Understanding Lactate Metabolism and Its Importance

Welcome to the Metabolic Classroom. I'm Professor Ben Bickman, Biomedical Scientist and Professor of Cell Biology. Thanks for joining me for the lecture today. In today's lecture, we are discussing lactate metabolism. Now, I know what you're thinking. When you hear the word lactate, in your mind, you may be immediately thinking of lactic acid. Let's just establish this and clarify it up front. In humans, as in other animals, there is no lactic acid. We're going to talk about the origins of lactate in just a moment and clarify this a little bit. But everything you've ever heard about lactic acid is probably false, including its very existence within the human body. A lot of people have incredible and remarkable even misconceptions. But in normal animal cells, in all sorts of possible conditions. It's lactate. It's in this what's called a salt form. It's not the acid. It's not a lactic acid. And it's not the cause of muscle soreness. It's not the cause of muscle fatigue. Whatever your track coach or your health authority told you as you were growing up and engaging in sports, it's not true. All right. Now, Now that I've dispelled that, let me just state it again very clearly without the rambling. Humans have lactate. We do not have lactic acid. Now, as we continue sort of an introductory concept here, lactate is a product of what's called anaerobic glycolysis. Now, I personally don't like that term, anaerobic. Anaerobic invites this idea of this phenomenon occurring in the… absence of oxygen. Now, there is not a situation in humans where there's no oxygen. And so that doesn't particularly apply. The term that I prefer is non-oxidative glycolysis or even non-mitochondrial glycolysis. Now, let me just give you a very brief primer on glycolysis, this being relevant because it's the origin of lactate. When you have a glucose molecule that has entered a cell with... And immediately, it commits to this path of glycolysis or the splitting or the breaking down of glucose. Everything is in common, what I call the preparatory phase, the payoff phase. And then you get to the end of this and you get to a molecule called pyruvate, not pyruvic acid. It's pyruvate that is produced. Now pyruvate has an option. And generally, it is whichever option predominates. is a function of whether there are mitochondria there, because some cells don't have mitochondria, well, one particular type, which I'll mention in a moment. And then the demand of the ATP, not so much is there oxygen present, there's always going to be oxygen present. So I don't like to focus on that particular aspect of it. Now, when you get down to pyruvate, glycolysis, now the pyruvate molecule, and thus the end of glycolysis has two options. It can either go through this non-oxidative or non-mitochondrial final step, or it can go through this final step, which ends up putting it at the beginning of a whole bunch of other steps through oxidative or mitochondrial glycolysis. Let's just stick with that one for just another second. If the pyruvate molecule goes into the mitochondria, it will become acetyl-CoA, and then you have the citrate cycle or Krebs cycle now, and then everything else that comes thereafter. electron transport, oxidative phosphorylation. However, if you get to the pyruvate molecule, let's go back to the first option, and now it is staying outside the mitochondria or non-oxidative or non-mitochondrial or anaerobic, again, which I don't love because of the potential confusion. Now the pyruvate goes through an enzyme called lactate dehydrogenase and becomes lactate, the lactate molecule that we know. even if we've been accidentally calling it lactic acid. It's not lactic acid and it never is in the body. So that's lactate. So lactate, we could say it very succinctly, is the end product of non-oxidative glycolysis. It's a product that comes whenever a tissue or a cell, to be more precise, needs to create a lot of ATP or the chemical energy very, very quickly. Thus, one common source is muscle. It's common. Muscle is a common source because not only we have so much muscle in the average individual, most of the tissue in their body is made of muscle. So muscle is the predominant tissue on the human body. So we have so much of it, but also it has moments of extraordinary. demand for energy. In those instances, like for example, high intensity exercise, lactate is going to be a common product because it is the end product of non-oxidative glycolysis. And non-oxidative glycolysis is a nice way to produce a lot of ATP very quickly. Now I mentioned the muscle. Of course, muscle have a lot of mitochondria and they use it. Muscle uses mitochondria, including a lot of oxidative glycolysis, a lot of beta oxidation of fat. So lots of fat burning, lots of glucose burning happening in the mitochondria. But there is a cell that flows through the blood, which does not have mitochondria. And that is the red blood cell. Because the red blood cell does not have any mitochondria within it, its only method of obtaining energy is through the only nutrient that can be metabolized or catabolized outside of the mitochondria. namely the red blood cell and glucose. So glucose is the only fuel that can be burned or used without reliance on the mitochondria or the only one that has a non-oxidative potential to it. And thus the red blood cell, which lacks mitochondria, must rely on non-oxidative glycolysis 100%. It is completely reliant. Thus, the red blood cell produces a lot of lactate because every time it's using glucose for energy, which is the only source it can use, it's producing lactate. And again, at the end of it, all lactate is coming from pyruvate and all pyruvate is a consequence of glycolysis. Okay, that is some of the introductory idea of what is lactate and where does it come from. Now we're going to get into what it does. That'll be the meat of the lecture today, which I'll get to in a moment. One of the things that I'm most grateful for through the course of my PhD in bioenergetics was a history of bioenergetics. Ever since that class, I'd never had a class that touched on the history of science, who were the people who made the seminal discoveries in whatever topic we were discussing. But ever since then, I can't help but also want to do the same. So let's just go through a brief history lesson of lactate. in the science surrounding it. Because there are some really neat people who ought to be acknowledged because of their contributions to what we know now. I think it's really a