We talk a lot on this show about one of the most basic principles of training—you do a workout that puts a stressor on your body, then yada, yada, yada, a bunch of stuff happens, your muscles adapt, and you become stronger and faster.
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We tend to skip over the “yada yada” part, but today’s guest, Dr. Brendan Egan, a professor at Dublin City University in Ireland, wrote a 2023 review paper all about that. It was a 118-page review with over 1,200 references. There are books that are shorter—and yet he still started the review by saying they didn’t have the space to go into all of the details!
In other words, what happens in our muscles to make us stronger and faster is miraculously complex. No one, not even Dr. Egan after writing his review, could remember it all. Fortunately, we’re not going to ask you to, either. This is not an episode about all those biochemical terms; instead, we’re going to help you understand at a high level how our muscles adapt to a training stress and turn it into power.
What we actually talk about, believe it or not, is proteins. At its simplest, stress from physical exertion creates signals that cause our cells to produce more proteins—very specific proteins that serve as the signalers, transporters, and raw materials of our muscles that make us stronger and faster.
We also talk about how even though weightlifting and endurance exercise are both forms of muscle contractions, they lead to very different adaptations. Again, it comes down to producing a different mix of proteins.
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You can be a good athlete or coach just by knowing what interval session or weight workout will produce the benefits you want. But understanding how that training impacts the body on a molecular level can help you make even better decisions.
So, get ready for some molecular fast talk (no, I didn’t say PGC-1a) and let’s make you fast!
References:
- Coffey, V. G., & Hawley, J. A. (2007). The Molecular Bases of Training Adaptation. Sports Medicine, 37(9), 737–763. Retrieved from https://doi.org/10.2165/00007256-200737090-00001
- Egan, B., & Sharples, A. P. (2023). Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training. Physiological Reviews, 103(3), 2057–2170. Retrieved from https://doi.org/10.1152/physrev.00054.2021
- Egan, B., & Zierath, J. R. (2013). Exercise Metabolism and the Molecular Regulation of Skeletal Muscle Adaptation. Cell Metabolism, 17(2), 162–184. Retrieved from https://doi.org/10.1016/j.cmet.2012.12.012
- Laursen, P. B. (2010). Training for intense exercise performance: high‐intensity or high‐volume training? Scandinavian Journal of Medicine & Science in Sports, 20(s2), 1–10. Retrieved from https://doi.org/10.1111/j.1600-0838.2010.01184.x
- Laursen, Paul B., & Jenkins, D. G. (2002). The Scientific Basis for High-Intensity Interval Training. Sports Medicine, 32(1), 53–73. Retrieved from https://doi.org/10.2165/00007256-200232010-00003
Episode Transcript
Trevor Connor 00:00
Trevor, hello and welcome to fast talk your source for the science of endurance performance. I’m your host, Trevor Connor, here with Coach Rob pickles. We talk a lot in the show about one of the most basic principles of training. You do a workout that puts the stressor on your body, and then yada yada yada, a bunch of stuff happens in your body and you become stronger. Thing is, we tend to skip over the yada yada part. But recently, today’s guest, Dr Brendan Egan, professor at Dublin City University in Ireland, wrote a review paper all about that yada yada part. It was 118 page review with over 1200 references. There are literally books that are shorter, and yet he still started the review by saying that he doesn’t have the space to go into all the details. In other words, what happens in our muscles to make us stronger and faster is miraculously complex. No one, not even Dr Egan, after writing his review, could remember it all. Fortunately, we’re not going to ask you two either. This is not going to be an episode about all those biochemical terms. But instead, we’re going to spend today’s episode helping you understand at a higher level how our bodies respond to a training stress and turn it into power or strength. What we’ll talk about, believe it or not, is proteins, at its simplest, the stress in our bodies produce signals that cause our cells to produce more proteins, importantly, very specific proteins that serve as the signalers, transporters and the raw materials of our muscles to make us fitter. We’ll also talk about how, even though weight lifting and endurance exercise are both just forms of muscle contractions, they lead to very different adaptations. Again, comes down to producing a different mix of proteins. You can be a very good athlete or coach just by knowing what interval session or weight workout produces the benefits you want, but understanding how that training impacts our bodies can help you make even better decisions. Today, Dr Egan is going to give us a fascinating look at just what goes on inside our muscles. So get ready for some molecular fast talk. No, I didn’t say PGC one alpha, and let’s make you fast Well, Dr Egan, welcome back to the show. We’ve been looking forward to this episode with you. I think we had you on a year ago, and at the end of that episode, we said, got to get you back on, so you’re back on with us.
Dr. Brendan Egan 02:07
Hey, I couldn’t believe when I checked that it was a year ago. It feels like yesterday. I’ve listened back to that podcast who did that time, and I was pleased as a result. So hopefully we can do something similar with this topic. Well,
Rob Pickels 02:18
that topic was a little bit more, I don’t want to say concise, but it was a singular topic of ketones, right? Awesome discussion that we had around that today. I think that we have a much, much bigger discussion on adaptation, biochemistry, all the processes within our body that are hopefully making us better. Yeah, and I
Trevor Connor 02:37
gotta share this. You sent two reviews to us that you wrote saying, hey, check these out if we’re going to talk a bit about the biochemistry. And I was sitting there on a Saturday a couple weeks ago going, Okay, well, I’ll just, I’ve got two hours. I’ll pound out one of these reviews. I open up your review 118
Rob Pickels 02:58
pages, yeah, not 118 references, which would be a lot of references for most papers? No, no, no,
Trevor Connor 03:05
no. In terms of the references, I remember getting to the point in your paper, you numbered your references and you had reference 1000 I have read a lot of review papers. I have never seen a review paper have over 1000 references. Yeah. That.
Dr. Brendan Egan 03:23
Well, look, there’s a few points to make on that. I mean, it was, it’s a big piece of work because it pulls on a lot of strands from both molecular biology, but also exercise physiology. And there’s a bit of looking into the past, looking at present, looking into the future. You know, there’s not that many journals that publish those types of reviews. So that particular journal, physiological reviews, is known for, you know, very large reviews. And the first review that I had sent to was the one from 2013 which in soil metabolism, which is, you know, reasonably long, um, but not the same level of detail. And the the invitation to write another review for physiological reviews, I think, was the reflection of that review, that 2013 review, being relatively well received, and the need for an expansion, because, to be honest, this area of research, there’s just so much going on. Now, the point I often make is when I present to conferences, is that from the moment that you publish a paper in this domain, a month later, there’s another 50 papers. And that’s not an exaggeration, if we’re thinking about papers are looking at muscle, for example, in rodent cells, humans looking at different molecular pathways. Now, in the advent of omics, so many more papers coming out, they require follow up of these new molecules, and there’s just a huge, huge topic area. So a lot of the times, you’ll have shorter reviews in journals that are more focused on specific topics under that broad umbrella, but within, as I said, that particular invited review and physiological reviews, the the scope was there to go, you know, as wide and as deep as possible. And so that’s where it landed. Think was 40 something 1000 words. Yep, it took a while. Some people ask me how long it took those things, they kind of percolate in your mind for a long. And from the moment you publish one review, you’re maybe thinking about the next one. But from the day we were invited to write that to when it was published was about four years. But I will say that there was two interruptions. One was that I was on sabbatical for a year, so did no work on it. The other was during COVID. We had actually quite long and severe lockdowns in Ireland. So we had the kids were at home from school for the best part of six months to eight months over the course of two years. And so I did no work while they were at home. So yes, I probably say it’s a two year project. Was to cook it longer than I needed to just
Trevor Connor 05:30
give everybody an idea. You said 40,000 words, a typical book is 60 to 70,000 words, so you essentially wrote a slightly short book.
