Science is making huge advances within the human physiology and metabolism fields. As a result, the traditional understanding of many events, molecules, processes, etc. within such fields is being challenged or even proved to be incorrect. Ideas change over time as knowledge builds up. To be precise, besides these ideas being challenged, what is actually occurring now is simply the ratification of models and theories created long time ago that didn’t have enough support until some researchers now looked deeper into them and proved them correct.
In this occasion I want to talk about one of the molecules that most controversy has created within the scientific community, and the view of which most drastically have recently changed. As you may have already guessed (or assumed after reading the title), I am talking about the well-known molecule called lactate. In this blog I will focus on the new understanding of this metabolite that, as you will soon understand, it is even claimed to be one of the most important metabolites of our body.
But before we dive into the new model, let’s review the traditional understanding of lactate.
Traditional understanding of lactate
Since its discovery in 1780 by Carl Wilhelm Scheele, lactate has generated huge interest among researchers. Since then, many studies have focused on understanding the physiological relevance of lactate as well as the causes of its formation. But it wasn’t until 1907 that the bases of the traditional model of lactate were established by a study run by Fletcher and Hopkins. I strongly encourage you to check out their published study (Fletcher & Hopkins 1907).
This study is, indeed,a landmark of the traditional understanding of lactate that have been accepted until a few years ago. With it, Fletcher and Hopkins showed that:
- Freshly excised resting muscles contain a low concentration of lactate.
- The concentration of lactate increases in excised, resting, anaerobic muscles.
- Lactate accumulates and its concentration increases to high levels during stimulation of muscles to fatigue.
- When fatigued muscles are placed in oxygen-rich environments, lactate disappears.
After that, in 1924, Hill and his colleagues postulated what is now known as the traditional or classic understanding of lactate (Hill et al. 1924). They postulated that lactate production and accumulation was due to inadequate O2 supply, and that it was, in fact, this lactate accumulation the cause of muscle fatigue. Thus, they reached the conclusion that lactate production and concentration was an indicator of hypoxia or dysoxia.
This idea also led 40 years later to the concept of “anaerobic threshold” to express the exponential lactate accumulation – also known as lactatemia – after the failure of the heart to adequately deliver O2 to the working muscles when the muscle O2 requirements are markedly increased by exercise.
And last but not least, to finish this historical section, I want to highlight the influence that this idea had on the terminology we still use, and that I tried to correct/replace in a previous blog about the 3 basic energy systems that I recommend you to have a look at. The classic view of lactate as the waste product that is accumulated due to inadequate O2 delivery to the working muscles led to the classic terminology of anaerobic alactic, anaerobic lactic, and aerobic pathway to refer to the 3 energy systems that our body uses to resynthesize ATP. However, as we will soon justify, this terminology should be updated and replaced by the phosphagen, glycolytic, and oxidative pathway, respectively, since O2 availability has been shown not to be what determines lactate production, but short-term challenges to ATP supply instead.
We now know what lactate has been considered for a really long time, and what even some people still currently believe it to be: lactate is a dead-end, waste product of glycolysis that accumulates when the O2 supply is inadequate.
But we are here to find out about the new understanding of this little but fascinating molecule that, as you will find out soon, has a crucial role within human physiology. However, how are we going to understand the role of a molecule without understanding where it comes from? Let’s review its origin very briefly.
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Lactate is the ultimate product of glycolysis
Glycolysis is the catabolic pathway through which cells obtain energy from glucose. This cytosolic pathway, in short, refers to the breakdown of glucose to pyruvate, a monocarboxylate thought to be the last metabolite of glycolysis. To continue its breakdown process, the pyruvate formed can follow different pathways. It can either enter the mitochondria and be further oxidized to Acetyl-CoA by the enzyme pyruvate dehydrogenase (PDH), that will subsequently enter the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC), or be converted to lactate by the cytosolic lactate dehydrogenase (cLDH).