shame if we don't recognize the efforts of those who've gone before us. Now, the first individual I would mention, and there are others beyond the few that I will bring up here. The first is Otto Meyerhoff. Otto Meyerhoff was a German biochemist who really led our understanding of muscle metabolism in particular. Now in the early 20th century, Meyerhoff discovered that if you could take a limb of an animal and force it to continue to contract, so force it to undergo extreme exercise, it would start releasing a lot of lactate. So he was the first one to see that if and if he put the working leg in a little chamber that was depriving it of oxygen, then even lactate would even be produced more readily and in much higher amounts. So he was the first one to start really teasing out lactate not only being a sign of intense exercise, but also more heavily produced based on the oxidative availability and potential of tissue. So connecting glycolysis to lactate, that was really his main finding, which was called the Meyerhoff cycle. This idea of lactate turning of... glucose turning into lactate through its metabolism. In fact, this discovery was so relevant and considered novel and important that he won the Nobel Prize in 1922 for this work. So Nobel Prize winning work. And it's to him, we owe our gratitude appreciating the origins of lactate in the first place, namely connecting it back to glycolysis. Now, That's not it. We're not done yet. Now, so he found that glycolysis would produce lactate if it's non-oxidative in its origins. But then it was another group who I really appreciate because they found one of the fates of lactate. Up until that time, including Meyerhoff's work, lactate was absolutely considered a waste product. It was just metabolic garbage. And even worse than just… benign trash, it was considered harmful, as you've heard before. So again, at best, lactate was considered just benign waste product that would somehow need to be eliminated. At worst, it was also considered a contributor to muscle fatigue and muscle soreness. Why are you feeling the burn? It's because of lactate. That's just not true. That's not why you feel the burn. Lactate has nothing to do with that. So that is where it sort of ended. Meyerhoff's work identified lactate as a product of non-oxidative glycolysis. And then what the lactate did after that, well, who knows? Well, then we come to the Corys. This is... I say plural, this is C-O-R-I, Carl and Gertie Corey. This is a husband and wife team of biochemists who made really groundbreaking contributions to understand carbohydrate metabolism, including the role of lactate. So we have Gertie Corey, who I will skip to the end of their story, was the first woman to win the Nobel Prize in Physiology or Medicine in the mid-1940s. And then her husband, Carl, who shared the Nobel Prize. Let's just pause and appreciate how cool that is. This is the Cori cycle, which is what I'm talking about now. We mentioned the Meyerhoff cycle, the creation of lactate from glucose. The Cori cycle is mind-blowingly cool because it represents some incredible recycling of molecules within the body in a way that would seem impossible. That it's like a... This idea of like a continual motion machine, you know what I'm talking about, this idea that you have something that can continually replenish itself. That's sort of what the Cori cycle identifies here as I'll get into. But again, this is a Hungarian couple, Carl and Gertie. This was a couple of biochemists, married couple working together on this who identified it. It's really, really neat. Now, what is so neat about it? They identified this cycle of lactate production. from the working muscle, and then the lactate would be exported. There are transporters that fit lactate that enable lactate to move in and out of a cell. That's a very important point that we'll come back to. Now, it's not a surprise that lactate can move out of a cell. Meyerhoff would have identified this even if he didn't know what the transporter was, and he didn't, because you could measure lactate in the blood. Someone's exercising hard. With higher intensity comes higher lactate. So of course, lactate has to have a way of getting out of the working muscle into the blood. Now, what the Corys found is that that lactate, one of the main recipients of that lactate is the liver. And then the liver will start to pull in that lactate. And then you could imagine that glycolysis pathway that I described earlier, where you take a glucose molecule and break it down and you get lactate at the bottom. What the Corys found is that when lactate comes into the liver. There's so much lactate coming in that it actually starts pushing that pathway in reverse. In other words, no longer is lactate a product of glycolysis. Now it's the origin or the substrate for gluconeogenesis, the synthesis of new glucose. That's the Cori cycle. But then, of course, we're not done. Once the liver has made glucose from scratch, from lactate, this gluconeogenesis, it can release the glucose. The glucose can come out of the glucose transporter on the surface of the liver cells, thereby giving the blood, dumping glucose back into the blood. Well, guess who can pull that glucose up and use it? The muscle. So the very tissue that gave birth to the lactate and those carbons breaking down glucose then receives those carbons back in the form of newly created glucose after having a spent the glucose and turning it into lactate. That is the Cori cycle. Now it took me a long way, kind of a roundabout way to describe that. So let me just say it one more time. So the working, the Cori cycle is that the working muscle is relying heavily on non-oxidative glycolysis, thereby producing and releasing a great degree of lactate. The liver being, as I've described it, the ultimate soccer mom of nutrient metabolism. It knows what to do with everything. It can pull in that lactate and turn it back. into glucose through gluconeogenesis and then release that glucose back into the bloodstream to then be taken up by any tissues that need the glucose for energy, including the muscles where the entire thing started. That's the Cori cycle. So it highlights this incredible efficiency in recycling these carbons or metabolites, converting what would be perceived as a byproduct, lactate, back into this. heavily relied on and usable energy source, namely glucose. Now, I'm not done. The Corey cycle was revolutionary in demystifying and clarifying the role of lactate, suggesting that it's far from being metabolic garbage. In