Dr. Brendan Egan 05:40
Oh, it’s nice to know I hadn’t actually worked out the numbers like that. It’s funny, actually, my co author on the paper, Adam Sharples, he actually, at the time, was also writing a book, and it was on molecular exercise science, molecular size physiology. Can’t remember the name. I contributed a couple of chapters to that as well. But it’s funny that you mentioned that, because in that particular book, we also have a chapter that’s even, I would say that it’s aimed maybe at the undergraduate to early graduate. So there’s a little bit more of the kind of the basic information there that might be missing from from the review. So if there are people who maybe find the reviews a little bit of a higher level than they would like, that’s a nice book chapter to get into as well.
Rob Pickels 06:17
Yeah. And if anybody wants to follow along at home, the 2013 paper, that is more of an appropriate length, I would say, is titled exercise metabolism and the molecular regulation of skeletal muscle adaptation. But the one that maybe encompasses more of what we’re talking about today is that 2023 paper with Dr Egan and Adam Dr Sharples, and that is titled molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training.
Trevor Connor 06:47
And we’ll put both these in the show notes, and we might put a giant warning sign in front of the 2020
Rob Pickels 06:51
Oh, no, no, no warning. Just let people dive in. The warning
Trevor Connor 06:55
is set aside some time. As
Dr. Brendan Egan 06:57
I joked by email, I said that I’m glad someone’s reading this.
Trevor Connor 07:02
Well, here’s why we’re focusing on the length of this. In the show, we talk a lot about adaptations, and we tend to talk about it as you do a stress to your body that your body can’t quite handle, so that disturbs homeostasis, and then something magical happens in the body, and then you’re stronger. So this paper is about that magical thing that we kind of skip over a lot. We touch on it a little bit, but the reason we’re focusing on the length is to make everybody understand how complex this is. And what I loved is when I opened up your paper and saw how long it was and went, Okay, this is going to be more than two hours, I started reading it, and in the intro, where you’re talking about what you’re going to cover, what amazed me was how many times you said, we don’t have the space to cover this in depth. And I’m sitting there going, this is 118 page paper, and you don’t have the space to cover it in depth. And there’s truth to that, which is, this is incredibly complex stuff. And no, we’re not going to go in an hour podcast into the complexity of this. We’re going to talk about some of the higher level stuff. But I really want our listeners to understand that when you’re doing these things to your body, when you’re going out and doing intervals, and you’re wondering what’s happening the biochemistry, I don’t think there’s anybody in the world who could say, Yeah, I have all this memorized. I know everything that’s happening. I
Dr. Brendan Egan 08:27
just echo all of that. You know, even when I, to be honest, go back to look over that paper, when I teach the concepts from time to time, it’s not like these things are on the tip of my tongue. You know, there’s so much there that it does take revisions, even among people who have written a lot about it and done a lot of papers on this. So as I said, sort of hinted at a few minutes ago, there tends to be more of where we have people who are working on individual pathways, and in this case, the majority of what we’re talking about in this particular podcast is going to be about Skeleton muscle, yet you’ve got adaptation taking place in multiple different organs around the body. So you’re completely right. I mean, no one has all of this to hand at all times and can describe all of this perfectly. But the working model that’s in the paper, and it’s the one that’s kind of widely accepted in the field, is, as you describe, which is that exercise provides the stimulus. There is a series of steps initiated and interpreted and sensed and translated by these various number of factors within the within the muscle, and sometimes extrinsic to the muscle. And as you say, something magical happens, and we get adaptation. And again, I think we can drill down into the concepts in each step or each stage there, and then maybe some of the broader outcomes that we recognize as the classic adaptation to train. I think it’s a good way to understand where the field is at at the moment. So
Trevor Connor 09:41
before we explain some of that, and what we’re going to dive into is we’re going to spend most of the day talking about proteins, and we’re going to explain why that’s really interesting. But before we get into the what, let’s you at the start of the paper talked about the how you basically said we have understood since the 1960s How we adapt. So basically, there’s a stressor. It causes a perturbation to homeostasis. And then if you’re doing resistance training, this is the main adaptations you see. If you’re doing aerobic training, these are the main adaptations you see. So can you just give us the two minute overview of what the major adaptations are, for
Dr. Brendan Egan 10:19
sure. So I would also just preface that by saying that from a didactic point of view, you know, when we’re teaching, this is the way that we kind of do it in that we say, okay, there’s an extreme phenotype or adaptation, which is the marathon runner, and on the other extreme, there’s the strength trainer slash bodybuilder. And these are two extremes, and that’s a way we can model extreme training in one domain, extreme training in another domain, resulting in these very divergent adaptations, and that’s kind of the way we teach it. And of course, there are those athletes in each of those domains, but there’s a huge amount of in between on that continuum. And my background is in team sports, where we do a little bit of endurance and a little bit of intervals and a little bit of strength training a bit of power. And that’s true of lots of different sports. So I would just make that first comment in that we again, experimentally, it’s useful to use the extremes in teaching. It’s useful to use the extremes, but in the real world, I think sometimes the practical application can sometimes be lost in this domain, because people are more concerned about, well, what about me? Who’s doing mixed training? You know, not the classic extremes that are described in these studies very quickly,
Trevor Connor 11:22
because we’re going to go into that a little more. But I loved in your paper, how you brought that up that I love the biochemistry papers and multiple biochemistry papers that are much shorter, kind of go resistance training, that’s a k, T, M, Tor pathway, and aerobic training, that’s the AM, PK, PGC, one alpha, which I talk about all the time, pathway. And you think it’s one or the other, and you make the point now you really seem both activated and almost all work. It’s just degrees fully
Dr. Brendan Egan 11:53
agree to kind of give a fine example there of the contradiction is that in many cases, what we’re talking about, and you mentioned already in your introduction about the idea that it’s changes in proteins that are often at the heart of what happens when the muscle adapts to exercise, and in many cases, it’s a greater amount of that protein. So there’s been protein synthesis. So to kind of suggest that mTOR has no role in the synthesis of new proteins in response to endurance exercise just because it happens to be activated to a greater extent in resistance exercise, there’s kind of a contradiction of sorts within that. So I think some of it, to be honest, comes from two issues. One is that that whole idea of studying extremes and studying models where we really over express the protein, or we completely inhibited with it, with the chemical inhibitor that is, again, extreme approaches. But the other sometimes, I think, is kind of laughable. It’s that the way we draw these cartoonish diagrams, the easiest thing to do is just to say there’s one molecule for one pathway, one molecule for another. In the case of that interference effect, I think that you’re alluding to there, we’re saying that, you know, mTOR inhibits the pathway, or MDK inhibits the other pathway, that kind of representation. And I think people, they gradually begin to kind of simplify these concepts in their head. And again, like I said, sometimes it’s necessary for the purposes of teaching, but it’s not often useful. You know, in terms of being able to explain these concepts in enough nuance and enough detail is to be meaningful.
Trevor Connor 13:14
I think some of it’s also just because if we try to draw just the proteins and pathways that we understand, it’d be such a complex diagram. As I said, nobody could have that memorized.
Dr. Brendan Egan 13:25
Oh, yeah. And I joked at one point, you know, a lot of people, they’re just looking at the cartoons now. They’re not reading the papers. And there’s a certain truth to that, which is why we begin to make the cartoons a bit more detailed, and we make more detailed legends to go with those and explanations to go with those figures, but they don’t capture so much of the complexity. And I think as we begin to maybe mention some of the recent omics studies that are being done in this domain, now you can’t really represent those on the kind of cartoons and figures that we use in papers anymore. Sorry.
