Lactate, Lactate Dehydrogenase, and Lactate Transporters

Key takeaways:
~ Lactate is an essential cellular energy source that is particularly important in skeletal muscles, the brain, and the heart.
~ Lactate also acts as a signaling molecule and influences metabolism and gene expression.
~ Lactate transport and metabolism play a fundamental role in several chronic health conditions, including cardiovascular disease, neurodegeneration, and fertility issues.
~ Genetic variants in the lactate transport genes can influence your need for lactate and response to exercise.

Lactate: Cellular Energy Source

Sore muscles after a hard workout is often the first thing that comes to mind when thinking of lactate. The classic view of lactate is that it is a metabolic waste product that accumulates in your muscles. However, this is far from the truth when it comes to this fundamental cellular compound.

Lactate is formed when cells create ATP from glucose. Rather than being a waste product, lactate is a major source of energy in the body. It is now considered a glucose-sparing molecule that can fuel the brain or muscles.

Let’s dive into the details on what lactate is used for, how lactate is formed, how it moves around in the body, and how your genes may influence cellular energy from lactate.

What is lactate used for?

1. Lactate as an energy source
2. Lactate as a signaling molecule
3. Precursor for gluconeogenesis
4. Interactions with the immune response and regulation
5. Cancer metabolism

1) Lactate as an energy source:

Cells make ATP to store energy for use in many different cellular reactions. In the cytosol, ATP can be generated by breaking down glucose into two molecules of pyruvate and NADH. This process produces two ATP molecules and is called glycolysis.

Cells can also produce a lot of ATP in the mitochondria through the Krebs cycle, also called the citric acid cycle, and through oxidative phosphorylation. The Krebs cycle uses the pyruvate from the cytosolic breakdown of glucose.

Where does lactate fit into this?
Pyruvate can either be transported into the mitochondria for ATP production, or it can be converted into lactate in the cytosol.

Pyruvate <–> Lactate

The enzyme lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate. This isn’t a one-way street, though. The LDH enzyme also catalyzes the conversion of lactate back to pyruvate.

The balance of glucose, lactate, and pyruvate in cells is important. Blood glucose levels and insulin resistance receive a lot of attention from health-conscious people, and rightly so. But lactate plays an important role in this balancing act as a substrate that can be used for ATP synthesis.

Isotope tracing shows that cells balance out the uptake of glucose, its conversion to pyruvate (glycolysis), and then either mitochondrial ATP production or lactate synthesis.

If the mitochondria aren’t able to handle or don’t need pyruvate for the Krebs cycle, it converts to lactate, which can then be transported out of the cell and used elsewhere in the body. When a cell needs more ATP from the mitochondria, lactate can be transported into cells to be converted to pyruvate and then ATP in the mitochondria.[ref]

The interconversion of lactate and pyruvate by LDH is driven by the lactate concentration. There is usually 20X more lactate than pyruvate in the cytosol.

This flux of pyruvate to lactate means that glycolysis can occur in the cytosol when glucose is available, but it doesn’t have to be coupled with mitochondrial ATP production. In other words, without the ability to convert pyruvate to lactate, every pyruvate molecule would need to be converted to ATP in the mitochondria. Lactate allows that to be decoupled.

Excess lactate can be transported out of cells and either into nearby cells or it can circulate. For example, in skeletal muscles, lactate is produced when exercising and is exported for use as energy in other muscle cells. There is cell-to-cell shuttling of lactate, and it can also circulate for use in other organs.[ref]

Studies show that heart and skeletal muscle cells preferentially use lactate over glucose as an energy source. In some situations, the brain also preferentially uses lactate. Lactate conversion to pyruvate for ATP production is a single step, while glycolysis (conversion of glucose) involves multiple steps that are less efficient. [ref]

2) Lactate as a signaling molecule

Circulating lactate acts as a signaling molecule in the brain, heart, and adipose tissue. The GPR81 receptor (HCAR1 gene) is stimulated by lactate. It acts as a metabolic sensor to regulate several systems in the body based on energy metabolism.[ref] In adipose tissue, higher lactate levels inhibit lipolysis.[ref][ref]

In the brain, lactate binding with CGRP receptors is believed to play a role in regulating fat metabolism during exercise.[ref] The GPR81 receptor also plays a role in protecting the brain during times of energy deficit, such as during a stroke or brain injury.[ref]

In the heart, lactate acts as an energy molecule, especially during exercise or exertion. Recent research also shows that in heart disease, lactate levels may rise in the heart muscle and accumulate, causing disturbances in the physiology of how the heart contracts.[ref]

