Dr. Gabrielle Lyon [0:00:01]

Welcome to the Dr. Gabrielle Lyon Show where I believe a healthy world is based on transparent conversations.

In today’s episode of The Dr. Gabrielle Lyon Show, I sit down with Kevin Murach, PhD. He received a master’s degree in exercise physiology at James Madison University in Virginia. He then earned his PhD in human bioenergetics from the Ball State Human Performance Laboratory in Indiana. His dissertation, which we talk about in this episode, was a collaboration with NASA aimed at optimizing the exercise prescription for astronauts on the International Space Station. After Ball State, he spent six years as a post-doctoral fellow and scholar studying one of my favorite topics, muscle stem cells, at the University of Kentucky Center for Muscle Biology in Lexington.

He is now an assistant professor at the University of Arkansas. He has a lab that’s called M3R, which stands for muscle mass regulation. What I love about this conversation is that it really highlights the basic science; we talk about nutrition, and we talk about exercise. What Kevin does so well is examine some of the genetic and epigenetic expressions of what exercise does. We spoke about the Yamanaka factor. These are the factors that we think about from an age reversal and, quote, regeneration perspective. We also discuss what DNA methylation is. We’re hearing a lot about methylation, and how does that relate to the aging and adaptation of skeletal muscle? Finally, how does exercise improve longevity from a genetic and epigenetic perspective?

I hope you love this episode. As always, we provide this content for free. It would mean the world to me and our team if you shared it and left us a review. We would love your feedback. Our goal is to educate. Let’s dive into this episode.

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Dr. Kevin Murach, thank you so much for joining us. I am thrilled, and a shout out to Dr. Chris Fry, who made the introduction. We are excited to talk about all things skeletal muscle and skeletal muscle epigenetics. You are doing some very innovative work. I would love for you to tell the audience a little bit about your lab. I see that you have a M3R shirt on. We want to hear everything that you are doing.

Kevin Murach [0:05:57]

So again, my name is Kevin Murach. I’ve been studying skeletal muscle for, well, over a decade, for sure. I did some of my early education at UNC in Chapel Hill, basketball, and all that. That was my undergraduate degree in Exercise Sports Science and a master’s degree in Exercise Physiology from James Madison University. I did my PhD at Ball State, which is the longest-running, still-open Human Performance Laboratory in America. It was a lot of skeletal muscle human work that we were interested in at that time. Then I spent six years, as you mentioned, with Chris Fry, who’s currently at the University of Kentucky. I spent six years there as a postdoc, and that’s where Chris and I crossed paths, just to close that loop. That’s where that came from. Chris is a collaborator, friend, and mentor. He’s a great guy, so I look forward to listening to his podcast.

Then I started my own laboratory at the University of Arkansas in 2021. We’ve been interested in trying to study skeletal muscle adaptation to exercise with a specific emphasis on aging, trying to understand how aging muscle can become more like younger people’s muscle. We’ve been trying to explore that using a lot of different molecular biology and biochemical techniques. We do use human muscle samples, not that we obtained here, but usually through collaborators. But we do have a human aspect to our work, so we try to make it as translational as possible. But we do use a lot of genetically modified mouse models as well as cell culture techniques to try and understand how skeletal muscle adapts to exercise at the cellular and molecular levels. We also try to do as much in vivo work as we can with the mice to, again, make it as translatable as possible to human beings. That’s what we’re on to right now as far as research. It’s very focused on skeletal muscle and just trying to make that muscle healthier, stronger, and more functional, and trying to understand what molecular things underpin that. That’s the focus of my lab.

Dr. Gabrielle Lyon [0:08:09]

I think it is very innovative. You talk about some very unique perspectives on skeletal muscle. For example, in the medicine and nutrition space, where you talk a lot about anabolic resistance and these changes to the actual tissue, regarding sarcopenia and even fat infiltration, but where your work is so unique, and I’m excited for you to highlight some of these aspects of aging, is that oftentimes, we don’t think about the epigenetic changes or the methylation changes in skeletal muscle. I would love for you to first lay the groundwork for what happens to aging skeletal muscle. I was reading some of your other papers, and I have a handful of them pulled up. What is so interesting is that the influence of exercise has an input to, and potentially some regenerative capacity, to skeletal muscle, which I think we can all agree is good for us. But how does that actually translate and how is it good for us? Is it, and what does that mean to our genetics or epigenetics? What does that mean for our transgenerational culture? So anyway, the first question is: what happens to aging muscle? Potentially, if the listener is thinking, does skeletal muscle become less responsive to exercise? Does skeletal muscle become less responsive to environmental influences?