Trevor Connor 13:55
So we went on a tangent there. Let’s go back to the really simple what are the major adaptations we see in resistance and aerobic training. So
Dr. Brendan Egan 14:01
for steroid resistance training, I think most people will picture, if we use the bodybuilder as an example, it’s that hypertrophy phenotype, where there’s muscle growth, usually the accretion of new protein, so the muscles are bigger, for want of a better word, and there are a number of other factors under the skin, so to speak, in terms of neural adaptations, better synchrony of motor unit firing, improvements, like I said, in some of the architecture, around angles of pennation and so on, so across a number of different domains within the muscle, and the way that force is transmitted through the muscle and the size of the muscle, they’re considered to be the kind of classic adaptations to resistance type training and then on. As I said, the other extreme is the endurance of phenotypes of the marathon runner, and oftentimes this is characterized really as an increase in mitochondrial digest. That’s the classic term that’s used. So the idea that the muscle now has got more mitochondria, better functioning mitochondria, but that is just one component that’s really ATP production and oxygen utilization. If. Got the whole delivery side of things. So better computerization, we also have changes then in the way that substrates are both stored and utilized during exercise. So again, I think the point you make is that these are not exclusive to either formal training. It’s just that the magnitude of change in any one of these variables tends to be greater with one form of training than the other. And
Trevor Connor 15:19
I’m assuming most of our listeners already know this. We’ve done a whole episode on this. I can’t remember the number. We’ll put it in the show notes, but just some very basics, mitochondria are little organelles within cells. Think of them as kind of mini cells within the main cell, and that’s where all of your aerobic metabolism happens. So great. So as you said, we’ve kind of known that since the 60s, what we’ve really been studying since is, how does that adaptation happen? What’s going on in the body that goes from you do some intervals, you do a long ride, or you lift some weights, to seeing those sorts of adaptations. As we said, There’s no way we can go into all the detail in this episode. So the place I would love to go and hear from you is this is all about proteins. So what are we talking about when we’re talking about proteins? And let’s start at the very basics, and we’ll get a little deeper as we go. So
Dr. Brendan Egan 16:11
I guess it’s worth saying that many of the things that we’ll discuss that are in that paper, whether that change is in mRNA, so messenger RNA, and maybe we’ll find some of these as we go along. But whether it’s a change in messenger RNA, whether it’s a change in DNA methylation, which is an epigenetic mark, whether it’s a change in so called post translational modification, so these little tags that are present on proteins that can change their function, these are all molecular events, and usually the way that we think about these is that their molecular events along that pathway that you mentioned of where you’ve got a stimulus being exercised and you’ve got an outcome, which is your training adaptation. But it’s these molecular events along that pathway that to a large extent, we’re going to discuss, but ultimately, if the muscle is going to change in function. So for example, if we’re going to be able to produce more ATP, it’s going to be because we’ve got more mitochondrial protein within a cell, or it’s going to be some change in the way that an enzyme within the mitochondria, for example, or can be glycolytic pathways as well, but it’s some change in the protein itself. So the kind of steps, if we think about DNA as our genes, that’s transcribed into messenger RNA, the messenger RNA is translated into protein. There’s a lot of steps to regulation along that way, but it’s ultimately that change in the end point the protein, as a colleague of mine used to say, protein rules the world, and his point was that, you know, studying molecular events is fine, but ultimately, if it’s going to be a change in the way that fuel utilization takes place, if there’s going to be a change in the size of the muscle. These changes are at the level of the protein, and a change in that protein’s function, or a change in its overall quantity within the muscle, if we’re thinking about, say, the microbial protein that influences muscle size, so does that sort of, yeah,
Trevor Connor 17:52
I gotta take it a step back, just for any of our listeners who don’t understand this. So everybody’s heard about DNA, and DNA is what determines who you are, determines how tall you are, what you look like, what sex you are, all of this. 90% of your DNA is just coding for forming proteins. It’s just, here’s how you make this protein, here’s how you make that protein. So if you think about it as an analogy, you’re building a building, the DNA is the blueprints, but proteins are the bricks, the mortar, the beams, all the pieces of the building, and the DNA is just, here’s the code for all those proteins. And so what you’re getting at is when you do some sort of exercise and you cause that perturbation to homeostasis, somehow your body then says, Uh oh, we need to make more of this protein. We need to make more of that protein, and the mRNA is what connects to the DNA, grabs the code for a particular protein and then goes and starts building that protein. Is that accurate?
Dr. Brendan Egan 18:51
Yeah, that’s a great analogy. So I suppose I’ll add a couple more points to that. Is that oftentimes when we talk about guessing colloquial terms, you might hear something like a gene is switched on. You do a form of exercise, and it switches on this gene or switches on that gene. And really what that’s referring to, and people talk about this in relation things like cold water immersion and breathing exercise and so on. This idea of switching on genes is kind of coming to the common parlance, and that’s really this idea that there’s a perturbation, a signal, a change in the messenger RNA, and then some translation into a change in protein somewhere down the line. So this idea of change in protein in response to a stimulus, it’s true of exercise, but it’s true a lot of the adaptive processes that take place in the body, when we’re talking about change over time, there’s lots and lots of things, by the way, that happen just acutely in response to an exercise session that might not necessarily be part of the adaptive process, and that’s one of the, I suppose, caveats within the field at the moment, is that we measure hundreds, if not 1000s, of things that change in response to exercise at a molecular level, not every single one of them is involved in adaptation. Some of it can be around just a disturbance to homeostasis and. An attempt to restore homeostasis, rather than a longer term change in the function of the muscle or of other organs. So I think your analogy is appropriate. I think it explains it well in terms of a concept, but it ultimately is, as you say, the phenotype of the trained individual, whether it’s strength trained, whether it’s endurance trend, or anything in between, it is manifested by these changes in many proteins that involved in cellular function.