3) Gluconeogenesis from lactate

Again, two lactate molecules are created from the catabolism of glucose (with pyruvate as the intermediary). Gluconeogenesis is the way that the liver can synthesize glucose as a way of maintaining blood glucose levels when fasting or when eating a low-carbohydrate diet. Gluconeogenesis can use lactate, pyruvate, glycerol, or a couple of amino acids as precursors for producing glucose. Lactate is the most common precursor used in gluconeogenesis. About 25% of the body’s lactate production is disposed of via gluconeogenesis in the liver.[ref]

4) Lactate in the immune response:

Lactate is important as a signaling molecule in the immune response in a couple of ways.

Macrophages are a type of white blood cell that are activated during infections, and HMGB1 is released from macrophages to activate or rev up more of an immune system response. Higher circulating lactate levels during an infection are involved in lactylation of HMGB1 — essentially turning on more HMGB1 to be released during an infection.[ref]

5) Cancer metabolism

Tumor cells need a lot of energy in order to replicate quickly. Lactate is a primary energy source for tumors, which often have rapid glucose consumption and lactate production. Interestingly, tumor cells can also convert glutamine to lactate.[ref]

Ok – that’s the big picture on lactate as an energy source and signaling molecule. Let’s move on to look at how lactate moves in and out of cells.

Lactate transporters:

To move lactate across the cell membrane or across the mitochondrial membrane, monocarboxylate transporters (MCTs) are utilized. MCTs are a family of plasma membrane transporters that move lactate, pyruvate, and ketone bodies.[ref]

These transporters are concentration-dependent, meaning if the concentration of lactate is high inside a cell, it can easily move outside the cell. They do not utilize ATP in the transport, and they are temperature and pH dependent. The key MCTs for lactate are: [ref]

• MCT1 (SLC16A1 gene) transports lactate into and out of cells, especially in the brain and skeletal muscles. It has also recently been found to move lactate into the mitochondria, especially in heart muscle and skeletal muscle.
• MCT2 (SLC16A7) is expressed in neurons and helps to move lactate into neurons for brain energy.
• MCT3 (SLC16A8) is important in the retina and choroid plexus.
• MCT4 (SLC16A3) is important for the export of lactate in slow-twitch skeletal muscles as well as the export of lactate in astrocytes, which provides energy to neighboring neurons.

The expression of the lactate transporters, such as MCT1, is driven by lactate levels. This means that higher lactate levels in the skeletal muscles will result in higher MCT1 expression. In addition, lactate can be transported by sodium-dependent transporters in immune system cells.[ref][ref]

Next, let’s take a look at some of the more specific roles that lactate plays in health and what can go wrong.

How lactate levels interact with health:

Altered lactate transport or lactate shuttling is linked to several health conditions.

I find it helpful to think of lactate like glucose — essential for cellular energy, but it also needs to be in the right amount and able to change in response to changing conditions.

Lactate in the Brain:

The brain uses a lot of energy (20% of the body’s energy production is for the brain). Lactate concentrations in the brain are similar to glucose concentrations, and glucose is considered the main energy substrate in the brain under normal conditions.

Neurons use about 80% of the brain’s energy, but neurons can’t sustain a high enough rate of glycolysis to supply their energy needs. Astrocytes are a type of glial cell found alongside neurons in the brain that help neurons function in several ways. One way that they support neuronal function is by taking in a lot of glucose for glycolysis and exporting lactate, which is then taken up by neurons. The neurons can then convert lactate to pyruvate for use in mitochondrial ATP generation.[ref]

The shuttling of lactate to neurons from astrocytes, called the astrocyte-neuron lactate shuttle, is a focus of current research, with questions still to be answered.  The astrocyte-neuron lactate shuttle is particularly important during times of high brain energy demand or cellular stress, but it is also active at lower levels during times of lower brain activity.[ref]

Neurodegenerative diseases: In Alzheimer’s, Parkinson’s, and ALS, lactate levels in the specific brain regions are low. The export of lactate from astrocytes is reduced, and neurons can’t get enough lactate or glucose to meet energy demands. A recent study in mice showed that inhibiting IDO1, which converts tryptophan to kynurenine, improved the production of lactate from astrocytes. IDO1 is upregulated in response to amyloid-beta plaque. Other studies in mice show that supplemental lactate restores synaptic plasticity in Alzheimer’s mice.[ref][ref][ref]