Kevin Murach [0:09:42]

I think it’s important to preface anything I’m about to say with the fact that there’s very few instances where exercise isn’t good. You’re almost always going to benefit. If you’re a healthy person to begin with, you’re almost always going to benefit from exercise, and you can start it at almost any age and obtain some benefits. Even if maybe you can’t put on muscle mass like a bodybuilder in your 70s and 80s, it doesn’t mean you’re not going to benefit from doing something because you most certainly will. Sometimes those functional benefits happen even in the absence of overt changes, like really large increases in muscle mass and things like that. Again, I view things through the lens of resistance training, although I do endurance training as well. I mean, I endurance train three days a week and resistance train three days a week; it’s a mix of both, and they’re both very important. But I’ve always been very interested in resistance training, lifting weights, and how muscle grows. Those are things that fascinate me.

But anyway, to answer your question, as we age, a lot of changes happen in skeletal muscle that can lead to functional decline, which is not ideal, of course. I mean, if you lose enough muscle mass and enough muscle function, you can get to a place where you can’t even live independently anymore. That’s not ideal. The amount of muscle mass and beginning function that your muscle has is very much related to your independence, what you’re able to do, and really how much you can even enjoy your life. Because if you can’t walk up a set of stairs, it’s going to be tough to live an active, vibrant lifestyle, and so on. But as we age, obviously, the muscle starts getting smaller, which is not ideal. We call this age-related sarcopenia often. but it’s just a natural decline in muscle mass that tends to happen.

That decline in muscle mass often occurs in lockstep with reductions in physical activity too. A lot of times, as you get older, you’re not as physically active anymore, and so these two things go hand in hand. But it is something that happens even independently, to a certain degree, of your physical activity level. It’s an unfortunate natural process of a loss of muscle mass, which often leads to a loss of strength but also power production. Actually, power production as we get older is a very important factor, and that declines fairly precipitously. That is, functional measures—power and force production—are really what enable you to do your activities of daily living and to be active.

As we get older, those things start declining. That is due to a variety of different factors. There’s a lot of debate in the field. What exactly causes these things is that the nerves that are communicating with your muscle cells are starting to not communicate so well. Maybe you lose some of those nerves and eventually start losing some of the muscle cells or the muscle fibers. They start getting smaller. There tends to be changes in your metabolism. So the mitochondria, the powerhouses of the cell, tend to not function as well sometimes as you get older, especially if you’re not active. This can lead to various deleterious consequences that can lead to a loss of muscle mass and function. There are things that happen all the way down to the level of your genes and your epigenetics.

Dr. Gabrielle Lyon [0:13:10]

Before you continue, I have a question for you. You mentioned these changes of aging, and with the changes of aging in step is this decrease in activity, this decrease in power. Is it an aging process? I know that in your lab, I’m sure that you’ve identified it. I mean, I’m looking at these Yamanaka factors that you’ve written about, etc. Is it a decrease in activity? If age is not a factor, is it the actual decline in the stresses from the environment? Is it a decrease in activity? I mean, obviously, I even wonder, with the decrease in capillary perfusion, is it an aging phenomenon, or is it an inactivity phenomenon that accelerates aging?

Kevin Murach [0:14:02]

That’s the perpetual question, really, because a lot of times, as you say and as I mentioned, these two things happen simultaneously. You’re losing muscle mass and function, and you tend to become less active as you get older. So is it a chicken or an egg thing? I mean, there is a natural decline that happens with aging, irrespective of the physical activity aspect. Can you be really physically active and mitigate some of those declines? Most certainly. But there is a natural decline that occurs, and I think it’s probably exacerbated by the loss of physical activity. I mean, even if a young person, for instance, has to lay in bed for a long period of time, for whatever reason, if it’s an injury or if it’s just a prolonged period of inactivity for one reason or another, you’re going to lose muscle mass and function. That is something that absolutely happens when you’re not active. That happens to astronauts, for instance, when they go to space and they can’t use their muscles the same way anymore. They can’t work against gravity. They lose muscle mass and function precipitously.

Dr. Gabrielle Lyon [0:15:04]

By the way, and for the listener, I think you were very interested in space and astronauts. I think you did an early project for NASA at the beginning of your career.