Trevor Connor 20:22
And I think another thing, and I’ll kind of start this and throw this to you, a lot of people, when they think about protein, I mean, they all hear, you know, after exercise, you got to eat more protein. And a lot of us just think of that as well. That’s just for bodybuilders, because protein is just building more muscle tissue. That’s all the proteins do. And that’s a dramatic oversimplification. Yes, when you’re increasing the size of a muscle and increasing that cross sectional area of a muscle, you do that by laying down actin and myosin, more of those types of proteins. But proteins do so much more in the body. They’re messengers, they’re hormones. Tell us about all the different things that proteins do in the body. Great
Dr. Brendan Egan 20:59
points. I’d start with the point about protein after exercise and its role there. Oftentimes that’s focused on an outcome measure called muscle protein synthesis, and that’s just a broad term for measuring the synthesis of new proteins within a muscle. In this case, we’re talking about a muscle biopsy, and that is part of the accretion of new tissue, if we’re talking about building muscle, but it can also be to do with the accretion of new mitochondrial proteins as well, which, again, if they’re not structural or myofibrillar proteins, they’re not going to result in a larger muscle, but they are going to change them the fundamental properties that are present within the muscle. So in that case, we’re talking about one example of a protein could be a structural protein that’s involved in the in the myofibril. Another example of a protein could be an enzyme that’s present in the TCS, then the Krebs cycle in the mitochondria, or in the electron transport chain in the mitochondria, you have other proteins then that are transcription factors. So they are proteins that are involved in that process that we talked about, from the DNA being transcribed into the messenger RNA. You’ve got other proteins that are part of the overall cellular machinery that take those messenger RNAs and convert them into proteins. And then you mentioned hormones. So again, hormones are proteins. Antibodies within the body are proteins. Not everything, by the way, is all part of the of the exercise response, but it just gives you a sense that when we talk about proteins within the body and their function within cells, it’s rather different to protein powder sitting on the table getting ready to be drank. So
Trevor Connor 22:30
I think one of the important messages here to our listeners is, I’ve heard endurance athletes say, Well, I don’t want to put on muscle mass, so after a long workout, I’m not going to have any protein in my diet because I don’t want to put on muscle put on muscle mass. But you need that protein because it does so many other things in your body. And if you want to see these adaptations, your body needs those amino acids to do the
Dr. Brendan Egan 22:52
work for sure. I mean, that’s been a major change, and both of us know this or three was noticed that the you know, one of the big changes over the last couple of decades is around the appreciation of protein for recovery in endurance athletes, and the fact that endurance athletes do, in fact, need quite a large amount of protein, and it’s not for muscle growth, it’s for tissue repair and turnover of these proteins. So it’s, again, a major section in the review is about the fact that it’s not just protein synthesis that we’re thinking about here. It’s protein turnover. You know, we have pathways of protein degradation or breakdown that are switched on in response to exercise. And again, it sounds negative to say degradation or breakdown, but these are essential processes in terms of for whatever cleaning up the muscle cells, in terms of some of the breakdown products and misfolded proteins and everything that goes with that. So having this balance between protein breakdown and protein synthesis is protein turnover, and that, again, is elevated in response to exercise training. So there is a requirement, from a dietary point of view, for the purposes of growth and repair in the case of the endurance athlete, but also mitochondrial proteins. New proteins are being formed, and the building blocks do need to be provided. So I think that that whole message around the idea that you’ve got this broad measure of muscle protein synthesis that’s often associated with recovery from strength training or resistance exercise, but in actual fact, protein synthesis is elevated in response to endurance training as well. We need to provide the building blocks for that. In fact, it looks like things like mitochondrial protein synthesis are increased to a greater extent than myofibrillar protein synthesis in the case of strength training, and that seems to be one of the best examples where we can isolate you know why? When two individuals do divergent types of training, they’re both contracting their muscles, they’re both having disturbances to homeostasis, but one of them is doing a lot of reps at very low intensity, for one to the other description, another one is doing a smaller amount of reps, but at much higher forces, these somehow then produce radically different phenotypes. And the answer is, far as we know, is that these different types of contraction activate different pathways, different components of the cell. From a protein synthesis point of view. And that does seem to be the basis of the specificity of the response to training.
Trevor Connor 25:04
So there was a point in your paper that I heavily underlined because I really like the way you expressed it, which is adaptations, in a nutshell, are just about the upregulation of proteins. And as you said, if you’re doing strength training, you’re going to see more up regulation of certain proteins. If you’re doing aerobic training, you’re going to see more up regulation of other proteins. But that’s ultimately what it comes down to, is just which proteins are we up regulating? And
Dr. Brendan Egan 25:28
a point to add to that is that the individual protein so we keep saying proteins, protein, proteins, and it’s true when we say muscle protein synthesis as well. These are kind of global measures, but in the more recent papers that have been done, which again, I find to be some of the more exciting papers in this domain. Papers in this domain. It’s where they can tag these individual proteins and at the individual protein level. So why there’s transcription factors, bicondital proteins, proteins involved in the machinery of protein synthesis. When you can tag these individual proteins, you can begin to see that their activity, or the amount which they turn over, does differ on a protein by protein basis. And again, I think that is what’s at the heart of the specificity of training adaptation. And the other point to make there, I know you focus on upregulation, we sometimes actually try to make the point that you can have also down regulation. You know you can have certain factors that are down regulated in response to training. And that, again, is probably a refinement of the adaptive response over time. Someone once made the point to me years and years ago, it’s like, if everything’s just being up regulated and everything is about synthesis, why are we not just getting bigger, bigger, bigger all the time? It has to stop somewhere. So again, I know that’s a bit of a glib way of describing it, but it is a point worth making that not everything gets switched down and everything gets tuned up in response to training. There’s a bit more to it than that.
Trevor Connor 26:39
The other thing that I love that you brought up in the paper, you know, as I said on this show, we bring up PGC one alpha a lot, and it’s a real simplification. PGC one Alpha has been heavily studied, of course. PGC one alpha is a protein, and you see it get up regulated in aerobic training. But the idea that that’s all that’s up regulated and that handles everything there’s a pretty dramatic simplification I loved in your paper, you started talking about some of these newer studies that look at proteomics, where you basically just take a sample of all the proteins that are up regulated from a training session. And you made the point, we’re seeing hundreds and hundreds of proteins up regulated, and certainly we see the ones that we’ve identified. But you made the point that there’s probably more that we haven’t even identified yet.
Dr. Brendan Egan 27:25
Yeah, and I think that is a useful illustration of how the field has changed over the past couple of decades. Because initially, as these studies were being done, it was very much what we call single gene or single target types of studies. Typically it would be that in some extreme condition, a protein would have been identified as being highly upregulated or down regulated. And PGC, one is one of those. It was identified two screen of proteins that were up regulated during induced thermogenesis in brown adipose tissue. So it was an example of here’s a dramatic change in a protein that’s involved in mitochondrial metabolism. We know that the muscle is involved in mitochondrial metabolism. Let’s measure PGC one in muscle in response to exercise. And there you go. It changes by a lot. Again, I’m sort of simplifying a lot of very, very good research, and I don’t want to sound like it was too glib about it. But then there are a number of other models where you over express the protein in a muscle of a mouse or in cell culture, you knock that protein down, and you look at the different phenotypes that are generated, and what you begin to see is this pattern of where a molecule like PGC one is very heavily involved in situations where it can drive mitochondrial biogenesis when it’s active or over expressed, and it that there’s a dampening of aerobic metabolism or adaptation when PGC one is knocked out. This kind of leads then to this concept of a master regulator. But in some ways it’s a master regulator because it’s the thing that’s measured mostly and when, again, without getting too much into the weeds, when more experiments are done, when you look at different variations, or isoforms, as we call them, of the protein, and you think about it as part of a family as such, you begin to realize that it’s not really a master regulator, because we still do get adaptations in response to training, in absence of PUC one alpha. So it’s one of those things that, like I said, there’s an awful lot of good science goes into documenting and describing these pathways. Sometimes it gets a little bit, I would say, over interpret when we call something like that a master regulator. But it doesn’t negate the fact that it’s a really important component to the overall machinery in response, in this case, to aerobic training. But as time has moved on, though, there’s been more and more availability of methods that allow us to look at hundreds, if not 1000s of targets across whether it’s the transcriptome, which is the whole transcript body going to think of a good explanation for the for om basically every transcript that’s within the cell. Similarly, you can do with proteomics as well. So trying to look at every protein that’s present within a cell, and as those methods come online and become more readily available, and instead of being applied in cells, and now being applied in animal models, and then being able to be utilized in muscle biopsies from humans, you begin to. See that instead of just one or two or three molecules being changed, it is hundreds, if not 1000s, depending on the platform that’s being used. And then the question, which, again, I think we hinted in the paper, is really, how many of these things are really involved in the adaptive response? How many are out there that we just haven’t known until now that turn out to be really important regulators? And there’s a whole again, there’s enough questions in this domain to keep a lot of graduate students and researchers busy for a long time.