fact, it's substrate for energy. Now we go to the final individual who I want to bring up, which is George Brooks and his work at UCLA. I've met him. He's still alive. He's a wonderful guy, really, really remarkable in his contributions to bioenergetics and exercise science. Indeed, a contributor to a really incredible textbook on bioenergetics. Now, decades after the Corys, George Brooks found that far from just lactate being... So we've evolved here, right? First, lactate is metabolic garbage and maybe even harmful. The Corys find that, well, it's not metabolic garbage. It can actually contribute to viable energy in the body. George Brooks'contribution was that lactate itself is a viable energy source. And he proposed this as part of what he called the lactate shuttle theory. So George Brooks in his lab at UCLA demonstrated that lactate is not a waste product, but it has the ability to not only be exported from a cell and thereby contribute to the query cycle, but itself is a viable fuel on the mitochondria. As much as we have taught and we've looked at non-oxidative glycolysis. as coming down and stopping at lactate, then the lactate has to be dumped from the cell. That's not true. The mitochondria have lactate transporters. So mitochondria can pull in lactate and then pull in the lactate and then convert it to acetyl-CoA and send it into the citrate cycle or the Krebs cycle, getting all of this energy that we typically only think we're getting through oxidative glycolysis. So this is a huge... paradigm shift and i i worry that in my description i haven't adequately stated just how neat this is so let me be clear if you have a muscle cell that's creating lactate yes it can export it so the liver can turn it back into glucose through the quarry cycle but even if it exports it other cells that can take it up including the liver if it has if those cells have mitochondria every cell with mitochondria that i'm aware of is capable of pulling lactate into the mitochondria through specific transporters and burning that lactate for energy. So lactate once, so we've reached sort of the peak of this evolution. And in fact, there's even one more aspect of that I'll mention in a moment, but lactate went from being metabolic garbage to being good for being a substrate to rebuild glucose to now saying it's actually a viable energy source in its own right. mitochondria can pull lactate in and actually burn that lactate for energy, even in the muscles that create it. Now, as much as I've been focusing on the muscle, allow me to just go on a brief little tangent here. One of the first instances where I heard about the role and the benefit of lactate as an energy source was for traumatic brain injury. So it is very well known. And I'll have some links to some of these papers that I'm going to mention in a moment in the show notes, of course. But after a traumatic brain injury, one of the problems with the brain is that there is this disruption in the enzymes that the brain relies on to use glucose. In other words, glycolysis is compromised. Well, that's a problem if this is a brain that is primarily relying on glucose for energy. So. Again, part of the problem with a TBI or traumatic brain injury is that the brain starts to starve. So let's give the brain any fuel source we can. Of course, ketones are a very viable fuel source and are often used as part of the therapy for TBI, but so too is lactate. Lactate can serve as an alternate energy for the brain. It allows the brain to bypass this now sluggish glucose metabolism, thereby helping it create... adequate ATP. And that's important because the brain has a high metabolic rate. It is one of the trinity of so-called high metabolic rate organs being kidneys, heart, and brain, I think in that order. So the brain has a very high metabolic demand. And if the TBI is resulting in its glucose use being compromised, well, then all the more reason to give it something else. So again, commonly for TBI, Lactate will be actually infused. And sure enough, there's evidence to show that if you infuse a lactate solution, it can reduce brain swelling and it can improve the intracranial pressure in patients with TBI. And this could be because you're allowing the brain to maintain sufficient energy. And with that energy comes the ability to sufficiently regulate electrolyte movement and then the water movement along with it. But there's really compelling evidence in animals and humans showing that after TBI, if you administer lactate, you improve brain energy production. And then in the animal studies, this has been shown that you can prevent some secondary damage from following the trauma. So that's a very neat application of lactate in a pathology, in a disease or problematic state. Now, so far in my defense of lactate. I have described its main benefit as being energetic, that it's because of the energy that lactate can give, which is all good. That's all accurate, and I think it's important that we appreciate that lactate, not lactic acid, not only does not contribute to problems in the muscle or any other tissue that it's coming from, it actually can help by giving the tissue energy, where the lactate can be used as an energy source or be converted in. back into a different energy source, namely glucose. Now, I wanted to highlight one last part of lactate that I think is not appreciated before we get into some of its further relevance in clinical context. And that is the ability of lactate to send a signal to fat tissue. So there are multiple studies now showing that lactate, when it comes to fat cells, is capable of having a few remarkable effects. Very unexpected. One, for example, is that lactate has been shown to help in the beiging of white adipose tissue. Now, I am touching on a deeper topic that I've in fact talked about before in previous metabolic classrooms, but you'd be familiar with the idea that on the human body, there is white adipose tissue, which is the fat that we pinch and jiggle and has an extraordinarily low metabolic rate. which isn't surprising because it's one of its primary roles is to store energy. But at the same time, humans have brown adipose tissue, although relatively quite little of it. But this brown adipose tissue stands in stark contrast to the functions of white because brown adipose tissue, these fat cells have a very high metabolic rate. They aren't designed to store energy, but rather to burn it with a primary purpose, apparently being the creation of heat. So this is a way in which humans can maintain a body temperature