Kevin Murach [0:15:17]

That’s right. That’s very observant. Yes, during my PhD at Ball State, they had a long-running collaboration with NASA and still do. It’s been going on for a very long time, since the ‘80s, I think, perhaps the ‘90s. But it was a project trying to figure out the best exercise prescription for astronauts, for the reasons that I’m describing. When you go to space, there’s no gravity. It’s hard to even lift weights and load your muscles because dumbbells, barbells, and these things use gravity; that’s what makes them heavy. But when you go to space, there is no gravity, and so there is no weight; it’s weightlessness. You have to use different sorts of exercise devices and different types of exercise prescriptions to load the muscle effectively.

When you think about when you’re in a terrestrial environment and there’s gravity and you’re walking around, every time you take a step, you’re loading the muscles of your legs or loading the muscles of your back. Even when you’re just sitting, you’re still loading certain muscles, and they’re getting a stimulus. When you go to space, that’s all gone. There is no stimulus on the bones or stimulus on the muscles. Gravity is not there, so the first thing you have to overcome is: how often do we need to stimulate the muscles, the bones, all these different things to maintain what we have on earth? But then the other part is, okay, exercise is good; we know this. What type of exercise do we need to be doing to try and maintain functionality?

It’s important because these astronauts may go on spacewalks and be cruising around out in space, having to do things that are very physical to fix the spaceship, the space station, or whatever. They need to be functional in that respect, but they also need to go to a different planet. They need to be able to walk around and do the things that they’re supposed to do. If they have no muscle mass, they’re not going to be able to do that. Likewise, when they come back to Earth, if they want to resume their lifestyle here on Earth and have lost all their muscle mass, it’s going to be exceedingly difficult to do. The project was geared towards trying to understand the best exercise prescription for astronauts. We actually used a ground-based analog for that project. NASA had people lie in bed for 70 days in a six-degree head-down tilt position, which replicates the cardiovascular changes that happen.

Dr. Gabrielle Lyon [0:17:35]

They must have paid those participants a lot of money, you guys.

Kevin Murach [0:17:41]

Yeah, they did pay them a lot.

Dr. Gabrielle Lyon [0:17:44]

Just to bring us back to Earth—I’m joking—we actually had a NASA PhD, the head of the Physiology Research Lab at NASA, and one of the heads in Nutritional Science space.

Kevin Murach [0:17:59]

Oh, yeah. Who was that?

Dr. Gabrielle Lyon [0:18:00]

I can’t remember his name.

Kevin Murach [0:18:02]

I’ve interacted with a lot of those folks many years ago.

Dr. Gabrielle Lyon [0:18:06]

He’s been there for many years.

Kevin Murach [0:18:08]

Jeff Ryder, man, there were a bunch of people that I’ve interacted with. but my project was less nutrition-oriented and more exercise-oriented. There was a nutrition component. I mean, obviously, they have nutritionists that are giving these people food the whole time. They’re clinical studies. They’re in these big medical centers, and they’re highly controlled. They’re really fascinating. They’re expensive studies to pull off because, I mean, you have people in a ward. I don’t remember the sample size of my study; I think it was 12 or 10 or something like that. That’s a lot of people to have to do nothing in bed for 70 days. When they exercise, they also have to remain in a recumbent-type position. Once you start standing up and loading them, then you defeat the purpose. Everything has to be done lying down. It’s wild. They’re wild studies.

For that particular study, we had the 70-day bed rest group that we were using to replicate what it’d be like to go to space for that period of time. There was an arm of the study that I wasn’t involved in, but where astronauts were getting biopsied or muscle samples were being taken from their legs before and after spaceflight, which is how we study these muscles. We take muscle samples using these biopsy needles that are called Bergstrom biopsy needles, and we stick that into their leg. That sounds a little violent.

Dr. Gabrielle Lyon [0:19:27]

No, we talk about biopsies, so you’re in good company. Nobody thinks they are fun to have done or do. Your M3R lab, which is so cool, is your lab. Looking at one of your recent papers, A molecular signature defining exercise adaptation with aging and in vivo partial reprogramming in skeletal muscle, we thought that this paper was fascinating. myself and my team members, we were looking at a summary of this paper, which I’d love for you to highlight for the listener. The study explores the similarities between exercise-induced changes in muscles and this process, which we were talking about—partial molecular reprogramming, which you’re going to explain for us—often associated with the Yamanaka factors.