Trevor Connor 30:24
Well, you had a table, not of all the regulators that we know of, just the regulators that have been more heavily studied. And I read through that table, and the thought that went through my head is, I hope you’ve at least once handed that table to one of your first year graduate students and said, Here, memorize this. Just the torture. Yeah,
Dr. Brendan Egan 30:45
yeah. And, you know, most of the ones that we included in that table were ones that have been well studied. And again, we proposed a kind of frame. I mean, it was a casual, I would say, proposal. It wasn’t that we think it’s a defined framework. But looking at, you know, how do we characterize these will be they’re involved in some way in in the adaptive response in a tissue. It doesn’t have to be necessarily in in exercise, and then it’s documented to play a role in the context of exercise or in skeletal muscle. And then it’s measured to have changed in humans in response to exercise like, again, that’s a kind of a broad perspective, but there’s, again, a good number of molecules where that has been demonstrated for and there’s a large number that are what we call candidates at this stage. And some of the best papers in this domain are the ones that actually identify a broad range of new markers, and then they begin to look at them in terms of their function. Because that remains the question. Like, are some of these changes actually, as I said, involved in adaptation? Are they just a kind of consequence of the stress of exercise, you know, because in a lot of cases, these studies in humans in particular, are done on people who are physically inactive or sedentary, and we’re putting them through, you know, tough session, and there’s a stress response as well as, you know, signaling response that’s responsible for adaptation. And again, it’s sometimes difficult to parse out the differences between the two. But again, part of the challenges in the field.
Trevor Connor 32:02
So the other question I wanted to ask you so we’ve now established, basically, when you’re talking about that adaptation, that magic, that we tend to skip over, what you’re seeing is you have a stimulus, which is the exercise session, then you’re seeing an up regulation of particular mRNA to start building more of particular proteins. And you make the point in the paper that you see that up regulation of mRNA very rapidly after exercise, but then within a few hours or a day, it goes right back down to baseline. And so the question I had for you is, is adaptation over time, just a case where you up regulate, then it comes down to baseline, then you do another session, you up regulate, and then it comes back to baseline. But you’re always going back to the same point. Or if you do enough training, is there a point where some of that mRNA, some of the production of certain proteins, stays up regulated compared to somebody who’s sedentary?
Dr. Brendan Egan 33:03
Yeah, that’s a really good question, because it’s hard to answer that in the way that we do human biopsy studies, because we don’t really have the temporal resolution, you know, we don’t have enough biopsies at enough time points to be able to describe the up and down process. There’s a couple of papers we refer to in the in the review, where we’re talking about measurement over a number of days throughout the early part of training program. So one of one of those was, in fact, a piece of work I did during my PhD, and another was from Chris Perry, based in Canada. And these were looking at the time course of change in mRNA and protein in response to the onset of training. So in those studies, again, how would I say this? Depending on when you take the biopsy, you can see an mRNA elevated or not, and you can conclude that this is either a new steady state, which is often said, but it could just be that it’s a single point in time, and it’s either on its way up or its way down. Again, for want to a better phrase there. So that’s kind of one perspective the other way that this question has been looked at, and it’s why, I think the scenario you painted there, I think this is why it developed as this idea that mRNA is now at a new steady state, is that there were a number of early studies that looked at cross sectional studies in athletes compared to sedentary populations. And there did seem to be this elevation in mRNA, and the thinking there was that, as I said, a new steady state. But as you well know, in a cross sectional study, you don’t know if the, in this case, the mRNA is elevated because of training or because the individual has got a higher state of turnover of that mRNA compared to another individual. So it’s a tricky one to give a defined answer to. But what I would say is that what we do know is that the half life, as we call it, of mRNAs and proteins, again fairly dramatically on an individual level. But most people would agree that the half life of proteins tends to be longer. So what we’re thinking again, within this model is that you’re getting these pulses or trans. And changes in mRNA, whether they stay elevated with training or whether they go back down to this baseline value, probably doesn’t matter. It’s more that the change that occurs in response to every single training bout is translated into a new abundance of protein, or some change in that protein function potentially as well, and that it’s really come back to what we talked about early on the conversation, it’s really the change in the protein over time that matters, rather than the change in mRNA, if we’re talking about a new steady state. But just to say one more thing on that, there’s this whole concept that Adam Sharpe was actually the co author in this review has been very prominent in which his idea of muscle memory and the idea that there are these epigenetic marks or tags that are on some of these genes that will effectively allow a muscle that’s been, say, de trained, to become retrained more quickly, or essentially, think of it like this, you’ve done a block of training for or you’ve been busy for a whole season. You take a two month period of lower intensity, or maybe complete resting for a few weeks, but then when you come back to training, okay, that feels tough, but within a couple of weeks, you feel like you back to where you were, and it was an awful lot easier than when you did it the previous year, or, you know, when you were younger. And the the idea there really is that there’s a with repeated training, that we’re changing the epigenetic marks that are on on some of these genes, and that’s allowing for retraining effect to occur in a more either refined manner or in a more rapid manner, compared to, say, be naive to training altogether. So it’s a really interesting area of the of the molecular exercise audience fees, that
Trevor Connor 36:33
is really interesting. And just for any of our listeners who might be confused here, mRNA, and this is a simplification, but it’s what goes and grabs the code off of the DNA and then goes and builds the protein. So going back to that building metaphor, think of mRNA as the worker who goes and reads the blueprints and then goes and does the work in the building. And sometimes, when you’re trying to study this, it’s actually easier to measure changes in mRNA than it is to measure changes in protein levels.
Rob Pickels 37:05
Yeah, and something else to be considering too with these intermediate steps is that I don’t want to say that they may or may not be important, right? We can measure mRNA to understand what was that stimulus toward an adaptation but an upregulation of mRNA, or even molecules like PGC, one, alpha, AMPK, they don’t necessarily lead to performance in changes, we can see a huge upregulation in these intermediates not run a 10k any faster than we did previously. It’s
Dr. Brendan Egan 37:33
a brilliant point, and I would underscore that by saying that there are examples in the published literature where people, for example, may measure AMPK, which is an enzyme, and they’ll measure at mRNA level, which it’s before there is ever any change in protein. So when we talk about the function of AMPK, we’re talking about its function as a kinase. You know, it’s an AMPK activated protein kinase. It’s a kinase, it’s an enzyme that phosphorylates other target proteins. So when you measure that at the mRNA level, that’s really telling you nothing about its function as an enzyme, because as an enzyme, it’s regulated by a number of upstream factors. So there are examples of where when we talk about these differentially expressed genes. So you do a large screen, you see how many genes are changed, how much at the mRNA level, and then people begin to make inferences around what these changes in mRNA I mean, but there’s people like me and a few of us over the same mindset, which is almost like these are, as I said, earlier molecular events. And to your point, Rob, they don’t actually tell us a huge amount of what’s happening at a whole body performance level. And so the I’m not saying the field is divided as as such, but there’s a few of us in the field who are more leaning towards the exercise physiology side than the molecular biology side, and would be somewhat skeptical about how much you should interpret some of these molecular events relative to real world outcomes. And some people might say, ah, you know, you’re being cynical. Or, you know, just let us off and do our molecular work. But there is a point at which, I suppose there’s a responsibility where coaches, athletes, practitioners of all sorts, where they are becoming more familiar, or beginning to see more and more of this type of research and becoming more familiar with what it means. But there’s a chance that they’re maybe misinterpreting it. And I think maybe some of what we’ll talk about towards the very end might be, what is the practical relevance of some of these studies? You know, why are they relevant to coaches? And I do think it’s there needs to be some level of understanding of, you know, how much we should read into a molecular event relative to good coaching, appropriate training, appropriate recovery, good nutrition. You know, the other building blocks out the real world. Yeah. And
Rob Pickels 39:41
to continue bringing that full circle, the reason this is important is, if we take a specific example, training in a fasted state tends to up regulate PGC one. So if we then say, Okay, well, great, that’s the end all be all of exercise training, then we all ought to be training in a fasted state so that we’re really up regulate. In this particular molecule. But what we see when we further continue research is that training in a fasted state doesn’t necessarily improve performance down the line, but if we stop our thought process early, we might end up with an inappropriate at times, maybe it’s appropriate at other times, recommendation for how to best train. So we do need to be looking at sort of the full big picture of this. That’s