in the absence of shivering. But in adults, of course, it just means it works with shivering to help the body be warm. So lactate has been shown to make white adipose tissue behave a little more like brown adipose tissue. And separate from this has been the evidence that lactate does so by stimulating mitochondrial uncoupling. Now, once again, this is a... deeper topic. It's a fascinating topic and it's one that I love talking about, but it's a bit of a too big of a tangent right now. But suffice it to say, if you increase mitochondrial uncoupling, then you are making the mitochondria and the cell by extension burning energy just to create heat, which in an organism or within biochemistry, that's a generally an inefficient effect. Normally, if you're burning something, you want to get work. You want to flex a muscle more, for example. In this case, fat tissue, which has no flexing to do, now you're just telling the fat tissue to just burn through energy just to create heat. And again, lactate does this. So beyond its ability to be used as a fuel, it actually can stimulate greater fuel use. So lactate is acting as a signaling molecule. It's telling these white fat cells to be a little more. wasteful with their energy. And if you've got energy to burn, like most people do, as we all struggle with varying degrees of chubbiness or obesity, then that's not a bad strategy. So this is, in my mind, this represents another just fascinating interaction in the body where in the case of, let's imagine an exercising muscle producing lactate. That lactate then has further benefit. If this person, say, exercising to maintain or improve metabolic health, the lactate is further helping that happen by stimulating a little bit of an advantage at the fat tissue, just telling the fat tissue to run a little hotter to increase its metabolic rate just a bit. Now, likely, as I kind of near the end of the lecture topic here, I want to, like I said, I want to highlight its relevance, lactate's relevance in a clinical context. I think this is important because as we are approaching the widespread creation and use of continuous lactate monitors, the low hanging fruit for these soon to be available lactate monitors, and it is soon, the obvious relevance is going to be in athletics because people are going to want to be training and monitoring their lactate threshold. And for good reason, that's a nice effective training strategy of improving your overall fitness and your capability. But that is the low-hanging fruit. And in fact, I would suggest it's the less relevant fruit. I think the more relevant part of lactate monitoring and the widespread and continuous measuring of lactate is its role in predicting and being indicative of mitochondrial damage. So if you detect that people who have chronically high lactate levels, not because they exercise so much, in the absence of… exercise, it could be evidence of an inability to burn it very well. As you'll recall from Dr. George Brooks'work, lactate is an energy source. The body can literally burn it directly as a fuel, but to do so, it has to rely on the mitochondria. Well, what if people don't have as much mitochondria perhaps as they should, or the mitochondria aren't working particularly well? That brings us back to this idea of mitochondrial dysfunction. One of the most relevant disease states that have been shown to connect or be a result of mitochondrial dysfunction in part is type 2 diabetes. So there is a tremendous and even old area of research. There's one of the studies that I'm going to share with you in the show notes is from 2001, just documenting the ability of of a clinician to look at lactate levels in non-exercised state and connect it to a greater risk of type 2 diabetes so there's just a few studies that i just want to share as we start to wrap up one study this is the ishi tobi study 2019 they found that fasting serum lactate levels are elevated in people with type 2 diabetes and it was very consistent they another group sandquist you at all. This is the 2001 study found that in healthy, so non-diabetic first degree relatives of people who have type 2 diabetes, these non-diabetic individuals, but related to people with known type 2, had higher fasted lactate levels in the body. So this was thought to be an early indicator of an increased risk, which is very well known. If someone has a first degree relative with type 2 diabetes, they have a much higher risk of developing type 2. And interestingly, they also will have higher lactate. Another study, this is from the Atherosclerosis Risk in Communities, ARIC, A-R-I-C study. It demonstrated a strong association between lactate levels and development of type 2 diabetes. So this was a little more perspective following people over time, essentially concluding with higher lactate. there was a correlation of increased risk of diabetes. And then in that same study, but a different publication, but from that same overall project and data set, they found that this is evidence of reduced oxidative capacity. So kind of bringing it more conclusively back to the mitochondria. So I want these sentiments to affect you, where you think, That you have a better appreciation of the role of lactate well outside the realm of athletics, which is relevant but also less relevant than its ability to act as an early warning for a metabolic problem, specifically a mitochondrial problem. And then perhaps predicting a greater risk of type 2 diabetes. So as continuous lactate monitors are being developed and eventually will be hitting the market. This is one of the areas that I hope it will focus on. It being a sign, a potential sign of mitochondrial dysfunction and thereby a predictor of underlying metabolic risk, particularly with type insulin resistance and type 2 diabetes. All right. Thanks for attending the lecture today. I hope these ideas have been helpful and that you feel like you have a much greater appreciation and understanding of lactate. Despite it being much maligned through the decades, thankfully that reputation is changing and far from being viewed as a metabolic villain or garbage. increasingly appreciated as a hero not only acting as a viable fuel source for any busy cells but also damaged tissue like the brain and traumatic brain injury and then even now more and more being appreciated as a signal that can help people maintain ideal fat mass and thereby perhaps reduce risk of metabolic diseases again thanks for attending i hope the lecture was helpful and always remember more knowledge better health