For those who don’t know much about the Yamanaka factors, which I actually didn’t up until maybe a year or two ago, they’re known for reverting the cells to a more youthful state. You guys compare genes in the expressions that you compared gene expressions in muscles after exercise with these Yamanaka factor inductions in both mice and humans. I’d love for you to explain a little bit about this and how it’s relevant for us as we think about aging. Again, we always think about aging from this sarcopenic aspect—these very tangible aspects that we could almost touch—but your work is quite fascinating from a molecular level.

Kevin Murach [0:21:13]

There’s a lot to unpack there, so I’ll maybe just start with the Yamanaka factor, and then hopefully you can cue me to get back to the other parts of the exercise and all these things. But it’s difficult to explain, so I’ll do my best. Almost all cells in our body have DNA in them. That’s the blueprint for who we are as human beings, so every cell has the same DNA. For the most part, every single cell will have the exact same DNA template, and basically what happens as we develop into fully mature adults is that the DNA for each cell type changes. We start as stem cells, essentially, and those stem cells ultimately become all the differentiated cell types that comprise our body, so our skin, bone, or muscle—all these things.

They all started as one cell type, these stem cells, which eventually became specialized over time. How that happens is that we have all the genes that are in the DNA that are more or less accessible at the beginning when they’re these really young stem cells. Over time, different sets of genes get turned on and off. This is controlled by epigenetics. So essentially, we have the DNA template, the DNA code, that has all the genes, but which ones we turn on and off is dependent on epigenetics. There are a lot of different layers of epigenetic regulation of DNA.

Dr. Gabrielle Lyon [0:22:42]

What is epigenetics, for the listener?

Kevin Murach [0:22:45]

Essentially, the way I’ll define it for the purposes of this conversation is the changes to gene expression without altering the genetic code. We’re not talking about mutations. We’re not talking about adding in genes or taking away genes from the DNA; we’re just talking about how we turn them on and off and how we control their expression. Genetics is the DNA; that’s what we have. All the genes that our cells can express—that’s the genetics. Epigenetics is the control of how those genes are turned on and off. There’s a lot of different layers of regulation of epigenetics. Their DNA is wound around histones and nucleosomes, and that determines whether they can be accessed or not. Those histones can be modified in different ways to allow access to the DNA. So genes can be expressed and turned on or off.

But even the DNA itself can have modifications put on it or taken away from it that allow a gene to be expressed or repressed. I study muscle, for instance. In muscle, we want to express muscle genes. We want to express that myosins are important for contraction. We want to express titin and all these other structural proteins that are really important for our muscles to be functional. You wouldn’t want those things expressed in your eye cell or your skin cell because it doesn’t need those genes. It doesn’t need those proteins. If it expressed them, it wouldn’t be ideal. Basically, what happens is that when muscle becomes muscle during development, the genes that are ideal for muscle, like these myosins and all these things that are important for muscle contraction, get turned on, whereas all the stuff you don’t need, So the genes that make your skin cells your skin cells or your bone cells your bone cells get repressed and turned off epigenetically. You have this template, and then it just gets modified in different ways so that a cell can become what it ultimately needs to be and turn off all the other things you don’t need. I guess that’s the best way to describe epigenetics.

Dr. Gabrielle Lyon [0:24:57]

That’s very helpful. When we think about what we do on a daily basis to express certain genes, that epigenetic interface with the environment, would that be something like nutrition, exercise, environmental exposures from a negative capacity, or even sleep? Are there things that we do as humans that influence the genetic expression of what we have, primarily skeletal muscle? That’s what we’re interested in.

Kevin Murach [0:25:30]

That’s what I think about all the time: skeletal muscle. The answer is yes. I like to lift weights. I lifted weights this morning before I got on this call with you. I went to the gym this morning, and I lifted some weights. In order for those genes of adaptation to be expressed, when your muscle adapts, a lot of things are happening, like genes are getting turned on and they’re being made available so that an mRNA can be made, which is like a miniature template of that gene that can then get turned into a protein that can then have a function in the cell.

That process gets modified every time we go and exercise. When I go and lift a weight, there are epigenetic changes that occur that allow the genes for adaptation in my muscle to get turned on so that they get turned into mRNAs that can then get turned into proteins that can then lead to adaptation. These things are happening all the time. Especially in the context of exercise, there’s a change that occurs acutely with our epigenetics. Maybe a gene that’s been dormant gets modified epigenetically so that it can be expressed in a relatively short period of time, maybe within 30 minutes or so, and then it goes dormant again. Or there can be changes that happen if you exercise a lot throughout your lifespan. There might be more long-range or long-lasting epigenetic changes that happen in your skeletal muscle that can maybe allow you to be more adaptable to exercise in the future if you had a layoff.