Dr. Brendan Egan 40:21
a brilliant example. I use that example actually in class when I teach these concepts, and it’s sort of this idea of optimal adaptation versus optimal performance. And do the two things overlap for some of these strategies. And maybe I’m jumping the gun in terms of stuff we’ll talk about later, but I’ll just sort of follow on from that point. Is that the kind of trend low or the low carb approach to training, you know, restricted carb availability and so on. You may have covered this in detail before on the podcast, but that’s an example, actually, where there was a lot of molecular work that supports this idea of trend low or recover low or sleep low can have these very marked effects at a molecular level. I know you guys have talked about P 53 before, actually, that reminds me. And there are scenarios where, say, P 53 is up regulated when carbs are restricted, or as Rob, as you mentioned there, in terms of PGC, one tends to be elevated to a greater extent, also AMPK, for that matter, when training is performed in the Carib restricted state. But at some point you got asked the question, Does this matter at a whole body level? And again, the literature is quite mixed on this, and there are some examples of where so called characterization does lead to performance benefits. And there’s, again, a lot of anecdotal evidence, I think, in elite athletes, where they do find this benefit. But if you look at some of the studies that are done in like, five weeks of characterization, 10 weeks of characterization, which is basically putting these strategies into place, and in theory, have these market molecular effects, they oftentimes don’t translate into a performance benefit. And again, some of that is in the nuance and the types of studies that are done. But to your it kind of goes back to another point where you mentioned, oftentimes it’s very easy to measure a molecular response. You can get a very sensitive measure of a change in mRNA, and maybe it’s just that in the lab, we sometimes can’t find the performance benefit there. But I do think that we need to be careful that we don’t over interpret molecular responses to the detriment of real world coaching practices and performance outcomes in athletes. And
Trevor Connor 42:16
actually, just going to give an example of where the simplification could get you in trouble. I heard a podcast that was focused on longevity, and they were talking all about and to our listeners, you don’t need to worry too much about what this is. But they were talking about the balance between NAD and NADH, which is very important in our metabolic processes, and something we see as we age is a change in that ratio, we just have less NAD, and that ultimately can impact the function of our mitochondria. Just putting in very simple terms, and we know that mitochondrial function, maintaining that is very important for longevity, so they spent this whole podcast talking about supplementing with NAD, because if you have more NAD, you’re going to change that ratio, and you’re going to live longer and be healthier, and it’s just such a simplification, you know, a supplementing with it. Do you know if it’s going to get to your cells? Do you know if that’s actually going to change the ratios in your cells? What other impacts is that going to have, and everything else that’s going on? It’s just when you boil it down to just NAD NADH ratio. Yeah, I can go, oh, it makes sense. Let’s supplement with NAD. But you look at that broader picture and all the complexity, you’re spending a lot of money, and it’s probably doing nothing. I was very happy in that podcast, they basically said the same thing. This is kind of silly. Yeah, that’s a
Dr. Brendan Egan 43:35
good example. Another good one that’s out there. And it’s true, there are a number of different domains, I think longevity and biohacking, to use that word, and again, maybe some of this idea of exercise mimetics, which we might mention again shortly. I think these are concepts that lend themselves very well to novel findings on molecular level trying to be translated into novel strategy in the real world, whether that’s a drug or a bioactive of some kind or a new training strategy, or, you know, a new cold plunge, or whatever the case may be. But as I said, the molecular events don’t fully explain what happens in the real world. All right,
Trevor Connor 44:09
so I get to shift gears here a little bit, because there was one other big thing that we wanted to talk about. I think we’ve really established the important role of proteins all the different things that they do. But let’s just finally explain at a very high level how we get from this. You do some exercise so you have the again, I love the term used in your paper of this perturbation of homeostasis, this stressor, what are the steps that go from there to affecting this change in mRNA and production of protein? And I’m looking at a paper that you have here that has a whole bunch of these proteins, but you have this nice simplification of perturbation to signal to sensor, to effectors. So could you explain those to us? Yeah,
Dr. Brendan Egan 44:53
so it’s a model that I have to say sometimes it gets attributed to to myself and. Feeling zero to who wrote the first paper, the 2013 you mentioned, and we expanded upon that model, myself and Adam in this more recent review. But it’s not a concept, actually that we derived ourselves. This was actually fairly well described. Even back as far as 1996 there was a review by Williams and new for that in a handbook of physiology that more or less described this, but probably less, I would say, of the named players within each one of these buckets as such. But the concept of, as you say, the stimulus being passed on down through a number of different proteins and pathways eventually to a change in an mRNA and protein, I think that was well enough understood at that time to be the model. And we’ve, we and others. Again, there’s been a couple of other papers that I’ll do to serve as we start naming someone and forget others. But it’s not like we were the first to come up with this model, so it’s been around for a while. But to explain it a little bit of detail, it’s useful to think of it, I think, in the context of the different headings that we’ve used, but also to think about it in the context of time during and post exercise. So the onset of exercise is that stimulus and that perturbation. And so, as you explained earlier on in the intro, it was this idea that the perturbation to homeostasis activates a variety of signals. Perturbations are things like changes in the ANP to ATP ratio, which is caused by a turnover of ATP. You’ve got changes in calcium concentrations by virtue of the way that muscle contraction manifests. Changes in that NAD to NADH ratio that you mentioned a few minutes ago. Changes in partial pressures of oxygen in the muscle, mechanical tension caused by the actual contractile function of the muscle. And they’re all intracellular, as we call it. They’re all part of the signal within the muscle, external to the muscle, there are, of course, changes in catecholamines and hormones that occur at the onset of exercise. So we’ve got changes in circulating factors as well, but we classified that kind of cluster that I mentioned there as signals, and there has to be then something that moves the signal on further in the cell. So during exercise or soon into post exercise recovery. There’s a number of sensors or signal transducers. Effectively, these are proteins, then that are activated or repressed, but generally we often focus on think they’re activated in response to these different signals that have been induced by this perturbation homeostasis. So it’s probably useful to name some of these directly, just so people can kind of orientate themselves. But if one of the molecules you mentioned was AMPK, and as the name suggests, you know, the NPK activated protein kinase, one of the main activators is a change in the amp to ATP ratio. So as we get greater ATP turnover, as the intensity of exercise increases, or the duration of exercise is prolonged that is a signal to this sensor molecule, the NPK, which then is also a signal transducer, because that has its effect, like I mentioned earlier, of being a kinase that acts upon other downstream targets. Now I mentioned post translational modifications earlier, and one pro post translational modification is phosphorylation, and as I said earlier, NPK is a kinase, which means that it phosphorylates target proteins. So there are a number of downstream effector molecules, as we call them, that are oftentimes transcription factors, like PGC one. Well, okay, I have to correct myself. PGC one is a co activator. It’s not necessarily a direct transcription factor, but that’s getting into the weeds a bit. But PGC one is one of those targets of AMPK, and you’ve alluded to this, and it’s mentioned in lots of places that you’ve kind of got the AMPK, PGC one axis is often talked about as a means to describe the pathway towards mitochondrial biogenesis. So once you’ve now got down towards these effector proteins, usually transcriptional regulators. It’s the change in their activity that is then leading to changes in mRNA expression, or transcriptional processes. So that’s where we are now talking about, that amplification, or that increase, transient increase in an mRNA that’s again, somewhere down the line, is likely to result in a change in protein. Again, assuming that the protein synthesis machinery is also switched on and is able to translate that mRNA into a protein. So the early points that I mentioned there about the onset of exercise, that perturbation, some of those sensors being activated during exercise. It’s in that post exercise period that there is the change in the mRNA expression, and then again, varies from individual protein to individual protein, but sometime in hours after exercise is when we begin to see those changes in protein for again, depending on when the timing of that muscle biopsy has taken place. And again, as you mentioned earlier, it’s the thinking is that you repeatedly do these exercise sessions. You repeatedly activate these pathways. You repeatedly, then get these changes in protein content or function, and that ultimately is, what are the events that underpin the long term adaptive change to exercise? The
Trevor Connor 49:48
