect it—gut bacteria. Then there is the possibility of a metabolic shift that favors the production of methylglyoxal and thus D-lactate.
References
van Hall G, et al. (2009) Blood lactate is an important energy source for the human brain. J Cereb Blood Flow Metab. 29(6):1121-9.
Pucino, V., Bombardieri, M., Pitzalis, C., & Mauro, C. (2016). Lactate at the crossroads of metabolism, inflammation, and autoimmunity. European Journal of Immunology, 47(1), 14–21.
Ratter JM et al (2018) In vitro and in vivo Effects of Lactate on Metabolism and Cytokine Production of Human Primary PBMCs and Monocytes. Front. Immunol.,9: 2564.
Magistretti PJ, Allaman I. (2018) Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci. 19(4):235-249.
Lien K, et al. (2019) Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome. Physiol Rep. 7(11): e14138.
Cinar V, Nizamlioğlu M, Moğulkoc R. (2006) The effect of magnesium supplementation on lactate levels of sportsmen and sedanter. Acta Physiol Hung. 93(2-3):137-44.
Kiyici F, Eroğlu H, Kishali NF, Burmaoglu G. (2016) The Effect of Citrulline/Malate on Blood Lactate Levels in Intensive Exercise. Biochem Genet. 55(5-6):387-394.
Natelson, BH et al. (2015) Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-blind, Placebo-controlled Trial. J Pain. 16(11): 1211–1219.