When you hear the word lactate, in your mind, you may be immediately thinking of lactic acid. Let's just establish this and clarify it up front. In humans, as in other animals, there is no lactic acid. We're going to talk about the origins of lactate in just a moment and clarify this a little bit. But everything you've ever heard about lactic acid is probably false, including its very existence within the human body.

A lot of people have incredible and remarkable even misconceptions. But in normal animal cells, in all sorts of possible conditions. It's lactate.

It's in this what's called a salt form. It's not the acid. It's not a lactic acid.

And it's not the cause of muscle soreness. It's not the cause of muscle fatigue. Whatever your track coach or your health authority told you as you were growing up and engaging in sports, it's not true.

All right. Now, Now that I've dispelled that, let me just state it again very clearly without the rambling. Humans have lactate.

We do not have lactic acid. Now, as we continue sort of an introductory concept here, lactate is a product of what's called anaerobic glycolysis. Now, I personally don't like that term, anaerobic.

Anaerobic invites this idea of this phenomenon occurring in the… absence of oxygen. Now, there is not a situation in humans where there's no oxygen. And so that doesn't particularly apply. The term that I prefer is non-oxidative glycolysis or even non-mitochondrial glycolysis.

Now, let me just give you a very brief primer on glycolysis, this being relevant because it's the origin of lactate. When you have a glucose molecule that has entered a cell with... And immediately, it commits to this path of glycolysis or the splitting or the breaking down of glucose.

Everything is in common, what I call the preparatory phase, the payoff phase. And then you get to the end of this and you get to a molecule called pyruvate, not pyruvic acid. It's pyruvate that is produced. Now pyruvate has an option.

And generally, it is whichever option predominates. is a function of whether there are mitochondria there, because some cells don't have mitochondria, well, one particular type, which I'll mention in a moment. And then the demand of the ATP, not so much is there oxygen present, there's always going to be oxygen present.

So I don't like to focus on that particular aspect of it. Now, when you get down to pyruvate, glycolysis, now the pyruvate molecule, and thus the end of glycolysis has two options. It can either go through this non-oxidative or non-mitochondrial final step, or it can go through this final step, which ends up putting it at the beginning of a whole bunch of other steps through oxidative or mitochondrial glycolysis.

Let's just stick with that one for just another second. If the pyruvate molecule goes into the mitochondria, it will become acetyl-CoA, and then you have the citrate cycle or Krebs cycle now, and then everything else that comes thereafter. electron transport, oxidative phosphorylation.

However, if you get to the pyruvate molecule, let's go back to the first option, and now it is staying outside the mitochondria or non-oxidative or non-mitochondrial or anaerobic, again, which I don't love because of the potential confusion. Now the pyruvate goes through an enzyme called lactate dehydrogenase and becomes lactate, the lactate molecule that we know. even if we've been accidentally calling it lactic acid.

It's not lactic acid and it never is in the body. So that's lactate. So lactate, we could say it very succinctly, is the end product of non-oxidative glycolysis. It's a product that comes whenever a tissue or a cell, to be more precise, needs to create a lot of ATP or the chemical energy very, very quickly.

Thus, one common source is muscle. It's common. Muscle is a common source because not only we have so much muscle in the average individual, most of the tissue in their body is made of muscle. So muscle is the predominant tissue on the human body. So we have so much of it, but also it has moments of extraordinary.

demand for energy. In those instances, like for example, high intensity exercise, lactate is going to be a common product because it is the end product of non-oxidative glycolysis. And non-oxidative glycolysis is a nice way to produce a lot of ATP very quickly. Now I mentioned the muscle. Of course, muscle have a lot of mitochondria and they use it.

Muscle uses mitochondria, including a lot of oxidative glycolysis, a lot of beta oxidation of fat. So lots of fat burning, lots of glucose burning happening in the mitochondria. But there is a cell that flows through the blood, which does not have mitochondria.

And that is the red blood cell. Because the red blood cell does not have any mitochondria within it, its only method of obtaining energy is through the only nutrient that can be metabolized or catabolized outside of the mitochondria. namely the red blood cell and glucose.

So glucose is the only fuel that can be burned or used without reliance on the mitochondria or the only one that has a non-oxidative potential to it. And thus the red blood cell, which lacks mitochondria, must rely on non-oxidative glycolysis 100%. It is completely reliant.

Thus, the red blood cell produces a lot of lactate because every time it's using glucose for energy, which is the only source it can use, it's producing lactate. And again, at the end of it, all lactate is coming from pyruvate and all pyruvate is a consequence of glycolysis. Okay, that is some of the introductory idea of what is lactate and where does it come from. Now we're going to get into what it does. That'll be the meat of the lecture today, which I'll get to in a moment.

One of the things that I'm most grateful for through the course of my PhD in bioenergetics was a history of bioenergetics. Ever since that class, I'd never had a class that touched on the history of science, who were the people who made the seminal discoveries in whatever topic we were discussing. But ever since then, I can't help but also want to do the same.

So let's just go through a brief history lesson of lactate. in the science surrounding it. Because there are some really neat people who ought to be acknowledged because of their contributions to what we know now.

I think it's really a shame if we don't recognize the efforts of those who've gone before us. Now, the first individual I would mention, and there are others beyond the few that I will bring up here. The first is Otto Meyerhoff.