quick simplification of what you just said, which was fantastic, is so when your muscles are contracting, ATP is the energy source that allows your muscles to contract. And when you use that ATP, it breaks down to amp and ADP. So as your muscles contract, you start having less ATP, you start having more of AMP and ADP. So that’s your perturbation that change from ATP to the amp and ADP that causes the signal, which was the AMPK, alpha and gamma. Basically it goes to the sensor, AMPK, which says, hey, hey, hey, we got less ATP, we got more ADP and more amp we need to do something about it. And that sparks these effector proteins like PGC, one Alpha, to start doing something about this. So that’s kind of the pathway, the simplification of what you see with these protein pathways,
Rob Pickels 50:40
right? And if we back it up even further than that, and we discuss a concept like cycling in general, we can’t say cycling leads to this adaptation, because cycling is ultimately just an activity, and it’s these perturbations that come out of that activity that ultimately matter. So how does that play out like Dr Egan mentioned before, when we alter and Trevor, you were talking about the amount of ATP and ADP. That’s going to happen, really in one of two different ways. With cycling, we increase the intensity, we start burning through more substrate, or we ride for really long, and we’re going to burn through that substrate as well. Another perturbation in here is the calcium flux, which, again, is going to happen with increased volume. The other side of this is, hey, there is a mechanical component as well. And when we cause mechanical damage to our muscles, that is going to eventually, you know, mTOR is the signal on the mechanical side of things, if we’re just riding around at 50% vo two Max. We’re doing these nice concentric muscle contractions. Maybe we’re not really turning on that mechanical signal. We do a series of sprints. Maybe we’re turning it on a little bit more, but we’re only at 10% of our one rep max in terms of force. So we’re not going to be turning on that as much as if we were strength training and really causing these mechanical perturbations. So the activity is not weight lifting, it’s not cycling, it’s not running, it’s not swimming. That’s not necessarily what matters. What matters is what is happening underneath, with our calcium, with our mechanical reactions, with our redox state, with circulating hormones because of that. Yeah. Ed, you
Trevor Connor 52:26
have a great diagram in the paper that shows so many of these different perturbations, and that’s what the point that Rob’s making is, when you’re exercising it’s not one perturbation we talked about ATP to amp to ADP, but there’s many, many different perturbations that are going on that are going to many signals, which are going to many sensors, which are causing huge number of effectors. But you make the point, and please run with it. From here is depending on the type of exercise, you’re going to see more of one perturbation than another. So for example, Rob brought up calcium flux. I don’t think you’re going to see a ton of calcium flux from lifting to weight 10 reps. That’s more than going out and doing that three, four hour long ride, that you’re going to see much more of that sort of perturbation producing a much bigger signal. But Please doctor, you can take it from there. I
Dr. Brendan Egan 53:14
think you guys have summed it up brilliantly there. The piece I would add is that I think that is the next frontier, in some ways of understanding this molecular responses and how is specificity conferred. And as he’s described there, there are different types of exercise that have different degrees of perturbation and different flavors even of perturbation. And as a result, the downstream pathways of many of the ones we’ve mentioned before will have different degrees of activation or repression. So we have a sense of what might be responsible for the differences in, again, in those two extremes of aerobic versus resistance, and it probably is at the level of mechanical tension, and the pathways are activated by that. I think that’s a big factor in it, but I wouldn’t hang my hat on it, because there haven’t been enough studies I think, that have taken that type of model through to its end point that are done in physiological context. I think it’s kind of clear if we look at cell models and certain modern models, but we’re still awaiting that in the confirmation in the human models. But it does just to add to the piece that I mentioned earlier about current restriction and rob your point there about some of those pathways being activated, more or less to certain extent that effectively is what I was describing in the example of carb restriction as well. Is that that is adding a greater stress. There’s a greater perturbation, and it may be to do with some of the metabolites that are being produced because of greater reliance on fat oxidation. Or it could be that there’s greater cellular stress because the exercise feels tougher for the or creates more metabolic stress because of the relevance with the lower carb intake. So I think that is where a lot of the, I suppose, translational, as we call it, aspects, have been around, trying to link this question of what is the molecular event, and what does manipulation of substrate or ambient temperature or oxygen? Concentration, or whatever the case may be. How does that then impact on the molecular response, and how can that be translated into better training, prescription, or better knowledge of recovery, or a variety of things like that? So I think that is the translation element of this whole area. I think
Trevor Connor 55:13
that’s a really good segue into where we want to finish up this episode, which is now that we’ve talked about all this, is there any practical application that our listeners can take from this? Is there anything that they should be thinking about with their training, or was this just a really fascinating conversation about what goes on in the body?
Rob Pickels 55:31
Well, I just think it’s interesting. Yeah, the same. Yeah, there you go. You know, there’s some science.
Dr. Brendan Egan 55:37
It’s just good to know. You know, I just, I’d like to know at the end of my career to add the answer to some of these questions? No, I think there’s a couple of points that we made towards the end of the paper. I think that whole piece around understanding molecular pathways and muscle, because he’s potentially to be targeted by drugs in a kind of exercise and meta concept, I think that is what an awful lot of us write in grant applications. The promise is that we’re going to discover some new druggable target, and we’re going to solve all of these problems that are caused by physical inactivity. But there are some great papers out there actually that completely poo poo, the idea of the exercise mimetic. And the basic argument is that, again, just by studying one molecule or targeting one molecule within a muscle, it’s just an incomplete picture of how this regulation works, but muscle, again, is also just one organ that responds to exercise. Studying only the muscle means that you’re completely neglecting a large chunk of the health benefits of exercise, whether that’s in the heart, the liver, the brain and so on. So I think that is one take home is that in theory, this could all be great information that can be translated into solving some of the world’s biggest problems from an inactivity point of view, but in practice, that might not actually work. And that leads a little bit into the question you asked about application to train, is that a lot of this work gives us an indication of something that might be trialed in training. So what I mean by that is, if you do an acute study of a single exercise bout, and we do some molecular analysis around that single exercise bout, and we manipulate variables like intensity, light, duration, training, modality, like I mentioned, heat, cold, altitude, high carb, low carb, in a variety of different factors, nutrient and Environmental you can manipulate you get a different molecular signature. In an awful lot of cases, it’s molecular signature is quite sensitive to those types of changes in the environment or nutrient status. And the thinking is that if you do that on an acute session, that may give you an insight into what might be useful from a training point of view. But as the care restriction example gives kind of lesson is that sometimes the promise of what’s seen in the molecular acute event does not necessarily translate into practice. And again, I sound like I’m poo pooing the whole characterization model. I’m not. There is certainly some value in it, but I think that it’s not, in some cases, not fully explained by what we see the molecular level. And some cases come back to a point of said, several times now we can over interpret molecular findings when it comes to training prescription. So it’s just a caveat, I think, to add to this literature,
Rob Pickels 58:06
I think if we want to further that conversation a little bit, Dr Egan, in your paper, you brought up some pharmacological treatments. And I want to tie this back. Trevor to you had discussed a longevity podcast that you were listening to at one point, and oftentimes, these very focused pharmacological agents are discussed in these longevity conversations. And we’ve actually kind of done an episode on this in the past where people are utilizing things like Metformin, like resveratrol, which are supposed to have these very targeted actions within our body. And hey, they may or may not improve your longevity. It’s not necessarily the point of this conversation. But if we look at something like Metformin as an AMPK agonist, and we say, Oh, we just talked about amp AK is important for all of these reasons, this is what it does. I’m going to go out and take some metformin and I’m going to become a super athlete. We don’t necessarily see that right, because we’re really trying to tease just this one specific pathway, but we need to be looking at the larger overall picture of what it means to adapt, of what it means to improve performance. And it’s not so simple that we can take one drug, improve one thing, and get a whole host of improvements out of that. That’s exactly
Trevor Connor 59:15
where I was going to go, which is, I think the danger here in studying these pathways is when you look at one pathway, you can really simplify it down and then get into this, well, if I take this supplement, then I’m going to be a monster at whatever I’m trying to do when you look at just the one pathway,
Rob Pickels 59:32
or even just to interject, or even do one type of training that targets one pathway, right?