Related article: Tryptophan, IDO1, and Kynurenine

Lactate also acts as a signaling molecule in the brain, modulating neuronal excitability and regulating physiological processes such as respiratory control.[ref]

For brain injuries, such as a TBI, lactate infusion by IV is often used to supply the brain with energy. Studies are still underway to determine the best dose.[ref]

Lactate in peripheral nerves:

Research also points to a lactate shuttle in peripheral nerve cells. Schwann cells are glial cells that help to support peripheral nerve function (nerves outside the brain and spinal cord), and they can shuttle lactate to peripheral nerves.[ref]

Diabetic peripheral neuropathy may involve a lack of lactate transport from Schwann cells to peripheral nerves. Animal studies show that prediabetes can also disrupt lactate shuttling in nerves.[ref][ref]

Lactate levels and the control of breathing:

There are several feedback mechanisms that control your rate of breathing. Lactate is involved in a couple of ways. The carotid body is located in the carotid artery in the neck and has chemoreceptors to control breathing through sensing both oxygen and lactate levels. Lactate binds to OLFR78, which is thought to be an atypical olfactory receptor. Higher lactate levels and low oxygen levels activate the cardiorespiratory reflexes. Essentially, it sends a signal via the carotid sinus nerve to the brainstem to increase respiration.[ref]

Male fertility:

Sperm need a lot of energy, and lactate is essential for sperm movement. Genetic variants that affect the lactate transporters are associated with male infertility.[ref]

Lactate and cardiovascular health:

Lactate oxidation provides up to 50% of the cellular energy supply for cardiac muscle under normal conditions. The cardiomyocytes (muscle cells in the heart) can use lactate, ketone bodies, and amino acids for energy production. In several types of cardiovascular disease, including heart failure, atherosclerosis, and atrial fibrillation, lactate levels and lactate transporter levels are altered.[ref]

In acute heart failure, a high blood lactate level is considered a marker of poor prognosis since the lactate level rises due to decreased blood oxygen to the muscles as well as liver or kidney dysfunction in the regulation of lactate clearance. However, in people with chronic heart failure, there usually is little change in lactate levels. In persistent AFib, lactate is thought to play a role in the atrial remodeling.[ref]

Related article: Atrial fibrillation

Lactate in the heart is more than just an energy source (or a waste product). It also acts as an epigenetic modifier, altering gene expression of different ion channels.

Lactate in mast cells and asthma:

IL-33 is an inflammatory cytokine that is elevated in asthma and exacerbates mast cell activation. A recent study showed that lactic acid (not lactate) can suppress IL-33 by decreasing a microRNA, miR-155-5p.[ref] The activation of mast cells through the MRGPRX2 receptor is also suppressed by lactic acid.[ref]

Lactate as an epigenetic modifier:

The process of a gene being transcribed and translated into a protein – gene expression – is controlled through a bunch of mechanisms in cells. For example, methylation can stop a gene from being expressed, and acetylation can promote the translation of a gene.

Researchers have recently found that lactate can act on gene expression through lactylation. Lactate is converted to lactyl-CoA in the cytosol. Lactylation adds a lactyl group either to the histone (nuclear modification) or post-translationally to a protein. In this way, lactylation can either inhibit or promote gene expression, depending on the context.[ref]

Mitochondrial biogenesis:

Mitochondrial biogenesis is the creation of new mitochondria in a cell by self-replication – essentially, mitochondria growing and dividing. This process is especially important in skeletal muscle cells to ensure enough ATP production to meet the cell’s energy needs. Recent studies show that mitochondrial biogenesis in skeletal muscles is actively promoted by lactate transported via MCT1. Exercise, especially high-intensity exercise, increases lactate levels, which induces mitochondrial biogenesis both in the brain and in muscle tissue.[ref][ref]

Synaptic plasticity in the brain:

In the brain, lactate is produced by astrocytes and shuttled to neurons for energy. Studies show that lactate is required for memory formation and consolidation, and it also plays a role as a signaling molecule to increase the expression of plasticity-related genes. One study showed that lactate increases synaptic plasticity, and the effect is dependent on the NMDA receptor (glutamate receptor). Another study shows that lactate promotes adult neurogenesis (new brain cells). This is one way that exercise, through increasing circulating lactate, is beneficial for brain health.[ref][ref]

Lifehacks

Lactate test kits:

Want to know your lactate levels while you work out (or while ill)? Lactate test kits, similar to blood glucose test kits, are readily available online. However, they are a bit expensive, and the test strip costs can add up.