Otto Meyerhoff was a German biochemist who really led our understanding of muscle metabolism in particular. Now in the early 20th century, Meyerhoff discovered that if you could take a limb of an animal and force it to continue to contract, so force it to undergo extreme exercise, it would start releasing a lot of lactate. So he was the first one to see that if and if he put the working leg in a little chamber that was depriving it of oxygen, then even lactate would even be produced more readily and in much higher amounts.

So he was the first one to start really teasing out lactate not only being a sign of intense exercise, but also more heavily produced based on the oxidative availability and potential of tissue. So connecting glycolysis to lactate, that was really his main finding, which was called the Meyerhoff cycle. This idea of lactate turning of...

glucose turning into lactate through its metabolism. In fact, this discovery was so relevant and considered novel and important that he won the Nobel Prize in 1922 for this work. So Nobel Prize winning work.

And it's to him, we owe our gratitude appreciating the origins of lactate in the first place, namely connecting it back to glycolysis. Now, That's not it. We're not done yet.

Now, so he found that glycolysis would produce lactate if it's non-oxidative in its origins. But then it was another group who I really appreciate because they found one of the fates of lactate. Up until that time, including Meyerhoff's work, lactate was absolutely considered a waste product.

It was just metabolic garbage. And even worse than just… benign trash, it was considered harmful, as you've heard before. So again, at best, lactate was considered just benign waste product that would somehow need to be eliminated.

At worst, it was also considered a contributor to muscle fatigue and muscle soreness. Why are you feeling the burn? It's because of lactate. That's just not true.

That's not why you feel the burn. Lactate has nothing to do with that. So that is where it sort of ended. Meyerhoff's work identified lactate as a product of non-oxidative glycolysis. And then what the lactate did after that, well, who knows?

Well, then we come to the Corys. This is... I say plural, this is C-O-R-I, Carl and Gertie Corey. This is a husband and wife team of biochemists who made really groundbreaking contributions to understand carbohydrate metabolism, including the role of lactate.

So we have Gertie Corey, who I will skip to the end of their story, was the first woman to win the Nobel Prize in Physiology or Medicine in the mid-1940s. And then her husband, Carl, who shared the Nobel Prize. Let's just pause and appreciate how cool that is.

This is the Cori cycle, which is what I'm talking about now. We mentioned the Meyerhoff cycle, the creation of lactate from glucose. The Cori cycle is mind-blowingly cool because it represents some incredible recycling of molecules within the body in a way that would seem impossible. That it's like a...

This idea of like a continual motion machine, you know what I'm talking about, this idea that you have something that can continually replenish itself. That's sort of what the Cori cycle identifies here as I'll get into. But again, this is a Hungarian couple, Carl and Gertie. This was a couple of biochemists, married couple working together on this who identified it.

It's really, really neat. Now, what is so neat about it? They identified this cycle of lactate production. from the working muscle, and then the lactate would be exported. There are transporters that fit lactate that enable lactate to move in and out of a cell.

That's a very important point that we'll come back to. Now, it's not a surprise that lactate can move out of a cell. Meyerhoff would have identified this even if he didn't know what the transporter was, and he didn't, because you could measure lactate in the blood.

Someone's exercising hard. With higher intensity comes higher lactate. So of course, lactate has to have a way of getting out of the working muscle into the blood. Now, what the Corys found is that that lactate, one of the main recipients of that lactate is the liver. And then the liver will start to pull in that lactate.

And then you could imagine that glycolysis pathway that I described earlier, where you take a glucose molecule and break it down and you get lactate at the bottom. What the Corys found is that when lactate comes into the liver. There's so much lactate coming in that it actually starts pushing that pathway in reverse.

In other words, no longer is lactate a product of glycolysis. Now it's the origin or the substrate for gluconeogenesis, the synthesis of new glucose. That's the Cori cycle.

But then, of course, we're not done. Once the liver has made glucose from scratch, from lactate, this gluconeogenesis, it can release the glucose. The glucose can come out of the glucose transporter on the surface of the liver cells, thereby giving the blood, dumping glucose back into the blood.

Well, guess who can pull that glucose up and use it? The muscle. So the very tissue that gave birth to the lactate and those carbons breaking down glucose then receives those carbons back in the form of newly created glucose after having a spent the glucose and turning it into lactate.

That is the Cori cycle. Now it took me a long way, kind of a roundabout way to describe that. So let me just say it one more time.

So the working, the Cori cycle is that the working muscle is relying heavily on non-oxidative glycolysis, thereby producing and releasing a great degree of lactate. The liver being, as I've described it, the ultimate soccer mom of nutrient metabolism. It knows what to do with everything. It can pull in that lactate and turn it back. into glucose through gluconeogenesis and then release that glucose back into the bloodstream to then be taken up by any tissues that need the glucose for energy, including the muscles where the entire thing started.

That's the Cori cycle. So it highlights this incredible efficiency in recycling these carbons or metabolites, converting what would be perceived as a byproduct, lactate, back into this. heavily relied on and usable energy source, namely glucose.

Now, I'm not done. The Corey cycle was revolutionary in demystifying and clarifying the role of lactate, suggesting that it's far from being metabolic garbage. In fact, it's substrate for energy. Now we go to the final individual who I want to bring up, which is George Brooks and his work at UCLA.