Trevor Connor 59:38
And I think the really great theme you had going through the paper was it’s not one pathway. There’s many, many pathways. We don’t even know all of them, and it’s just different intensities of the different pathways. And when you look at that way and say, Oh, I’m going to take this one supplement that’s going to affect that one pathway, it just often doesn’t play out. It’s just too. Much of a simplification? Yeah,
Dr. Brendan Egan 1:00:01
I’d certainly echo that, and there’s been lots of examples. One is that old resveratrol story. You know, there was a number of different cell and animal models that seemed to indicate that resveratrol was a assert to an activator, which, again, we didn’t talk about, but it’s one of the pathways that’s often mentioned, an exercise adaptation. But when resveratrol was then taken in a couple of studies by humans doing exercise training, it looked like it was blunting the adaptive response exercise, rather than augmenting it. Another example that comes to mind is phosphatidic acid, which is one of the signaling molecules that is released from a reaction that takes place in the cell membrane under mechanical tension. And again, cell models and mouse models would indicate that Fauci acid can drive the mTOR pathway. So you can buy phosphatidic acid on the shelf, and there’s a couple of companies selling it, and there’s a couple of studies that seem to indicate it could do something, but the majority of studies would say that it doesn’t do anything as a supplement to drive muscle growth. And so again, lots and lots of examples, they’re just two off the top of my head, that kind of illustrate the point. I think
Trevor Connor 1:00:59
the other good takeaway here is, I do think doing all this research, at the very least helps us understand better effective training and ineffective training. An example I’m going to give, which, again, is still a simplification. We talked about that perturbation of ATP to ADP in a trained endurance athlete. You’re only ever really going to see that at very high intensity. If you’re just going and noodling around your body is going to do a very good job at maintaining ATP. So understand, if you want to get am PK activated and have it start producing some of the effectors that we know help with endurance adaptations. You got to go really hard. But Rob you also brought up that calcium flux as another perturbation. And again, that’s something in endurance athletes you really only see over time, so you need those longer, steadier, not necessarily really hard, rides. So this, right there is a molecular way of explaining why the best training for endurance athletes is a mix of some intensity with just some longer, slower training. Yeah,
Rob Pickels 1:02:06
and Trevor this point, actually, as I was reading the paper, I thought the exact same thing that you’re thinking here. And if we discuss sort of that progressive overload right, as we get stronger, we need a larger and larger stimulus to have these perturbations to then lead to, hopefully, some exercise adaptation. And I love to do an episode in the future of, what can we do with programming or with exercise that when we’ve kind of maxed out, what our progressive overload is, is there something else that we can do to continue, you know, increasing the perturbation? Maybe that’s a timing within the day. Or, as we talked about in here, you know, manipulating carbohydrate availability. But I think it would be an interesting discussion to say, hey, we can’t ride any longer. I can’t ride any harder. What do we do to keep improving? Yeah. Dr,
Trevor Connor 1:02:53
yeah, that might be a great place to leave. It is to throw that to you and ask the question, of all this biochemistry that you’ve studied. Have you ever at any point gone? Wow, we should be doing this with our training that you got out of the biochemistry. I
Dr. Brendan Egan 1:03:07
was actually going to jump in with a very specific example just after I finished there. And it’s around about 2006 2010 there was a quite a number of opinion papers and reviews around this idea that AMPK, when it was activated, it inhibited mTOR. And the concept that was being used at the time was, well, this explains the concurrent training phenomenon that Hixson had described in the 80s, which is effectively that when people train for endurance and strength at the same time, you usually get in, you know, you don’t get as a strong response in either domain as you would if you trained in isolation. Kind of a simplification of it there. So this was a very prevalent concept that the molecular explanation for this, as I said, around the late 90s. And as a result, there was a fairly big change in the way that people trained, at least in the domain I was training, and at the time, I can’t remember if I mentioned I played at a decent level of Gaelic football when I was on the podcast before, but it’s an example of a team sport, a bit like rugby, which is also very popular here in Ireland, where we do a lot of strength based training and power training, as well as our on pitch field training. And the whole concept became, well, you know, if you’re switching to switching off M tour, this just is not compatible with good training. And there became this whole focus on the idea of the order in which training should be had, and manipulating, you know, the time of day and all this kind of stuff that actually, in the end, as amateur sports, people became very difficult to try and stick to, because effectively, what you’re trying to do is, I think the at the again, I’ve forgotten it now, because it sort of seemed like it went by the wayside fairly quickly afterwards. But it was something like, you know, you couldn’t do an aerobic training session within 24 or 36 hours of having done a strength training almost like it’s going to block all your gains. But of course, the nuance here was really that the mTOR pathway and the hypertrophy response is not exactly what we’re always looking for from strength training, like there are neural adaptations and improvements in strength and power that can occur in the absence of any gain in muscle size and. So it just felt like at the time, and I think people realized it was kind of majoring in the minors quite some bit. And although, as I said, it influenced training for a while, it actually hasn’t, at least in the team sport domain, it hasn’t been something that stuck. I can see why in a sport perhaps, you know, maybe this is why bodybuilders tend to do very little cardio unless they’re in the cutting phase, because it can potentially impact on the hypertrophy response. But you know, for most mixed sport athletes, it’s just not practical to try and use those molecular insights as part of the training prescription.
Rob Pickels 1:05:30
And if this particular topic is interesting to people, Trevor and I talked with Dr bent ronstad Back in episode 211 the title was, does strength training hurt or help endurance sports performance. So you can listen to another in depth conversation right there.
Trevor Connor 1:05:45
Well, guys, I hate to say it, we’re past our time here. As you know, I would talk about this all day. I do have a question for the forum for anybody who found this interesting. And note, I wrote this question beforehand I knew where this episode was going to go. So here’s the question. This was a science heavy episode. What did you learn that you found very interesting and may help your training. So if you want to get involved in that conversation, come to our forum and give us your response to that question. Forums, dot fast talk labs.com, yeah. Dr, E, normally we finish out with our one minute take homes, but I kind of feel like we just covered that. Yeah, I don’t have a take home, so I don’t have anything beyond that. So I’m just gonna say that was a really fun conversation. Being the biochemistry geek, I gotta say, even though it was 118 pages, your review was one of my favorite reads in a long time. Great here.
Dr. Brendan Egan 1:06:35
Well, I’m glad it wasn’t time wasted. For sure, it’s been look. They were great questions, a great discussion. I really enjoyed it. So thanks again for having me on it was
1:06:43
a pleasure having you on the show. Thanks so much. That was another episode of fast talk. The thoughts and opinions expressed on fast talk are those of the individual. Subscribe to fast talk wherever you prefer to find your favorite podcast, be sure to leave us a radio and a review. As always, we love your feedback. Tweet us at at fast talk labs, join the conversation at forums dot fast talk labs.com or learn from our experts at fast talk labs.com for Dr Brendan Egan and coach Rob pickles, I’m Trevor Connor. Thanks for listening. You.