Dr. Gabrielle Lyon [0:27:02]

Would that be something like muscle memory? I know that people talk about muscle memory as it relates to nerves, but this idea of training and then detraining and going back to that activity?

Kevin Murach [0:27:15]

Most certainly, at least in my opinion, that is an epigenetically regulated process. If you buy into the idea that if you exercise and take time off and start exercising again, you adapt more quickly, I would say that that’s probably an epigenetically mediated process. We’ve done some research to try to unravel that a little bit. There is good scientific data for that process. oftentimes, even human beings, long-term studies where you train someone, then you have them detrain and train again. Who gained back muscle mass more quickly that second time? They had trained before, so there was some memory of their muscles being bigger and stronger previously. We’ve delved into that topic a little bit, looking at epigenetics and muscle fibers to try and see if there are long-lasting epigenetic marks from when you were well trained. We did find some things that pointed in that direction. We’re still following up on that, actually. That’s an area of research in my laboratory.

But we think that that’s an epigenetically mediated process because we’re not changing our genes. We’re not saying okay; when you lift a weight, you somehow get different or more genes. Your DNA is your DNA. That’s what you’re doing: you’re just changing how it gets accessed, which genes get access, maybe how quickly they get access, or for how long, so that they get turned on for a longer or shorter period of time, which would then lead to a more efficient adaptive process.

Dr. Gabrielle Lyon [0:28:49]

Is that why people care about it? So for example, the listener might be thinking, okay, well, why do I actually care about any kind of epigenetic change? Or these Yamanaka factors or this MIC gene? Why does the listener care? Is there a unique expression for individuals? For example, if I went and did resistance training, would my gene expression be different than yours? Who went and did resistance training? Why would one care about that from an aging perspective? What would be the benefit of creating epigenetic changes versus not doing anything and leaving things as they are?

Kevin Murach [0:29:33]

I think for me, it’s motivation to be as fit as possible when I’m young because if I do run into some situation where maybe I’m injured or I have to take a long layoff from exercise or whatever the case may be, or maybe the whole world flies off to another planet and we go populate some other planet and I can’t exercise on the spaceship, whatever crazy hypothetical we want to talk about, whatever changes I’m inducing in my muscles now when I’m young and healthy may have benefit for me down the road. We use the word “plasticity” to mean how adaptable your muscle is to exercise. at a time when maybe plasticity starts to go down as you age, maybe having fitter muscle earlier in your life because of these epigenetic changes could help to mitigate some of that muscle loss or help to amplify your ability to adapt when you start exercising again. I do see some tangible benefit there.

Now, how could we specifically leverage this? We know that these genes are epigenetically modified with exercise. How can we go in and specifically target those sites and make it so that those genes get turned on more, longer, or whatever to induce exercise adaptation? I think we’re still pretty far away from that. But the thing is, we have to understand it. We have to understand it first before we can design any sort of therapeutic intervention. to leverage the benefits of something. If we don’t understand it, it’s going to be really hard to target.

That’s what the whole pharmaceutical industry is trying to do. Sometimes they target things that they don’t understand, and it just works, like, okay, great. But I mean, it’s better to have a good understanding of how the process works so that you can design an effective therapeutic down the road. That’s where my lab and my research slot in, I guess, in some capacity, as just like, what’s going on here? How does this process work so that maybe in the future, maybe me or maybe someone else will be able to design a therapeutic or exercise program that optimizes some of these epigenetic changes so that we can have a better response?

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I am curious; do you think that there is a—and I know what you’re going to say. But I want to frame this because, selfishly, I’m very interested. I always want to know the effective dose of something. We are very physically active, or many people are, or at least many people that are listening to this, and they want to know how they are going to execute a training protocol that is effective, not just effective in strength or power, but effective in some of these epigenetic changes that you’re talking about, which I think will bring us back to the Yamanaka factors that we need to hear about again, which are very unique to your lab. How do we know if we’re doing it right, period?

Kevin Murach [0:34:53]

That’s a great question. I’ll do my best, but I don’t want to step out of my lane. I have lots of friends that are more practitioners, like you’ve maybe heard of Andy Galpin.

Dr. Gabrielle Lyon [0:35:08]

Of course, Andy is a very dear friend. I recently saw him. We read about a special operations conference together. Andy, just shout out to you. We’ve been trying to coordinate a podcast, but Andy’s very famous nowadays, so I need to go visit him.