A study examined the reliability and accuracy of five available lactate test kits. They found that the Edge and Xpress test kits had a low error rate for lactate concentrations <15 mM.[ref]

Lactate boosting supplement for endurance athletes:

There are lactate supplements marketed for boosting workout endurance, such as for cycling or running. These supplements (or drinks) directly supply lactate during intense exercise. Some of the oral lactate (or lactic acid) supplements include electrolytes, glucose, and fructose for a full-spectrum energy boost.

One study found that oral lactate did not change VO_2peak, but it did improve the work rate slightly. The conclusion was that the 19mg/kg body weight lactate supplement “elicited a modest ergogenic effect during the short-duration time trial.” [ref] Another study found that 120mg/kg of lactate increased time to exhaustion in trained cyclists.[ref]

Baking soda (sodium bicarbonate):
Lactic acid readily converts to lactate when the pH is right. During exercise, buffering pH by consuming baking soda is theorized to reduce lactic acid levels by increasing conversion to lactate.

In endurance cyclists, sodium bicarbonate mini-tablets combined with carbohydrates increased performance and buffered blood pH.[ref] Another study in cyclists found that sodium bicarbonate (300mg/kg BW) increased lactate levels and improved performance.[ref]

Citrulline Malate:
In young male athletes, 6g of citrulline malate before a workout reduced lactate dehydrogenase levels. However, it didn’t have an effect on the rate of perceived exertion.[ref]

Role of lactic acid producing gut microbes:

Lactic acid bacteria in the gut, such as Lactobacillus and Bifidobacteria,  are generally beneficial. A yeast, Saccharomyces cerevisiae, also produces lactic acid, and it has been shown to reduce inflammatory cytokines in the gut. Certain gut microbes can also utilize the lactic acid produced by other bacteria.[ref][ref]

There are two different structural forms of lactate – D-lactate and L-lactate. Humans produce mainly L-lactate, with minor D-lactate produced in certain circumstances. Microbes in the gut, though, can produce either L-lactate or D-lactate. In healthy individuals, the D-lactate produced in the gut is usually in small enough amounts that it is rapidly cleared by the kidneys. In people with short bowel syndrome, an overgrowth of D-lactate-producing bacteria can occur, leading to D-lactic acidosis, which causes neurological symptoms such as confusion, slurred speech, headache, and problems walking.[ref]

Lactic acid (both D-lactic acid and L-lactic acid) is also produce by bacteria in food fermentation, such as fermented sauerkraut, kimchi, and yogurt.

Studies show that lactic acid produced by gut microbes or in fermented foods can be absorbed in the intestines in sections where the pH is correct for the conversion to lactate. The MCT1 transporter in intestinal epithelial cells moves lactate from the intestine into the body.[ref][ref][ref][ref]

Dietary lactate interactions:

Lower-carb diet:
Decreasing carbohydrates or going with low glycemic index carbohydrates in the diet causes a slight decrease in lactate levels.[ref]

Lower-fat diet:
A diet that is lower in fat (25% of calories) causes an increase in the lactate to pyruvate ratio and a shift towards more glycolysis.[ref]

Medium-chain fatty acids:
Medium-chain triglycerides, such as in coconut oil, increase lactate levels in astrocytes.[ref] This may be one way that MCT oil is helpful in Alzheimer’s.

Interactions with supplements:

Keep in mind that in some situations, you may want to keep lactate in cells or move more lactate into cells. These supplement interactions are neither good nor bad, just something to be aware of as you look at how lactate is used by your body.

You may want to consider the timing of supplements and not take supplements that reduce MCT1 before doing a hard workout.

Hesperidin:
Studies show that hesperidin, a compound found in citrus fruits and used as an anti-inflammatory supplement, can inhibit MCT1 (SLC16A1), which is the lactate transporter for skeletal muscles and cardiac muscles. [ref][ref]

Quercetin:
Studies show that quercetin also inhibits MCT1 (SLC16A1), potentially keeping more lactate inside the cell. Cell studies show that quercetin reduces lactate production as well.[ref][ref][ref][ref]

Resveratrol:
Another polyphenol, resveratrol, also reduced lactate production and increased insulin-stimulated glycogen synthesis in muscle cells.[ref]

Curcumin:
In a cancer cell study, curcumin was found to decrease lactate and increase pyruvate levels.[ref]

Recap of your genes:

Related Articles and Topics:

Athletic Performance Genes

Insulin Resistance and Genetics: Finding the Root Cause