I've met him. He's still alive. He's a wonderful guy, really, really remarkable in his contributions to bioenergetics and exercise science.

Indeed, a contributor to a really incredible textbook on bioenergetics. Now, decades after the Corys, George Brooks found that far from just lactate being... So we've evolved here, right?

First, lactate is metabolic garbage and maybe even harmful. The Corys find that, well, it's not metabolic garbage. It can actually contribute to viable energy in the body. George Brooks'contribution was that lactate itself is a viable energy source. And he proposed this as part of what he called the lactate shuttle theory.

So George Brooks in his lab at UCLA demonstrated that lactate is not a waste product, but it has the ability to not only be exported from a cell and thereby contribute to the query cycle, but itself is a viable fuel on the mitochondria. As much as we have taught and we've looked at non-oxidative glycolysis. as coming down and stopping at lactate, then the lactate has to be dumped from the cell.

That's not true. The mitochondria have lactate transporters. So mitochondria can pull in lactate and then pull in the lactate and then convert it to acetyl-CoA and send it into the citrate cycle or the Krebs cycle, getting all of this energy that we typically only think we're getting through oxidative glycolysis.

So this is a huge... paradigm shift and i i worry that in my description i haven't adequately stated just how neat this is so let me be clear if you have a muscle cell that's creating lactate yes it can export it so the liver can turn it back into glucose through the quarry cycle but even if it exports it other cells that can take it up including the liver if it has if those cells have mitochondria every cell with mitochondria that i'm aware of is capable of pulling lactate into the mitochondria through specific transporters and burning that lactate for energy. So lactate once, so we've reached sort of the peak of this evolution. And in fact, there's even one more aspect of that I'll mention in a moment, but lactate went from being metabolic garbage to being good for being a substrate to rebuild glucose to now saying it's actually a viable energy source in its own right.

mitochondria can pull lactate in and actually burn that lactate for energy, even in the muscles that create it. Now, as much as I've been focusing on the muscle, allow me to just go on a brief little tangent here. One of the first instances where I heard about the role and the benefit of lactate as an energy source was for traumatic brain injury. So it is very well known. And I'll have some links to some of these papers that I'm going to mention in a moment in the show notes, of course.

But after a traumatic brain injury, one of the problems with the brain is that there is this disruption in the enzymes that the brain relies on to use glucose. In other words, glycolysis is compromised. Well, that's a problem if this is a brain that is primarily relying on glucose for energy. So.

Again, part of the problem with a TBI or traumatic brain injury is that the brain starts to starve. So let's give the brain any fuel source we can. Of course, ketones are a very viable fuel source and are often used as part of the therapy for TBI, but so too is lactate.

Lactate can serve as an alternate energy for the brain. It allows the brain to bypass this now sluggish glucose metabolism, thereby helping it create... adequate ATP.

And that's important because the brain has a high metabolic rate. It is one of the trinity of so-called high metabolic rate organs being kidneys, heart, and brain, I think in that order. So the brain has a very high metabolic demand. And if the TBI is resulting in its glucose use being compromised, well, then all the more reason to give it something else. So again, commonly for TBI, Lactate will be actually infused.

And sure enough, there's evidence to show that if you infuse a lactate solution, it can reduce brain swelling and it can improve the intracranial pressure in patients with TBI. And this could be because you're allowing the brain to maintain sufficient energy. And with that energy comes the ability to sufficiently regulate electrolyte movement and then the water movement along with it. But there's really compelling evidence in animals and humans showing that after TBI, if you administer lactate, you improve brain energy production.

And then in the animal studies, this has been shown that you can prevent some secondary damage from following the trauma. So that's a very neat application of lactate in a pathology, in a disease or problematic state. Now, so far in my defense of lactate.

I have described its main benefit as being energetic, that it's because of the energy that lactate can give, which is all good. That's all accurate, and I think it's important that we appreciate that lactate, not lactic acid, not only does not contribute to problems in the muscle or any other tissue that it's coming from, it actually can help by giving the tissue energy, where the lactate can be used as an energy source or be converted in. back into a different energy source, namely glucose.

Now, I wanted to highlight one last part of lactate that I think is not appreciated before we get into some of its further relevance in clinical context. And that is the ability of lactate to send a signal to fat tissue. So there are multiple studies now showing that lactate, when it comes to fat cells, is capable of having a few remarkable effects. Very unexpected. One, for example, is that lactate has been shown to help in the beiging of white adipose tissue.

Now, I am touching on a deeper topic that I've in fact talked about before in previous metabolic classrooms, but you'd be familiar with the idea that on the human body, there is white adipose tissue, which is the fat that we pinch and jiggle and has an extraordinarily low metabolic rate. which isn't surprising because it's one of its primary roles is to store energy. But at the same time, humans have brown adipose tissue, although relatively quite little of it. But this brown adipose tissue stands in stark contrast to the functions of white because brown adipose tissue, these fat cells have a very high metabolic rate. They aren't designed to store energy, but rather to burn it with a primary purpose, apparently being the creation of heat.