Kevin Murach [0:35:23]

Yeah, he is. He overlapped with me at Ball State by about, I don’t know, six months or something like that, because he was leaving as I was coming.

Dr. Gabrielle Lyon [0:35:31]

Andy, I love you; you know I love you. I’m busting your chops. But anyway, back to the effectiveness and the Yamanaka factors.

Kevin Murach [0:35:39]

I’ll distill the question a little bit, which is, do we see epigenetic changes? With a small amount of exercise, I guess, like a 30-minute exercise bout? The epigenetic changes that happen often have to happen in order for adaptation to even proceed. The answer there is that it doesn’t take much activity, I don’t think, to undo some of these changes. If you see a change, it’s not always the case. But if you see a change in gene expression, for instance, or you do an exercise bout, you take a sample of muscle before and after the exercise bout, and you look at changes in gene expression, not always, but many times, sometimes I’ll say, there was a change in the epigenetics of that gene before the gene became expressed. In order for adaptation to occur, this first step, this alteration to epigenetics, often precedes gene expression, which then results in the protein being translated.

The thing to understand is that there’s a lot of steps in the process, and we’re oftentimes looking at the pre-step one because, when we think about the central dogma of molecular biology, it’s like a gene gets transcribed, and then it gets translated into a protein, and then it has a function in the cell, and we’re talking about the step even before the gene gets accessed and becomes something that can be usable by the cell. A lot of times, it should be linear, but it’s not. But we do look at different types of resistance exercise, endurance exercise, concurrent training, and all these different things to look at the different epigenetic marks that are changing. With almost any type of exercise, we do see changes that are occurring, which is a good thing. But how long those changes last, I think, is a different question and perhaps a more pertinent one. When we think about this memory that we talked about, like if you train and then become detrained and then want to retrain, how long does that memory last, this epigenetic memory? In what genes is it active, and why is it active in those genes? We don’t know the answers to that yet. Those are things we’re still trying to explore.

Dr. Gabrielle Lyon [0:38:03]

What about the type of training and these Yamanaka factors? Is there a type of training that seems to influence them more than others?

Kevin Murach [0:38:14]

Maybe we’ll talk about Yamanaka factors just in a global sense before I address the exercise question. I said before that how we become fully formed human beings is through these changes in epigenetics. We start with these stem cells, which could almost become just about any type of cell. then these epigenetic changes happen as the cell progresses through its fate transition to become whatever it is it’s going to be—a muscle cell, a skin cell, what have you. This was, I think, 2006; I’d probably Google it. It was discovered that you can take a differentiated cell, so let’s just say a skin cell, for instance, and you can put it in a dish and overexpress these Yamanaka factors. They are called Yamanaka factors because they were discovered by a guy named Shinya Yamanaka, who won the Nobel Prize for this discovery. This discovery has really transformed the face of cell biology, and entire industries are built around the idea that you can make stem cells out of differentiated cells because of Yamanaka factors.

Essentially, let’s say you take a skin cell, a dermal cell, and its fate is decided; it’s a dermal skin cell. You put it into a dish and you overexpress these four factors, and they’re called the Yamanaka factors, which he discovered, so Oct3/4, Sox2, Klf4, and c-Myc. He didn’t discover each one of those individually, but he discovered all four of them together and the way they function. What it does is allow that fibroblast to turn back into a pluripotent stem cell, which can then go on to become a bone cell, a muscle cell, or any other number of things. This really transformed cell biology. You can take something that is older. You can take a skin cell that has a defined trajectory and a defined identity and basically turn it back into the youngest form of itself, a stem cell, that can then go and become something completely different. That was a huge discovery, and again, entire industries have been built around this idea now, and this research has been expanded on tremendously since that discovery and since he won the Nobel Prize.

But to answer your question, specifically with Yamanaka factors, do they get turned on with exercise in muscle? Which ones, and what type of exercise? This is the area that I’ve become more interested in in the last three or four years. To answer the question, when you go exercise, all these Yamanaka factors’ basic function is to epigenetically reprogram, so wipe the epigenetic slate clean, so to speak, so the cell can then revert back to its earlier state, a stem cell state. That’s the best way I can describe it. But these Yamanaka factors are transcription factors, and they can basically turn on thousands of genes at the same time. That’s part of the reason why they’re so powerful: they can turn on a lot of genes, and they can also rewrite the epigenetic code, not the genetic code, so that genes can be accessed in certain ways.