From the traditional standpoint, the conversion of pyruvate to lactate happens only in the absence or inadequate supply of O2. However, it is now proved that this conversion occurs even in fully aerobic conditions – with adequate O2 supply – such as at rest, and it is increased due to challenges in ATP supply to the working muscles as their energy demands are increased by exercise. If you think about it, the higher the glycolytic flux, the higher the lactate production – by mass action.
Besides, if we analyze the concentration of lactate and pyruvate in blood and muscle, it is observed that lactate levels are 10 times higher than pyruvate ones – the lactate/pyruvate ratio is 10 (L/P = 10). This is because the equilibrium constant (Keq) – it represents the relative quantities of products and substrates at which a reaction reaches its equilibrium, measured as the ratio between the concentration of products and substrates that accomplish the equilibrium state of the reaction – of cLDH for the reduction of pyruvate to lactate approximates 1,000. In other words, this means that cLDH will not stop converting pyruvate to lactate until there are 1,000 molecules of lactate per molecule of pyruvate, which makes lactate oxidation to pyruvate unlikely to happen. Knowing that, we can conclude, as Brooks does, that the last metabolite of glycolysis is actually lactate, and not pyruvate.
After understanding what lactate is, and how it is produced, let’s now move on and get to the substance of this article, that is why you probably came here!
The new understanding of lactate
As just mentioned, lactate has been considered a “waste” and “dead-end” product of glycolysis, and even the responsible of muscle fatigue during high-intensity exercise and anaerobiosis. However, new insights about physiology and metabolism have challenged this view, and even proved to be incorrect.
We already mentioned that lactate production is not increased as a result of O2 deficiency, but as a result of challenges in ATP supply to the working muscles instead. Besides that, the idea that its accumulation is the cause of fatigue and acidosis has also been challenged. Since lactate – the final product of glycolysis – is a base, it consume H+ and lowers the pH, instead of acidifying the environment and causing fatigue.
Beyond that, we are now certain that lactate is a metabolite of high relevance for the human physiology and metabolism at least for three reasons:
- Lactate is a major energy source.
- Lactate is the major gluconeogenic precursor.
- Lactate is a signaling molecule – it has given the name of lactohormone.
Let’s dive in more into that!
A major energy source
During high-intensity exercise, the L/P ratio becomes 500 or greater – remember that it was 10 at rest – despite O2 supply being high enough for maximal mitochondrial respiration. Most of this lactate (75-80%) produced during exercise is rapidly disposed via oxidation to CO2.
We have already talked about its production, but how is lactate oxidized? Lactate oxidation occurs in the mitochondria via oxidative phosphorylation – also called mitochondrial respiration.
This means that lactate must enter the mitochondria. This is enabled by the intracellular lactate shuttles proposed by Brooks, which can be divided into the cytosol-to-mitochondrial lactate shuttle and the mitochondrial lactate oxidation complex (mLOC). The former one is basically a monocarboxylate transporter (MCT) that transports lactate formed by glycolysis into the intermembrane space of the mitochondria. The mLOC – located in the inner mitochondrial membrane – contains the MCT1, its membrane chaperone CD147, the mitochondrial LDH (mLDH), and the cytochrome oxidase (COx). After lactate has reached the intermembrane space, mLOC oxidizes it to pyruvate and transports it into the mitochondrial matrix for further oxidation.
It is clear then that a high mitochondrial abundance and respiratory capacity is essential for oxidizing the lactate produced during moderate- and high-intensity exercise and avoid lactate accumulation. In fact, one of the characteristics of high-level elite athletes is a high mitochondrial functionality with the concomitant excellent oxidative capacity, which allows high lactate disposal to support high glycolytic flux during high work rates, thus avoiding lactate accumulation. This is an ability that an untrained or sick person doesn’t have, as excellently reviewed by San Millan & Brooks 2018.