So this is a way in which humans can maintain a body temperature in the absence of shivering. But in adults, of course, it just means it works with shivering to help the body be warm. So lactate has been shown to make white adipose tissue behave a little more like brown adipose tissue.

And separate from this has been the evidence that lactate does so by stimulating mitochondrial uncoupling. Now, once again, this is a... deeper topic. It's a fascinating topic and it's one that I love talking about, but it's a bit of a too big of a tangent right now.

But suffice it to say, if you increase mitochondrial uncoupling, then you are making the mitochondria and the cell by extension burning energy just to create heat, which in an organism or within biochemistry, that's a generally an inefficient effect. Normally, if you're burning something, you want to get work. You want to flex a muscle more, for example.

In this case, fat tissue, which has no flexing to do, now you're just telling the fat tissue to just burn through energy just to create heat. And again, lactate does this. So beyond its ability to be used as a fuel, it actually can stimulate greater fuel use. So lactate is acting as a signaling molecule. It's telling these white fat cells to be a little more.

wasteful with their energy. And if you've got energy to burn, like most people do, as we all struggle with varying degrees of chubbiness or obesity, then that's not a bad strategy. So this is, in my mind, this represents another just fascinating interaction in the body where in the case of, let's imagine an exercising muscle producing lactate. That lactate then has further benefit.

If this person, say, exercising to maintain or improve metabolic health, the lactate is further helping that happen by stimulating a little bit of an advantage at the fat tissue, just telling the fat tissue to run a little hotter to increase its metabolic rate just a bit. Now, likely, as I kind of near the end of the lecture topic here, I want to, like I said, I want to highlight its relevance, lactate's relevance in a clinical context. I think this is important because as we are approaching the widespread creation and use of continuous lactate monitors, the low hanging fruit for these soon to be available lactate monitors, and it is soon, the obvious relevance is going to be in athletics because people are going to want to be training and monitoring their lactate threshold.

And for good reason, that's a nice effective training strategy of improving your overall fitness and your capability. But that is the low-hanging fruit. And in fact, I would suggest it's the less relevant fruit. I think the more relevant part of lactate monitoring and the widespread and continuous measuring of lactate is its role in predicting and being indicative of mitochondrial damage.

So if you detect that people who have chronically high lactate levels, not because they exercise so much, in the absence of… exercise, it could be evidence of an inability to burn it very well. As you'll recall from Dr. George Brooks'work, lactate is an energy source. The body can literally burn it directly as a fuel, but to do so, it has to rely on the mitochondria. Well, what if people don't have as much mitochondria perhaps as they should, or the mitochondria aren't working particularly well?

That brings us back to this idea of mitochondrial dysfunction. One of the most relevant disease states that have been shown to connect or be a result of mitochondrial dysfunction in part is type 2 diabetes. So there is a tremendous and even old area of research.

There's one of the studies that I'm going to share with you in the show notes is from 2001, just documenting the ability of of a clinician to look at lactate levels in non-exercised state and connect it to a greater risk of type 2 diabetes so there's just a few studies that i just want to share as we start to wrap up one study this is the ishi tobi study 2019 they found that fasting serum lactate levels are elevated in people with type 2 diabetes and it was very consistent they another group sandquist you at all. This is the 2001 study found that in healthy, so non-diabetic first degree relatives of people who have type 2 diabetes, these non-diabetic individuals, but related to people with known type 2, had higher fasted lactate levels in the body. So this was thought to be an early indicator of an increased risk, which is very well known. If someone has a first degree relative with type 2 diabetes, they have a much higher risk of developing type 2. And interestingly, they also will have higher lactate. Another study, this is from the Atherosclerosis Risk in Communities, ARIC, A-R-I-C study.

It demonstrated a strong association between lactate levels and development of type 2 diabetes. So this was a little more perspective following people over time, essentially concluding with higher lactate. there was a correlation of increased risk of diabetes.

And then in that same study, but a different publication, but from that same overall project and data set, they found that this is evidence of reduced oxidative capacity. So kind of bringing it more conclusively back to the mitochondria. So I want these sentiments to affect you, where you think, That you have a better appreciation of the role of lactate well outside the realm of athletics, which is relevant but also less relevant than its ability to act as an early warning for a metabolic problem, specifically a mitochondrial problem. And then perhaps predicting a greater risk of type 2 diabetes. So as continuous lactate monitors are being developed and eventually will be hitting the market.

This is one of the areas that I hope it will focus on. It being a sign, a potential sign of mitochondrial dysfunction and thereby a predictor of underlying metabolic risk, particularly with type insulin resistance and type 2 diabetes. All right. Thanks for attending the lecture today.

I hope these ideas have been helpful and that you feel like you have a much greater appreciation and understanding of lactate. Despite it being much maligned through the decades, thankfully that reputation is changing and far from being viewed as a metabolic villain or garbage. increasingly appreciated as a hero not only acting as a viable fuel source for any busy cells but also damaged tissue like the brain and traumatic brain injury and then even now more and more being appreciated as a signal that can help people maintain ideal fat mass and thereby perhaps reduce risk of metabolic diseases again thanks for attending i hope the lecture was helpful and always remember more knowledge better health

Transcript for:Understanding Lactate Metabolism and Its Importance

Transcript for:
Understanding Lactate Metabolism and Its Importance