When we exercise, in skeletal muscle, a lot of different genes get turned on. But transcription factors, which are what these Yamanaka factors are, get turned on too, and the one that gets turned on the most with exercise is this one called c-Myc. We found that, first of all, it goes up in muscle a lot with exercise. Second of all, it goes up a lot, specifically with resistance exercise. It does go up with endurance exercise as well, but it does increase in response to resistance exercise quite largely to a pretty large extent. But it’s not a big, sustained increase. It’s not like you do an individual exercise or a bout of exercise, and it stays elevated for 96 hours. It goes up; maybe it peaks at three hours, starts coming back down, and is back to baseline by 24 hours or so. It’s like this pulse, and then it goes back down to baseline.

When this transcription factor, which is a Yamanaka factor as well, gets turned on, it activates a whole bunch of different genes that we think are important for exercise adaptation. That’s what we’ve become really interested in: trying to understand, well, what does this one Yamanaka factor do in response to exercise, specifically in response to resistance exercise? Can it be leveraged to make older muscle at least adapt more like a younger muscle because it has this role as a Yamanaka factor that can make older cells appear younger again? That’s the area we’ve become interested in.

Dr. Gabrielle Lyon [0:43:06]

How would one determine that? Obviously, through muscle biopsies, I know that you’ve got mouse models, and you’ve done a wonderful job creating some very exciting translations for humans. If an aging skeletal muscle becomes less effective, a decrease in power, we know your research is showing that there’s this Yamanaka factor, particularly Myc, that seems to be turned on with resistance training and may have somewhat of a, and I use this word cautiously, regenerative effect. I don’t know if that would be the appropriate terminology.

Is there a certain dose? Is it training-dependent? Do we know if an individual does? I don’t know if 10 sets of squats at their 10-rep max, whatever it is, or with a lighter amount of exercise, have any uniform influence that we could say everybody at a baseline level should be doing this to potentially, and I understand that targeting the Yamanaka factor is not the same as targeting a blood glucose number. But is there some influence that we could recommend, or does that relate again to this DNA methylation, which I want to talk about next? What are we telling people, and how can we think about that in a regenerative capacity? What does that even mean?

Kevin Murach [0:44:47]

I get a lot of blowback sometimes from a lot of times the word rejuvenation is thrown around, trying to rejuvenate a cell and things of that nature, and what does that mean exactly? It’s a hard thing to pin down. I mean, I like to say that when we induce these Yamanaka factors, we’re shifting them towards a state where they are, I guess, more plastic, so they have a greater ability to adapt potentially. as far as your question, because regeneration is a separate process. That is something I’m interested in, but the stem cells have to do with a lot of the stem cells and things like that. That’s a whole other conversation about regeneration with aging and all these things because I’d spent six years studying muscle stem cells prior to this, and so I’d spent a good deal of time thinking about that. That’s a very interesting topic in and of itself. But we’ll stick with the Yamanaka factors here.

As far as a dose of exercise that would induce Myc, for instance, I’ve never done this study. I’ve never done this study where I’ve taken somebody, and okay, we’re going to do five sets versus 10 sets, or three sets versus eight reps, or what have you. I’ve never done that. data might be somewhere out in the literature; I’m not sure. But the people that have focused on Myc, and Myc hasn’t been as focused on as a lot of other things that are exercise-responsive.

There was a study that was done a couple of years ago by one of my collaborators that took all of the gene expression data from all of the exercise studies that have been published to date. So basically, it was this big compendium of studies where people had biopsies done before and after different forms of exercise, and then they looked at all the genes that were being expressed in response to that exercise. You can do these big sequencing studies or these big microarray studies where you can basically look at all the genes more or less in the genome and which ones are being turned on or turned off in response to exercise and muscle.

There’s been many of those studies done over the years. They took all of them together and did a huge meta-analysis and said, “These are all the studies to date. What genes are being turned off and on with exercise?” when I looked through that database, which is dozens of studies—a whole bunch of studies—and they did a great job of putting it all together and making it usable. There’s a little website you can go to and plug in your favorite gene and see if it gets turned on with exercise and muscle. It’s really cool. It’s called MetaMEx. It’s Juleen Zierath and Nico Pillon in Sweden’s Karolinska that put this together. You can go in there, and you can look for your favorite gene. When I did that, that’s one of the ways I figured out that Myc was the one that was being expressed the most with exercise. It seemed, based on some of our data and some of the data that was in that big meta-analysis, that just resistance exercise in general was a better stimulus for Myc.