But this is not all: apart from being oxidized within the same cell that produced it, lactate represents an important energy source for other body cells where its production is not that high. Thanks to cell-cell lactate shuttles, cells that overproduce lactate – over their ability to oxidize it – send it to other cell types that possess a higher oxidative capacity to consume that lactate. A clear and easy example of that can be found in the muscle. Type II fibers (glycolytic or white) overproduce lactate due to their low oxidative capacity. However, lactate does not accumulate thanks to the fact that excess lactate is then consumed by type I fibers (oxidative or red), which possess a high oxidative capacity and, thus, a high ability to dispose lactate.
In the same way that happens in the muscle, lactate is also taken up by other organs such as the heart, the gut, and the brain among others.
This actually reflects the importance of this little molecule within our body. In fact, it has been shown that lactate flux raises up to 4 times that of glucose during exercise, which means that lactate is the preferred fuel over the glucose during exercise, unlike what it has always been thought – glucose was always thought to be the preferred body fuel. And that is true even in the brain! Such is the importance of lactate as a fuel, that even though glucose is also taken up by the brain, the path of its disposal is through conversion to lactate and a cell-cell shuttling.
After understanding that lactate is one of the most relevant energy sources, it is clear that its production is not a problem at all. Instead, an athlete that can generate the highest amount of lactate will have more substrate to get energy from in an efficient way. Obviously, it will require a high mitochondrial abundance and respiratory capacity to be able to utilize this lactate. This is what we actually call metabolic flexibility.
Major gluconeogenic precursor
Gluconeogenesis refers to the synthesis of glucose from certain non-carbohydrate carbon substrates, such as lactate, amino acids, pyruvate, and glycerol, among others. This anabolic pathway mainly occurs in the liver and is crucial for maintaining blood glucose levels during fasted states as well as during exercise.
Lactate produced by the muscles can be taken up by the liver to synthesize glucose, which can go back to the blood and be oxidized again by the muscles. This process is called Cori cycle. It turns out that, through the Cori cycle, lactate is by far the major gluconeogenic precursor. Such is the importance of lactate as the major carbon-supplier molecule for gluconeogenesis in the liver that it arises the “Glucose Paradox”.
Let me briefly explain such an interesting phenomenon to you.
Glycogenesis refers to the synthesis of glycogen from glucose in order to store it. After a CHO-containing meal, a significant portion of glucose that reaches the blood bypasses the liver and is oxidized through glycolysis in the peripheral tissues, leading to lactate production and the concomitant increase in blood lactate levels. This lactate, then, provides the precursor for hepatic glycogen synthesis, instead of the initial glucose that enter the systemic circulation – which would obviously save up steps and energy.
Isn’t it interesting how glucose from CHO-containing meal bypasses the liver and enters the systemic circulation only to return as a precursor – lactate – for glycogen synthesis? Again, this is a sign of the extreme importance of lactate in metabolism.
Signaling molecule: lactohormone
Since lactate is present in most tissues at a higher concentration than most other metabolites, it is easy to think of lactate having different effects in these tissues. On this matter, lactate has been shown to possess signaling and regulatory traits for different processes in most tissues and organs where it is present. In fact, it has even been described as hormone – lactohormone – with autocrine, paracrine, and endocrine functions.
Lactate not only plays a role in regulating metabolism, but it can also induce structural changes in the tissues where it is present.
Let’s try to explain this.
Regulation of metabolism
Lactate plays a crucial role when it comes to substrate utilization by the body. Its production limits fat oxidation, thus favoring carbohydrates as the main energy source. But how does it control that?
We know that during exercise, the L/P ratio increases over the value of 10 found at rest, and thus the lactate produced enters the mitochondria by mass action. In the mitochondria, it gives rise to Acetyl-CoA and, thereby, Malonyl-CoA formation, which inhibits the entry of activated fatty acids into the mitochondria for β-oxidation by inhibiting carnitine-palmitoyl transferase 1 (CPT1). The increase in Acetyl-CoA also causes a reduction in free carnitine availability which impairs CPT1 activity and further inhibits fatty acid oxidation – I wrote an article about it that I recommend you to check out. Besides this, it is believed that Acetyl-CoA could also downregulate β-ketothiolase, the terminal and rate-limiting enzyme of β-oxidation.
Apart from that, lactate inhibits lipolysis in white fat cells through interaction and activation of GPR81, which acts as a lactate sensor in adipose tissue. Activation of GPR81 leads to inhibition of lipolysis through cyclic-AMP (cAMP) and cAMP response element binding (CREB).
As you can see, lactate signals body cells to reduce fat oxidation, which involves a subsequent increase in reliance on carbohydrates as energy source.
Apart from being involved in metabolism regulation, lactate is an important molecule for inducing structural changes that involve gene expression, which are especially important for exercise adaptations as well as cancer – new insights into lactate metabolism are offering new ways to treat cancer.
As for exercise, it is well known that regular high-intensity interval training (HIIT) – a type of exercise known to accumulate high levels of lactate – significantly increases mitochondrial mass. What’s more, lactate has been shown to increase MCT1 expression – remember that MCT are monocarboxylate transporters such as lactate and pyruvate – through c-Myc and p53, two transcription factors also involved in mitochondrial biogenesis. Altogether, this has led researches to study the possible involvement of lactate in increasing the mitochondrial mass, reaching the conclusion that the increase in L/P ratio during exercise may be associated to activation of different transcription factors and gene expression that enhance the oxidative capacity of the cell. This actually makes sense if you think about the fact that lactate disposal depends on the oxidative capacity of the cell, in turn determined by the mitochondrial abundance and health – our body is just searching ways to enhance lactate utilization.
Similar to lack of oxygen, lactate has also been shown to be a powerful activator of hypoxia-inducible factor (HIF-1α), which upregulates all the machinery involved in glycolysis, thus enhancing the ability to produce lactate. Besides, it has been demonstrated that lactate is a key player in angiogenesis through the stimulation of vascular endothelial growth factor (VEGF) release, which enhances the delivery of oxygen and nutrients to the working muscles and other tissues by stimulating the circulatory system to expand. This, in turn, enhances the work rate that can be achieved and, therefore, the athletic performance.
And finally, to further show you how important is this metabolite, lactate improves cognitive function by stimulating secretion of brain-derived neurotrophic factor (BDNF). In fact, low circulating BDNF has been associated with Alzheimer’s disease and major depression.
Opposite to what it has long been though, lactate is the ultimate product of glycolysis that is produced even in fully aerobic conditions, and the substrate for mitochondrial respiration. Thus, lactate can be regarded as the link between glycolytic and oxidative pathways.
Thanks to the cell-cell and the intracellular lactate shuttle, excess lactate produced by low oxidative cells serves other body cells as an energy substrate, a gluconeogenic precursor, and a signaling molecule – referred to as lactohormone.
On a practical level, it is crucial to understand the role of lactate and its metabolism, and replace the “waste product” view of it by the modern one, where lactate plays a central role in exercise metabolism. Producing it in high amounts is nothing but beneficial for the athlete as long as their oxidative capacity copes with its production. Adequately interpreting the role of lactate is essential for designing training and nutritional strategies in the pursue of performance optimization.
At this point, I just want to thank you for your attention and patience during such a complex blog. I really hope that this article made you change the view you had of lactate, and really understand the basics of its roles. This blog, in fact, represents a step forward towards the understanding of human physiology and metabolism.
If you liked it, I would really appreciate if you share this article with the people around you so that the new understanding of lactate gets to everyone in the field.
And again, do not hesitate to contact me for discussing anything you want about this blog, or anything about physiology, nutrition, and sport!
See you soon!
- Brooks, George A. 2018. “The Science and Translation of Lactate Shuttle Theory.” Cell Metabolism 27 (4): 757–85.
- Ferguson, Brian S., Matthew J. Rogatzki, Matthew L. Goodwin, Daniel A. Kane, Zachary Rightmire, and L. Bruce Gladden. 2018. “Lactate Metabolism: Historical Context, Prior Misinterpretations, and Current Understanding.” European Journal of Applied Physiology 118 (4): 691–728.