We found that in our own studies, too. We published a study where we did a time course of biopsies after resistance and endurance exercise, so we took a biopsy. I say we, my collaborator in Sweden, did this; his name is Ferdinand. I helped him with it, but this was his study. But he took a biopsy before and then took a biopsy 30 minutes, three hours, eight hours, and 24 hours after a resistance exercise bout and an endurance exercise bout. For resistance exercise, I’m pretty sure it’s like your typical three sets of 10 with squats, leg extensions, and things like that. Then there are endurance exercises, which I think were just maybe a 45-minute cycling bout, if I’m not mistaken. It was pretty standard. It wasn’t anything fancy. We found that Myc went way higher with the resistance versus the endurance.

Now, all of that is to say that I’m not answering your question directly because I don’t know. I don’t know if one set or 10 sets is going to be better for inducing this response. But one thing I can say, and this is a word of caution, is that Myc sounds like a good thing. The Yamanaka factor may have quote, unquote, rejuvenating properties, and all these things are good, it sounds like. But in actuality, Myc goes up after exercise, and it comes back down. If you were to leave it up, that would be bad. Because it’s an oncogene as well. Myc was one of the first genes implicated in progressive cancer, so that’s not good. When it gets turned on chronically or gets turned on constitutively where it’s always on, that’s bad. It needs to be controlled in a way that’s pulsatile and more transient. If you just turned it on all the way and left it on, that would be really bad.

Your muscle doesn’t really form cancer; it can, but it’s pretty resistant, specifically the muscle fibers. but that would not be a good thing. in the same way that turning on mTOR, for instance, is called the master regulator of muscle growth. When you turn that on continuously for long periods of time, it actually results in pathology and muscle atrophy. It needs to be controlled because mTOR is implicated in cancer as well. And interestingly, as we get older, mTOR actually goes higher.

Dr. Gabrielle Lyon [0:50:10]

I know. I was wondering if you’re going to mention this: I sat down with Blake Rasmussen, and we were talking, and Elena Volpi. I didn’t get a chance to sit down with her, but I sat down with Blake when they were in Galveston, and it was one of the topics of conversation. We talked about mTOR and skeletal muscle in such a pulsatile manner that it requires exercise. It requires leucine. There are a handful of influences. But mTOR, for the listener, they’ve heard me talk about it, mechanistic Target of Rapamycin, and you’re the first person that’s actually saying this on the podcast, and you’re absolutely right, that as we age, it’s revving at a higher amount all the time. I don’t want to confuse anybody; you do need to stimulate it for muscle protein synthesis. What Kevin is saying is that in aging mTOR, there is an anabolic resistance nature. The efficiency of protein utilization and mTOR stimulation in skeletal muscle with the resulting muscle protein synthesis is somewhat less efficient. But overall, mTOR, which is in all tissues, is revving and turned on, for lack of a better word, at a consistent level, which is interesting.

Kevin Murach [0:51:37]

They call it hyperfunction, where it’s like—

Dr. Gabrielle Lyon [0:51:39]

They’re very elegant; there you go, hyperfunction.

Kevin Murach [0:51:42]

–where we’re being revved up, but also, it’s like, we’re maybe not being revved up in the right ways. Because mTOR is up, we may be translating a bunch of proteins that we don’t really need, and maybe they’re not getting turned over. So maybe they’re turning into aggregates, which is not good. We’re getting mislocalized. They’re pools of protein that are being turned over. Whereas there are other pools of protein that are being turned over at slower rates, at different rates, or not being turned over at all. then when you add in this component of mTOR being hyperactive, you may just be more or less creating more things you don’t want or need, and that’s not good. The muscle is getting smaller, but also because mTOR is up, you have to have some element of breakdown too, and breakdown must be going up too to compensate for that because you are losing muscle as you get older.

It’s not as simple as everybody says it is, which is what we’re beginning to discover. It could be the case with Myc too. From what I can tell, at least in human muscle, Myc protein levels don’t go up with aging, and at baseline, Myc is very low in the muscle, and in some studies, it’s not even detectable. In our mice, when we probed for it at rest, we didn’t see anything. It’s only when we exercise that we see it.

Dr. Gabrielle Lyon [0:53:08]

Does it matter the fiber type in adults?

Kevin Murach [0:53:17]

That’s a wonderful question. I can’t answer that question in humans. The data might be out there, and I think we’re going to have the data eventually. There are some datasets I haven’t combed through yet where I could look and see if fiber type matters. As far as MyC responsiveness, What I can say is that we have a genetically modified mouse model where we can control Myc expression only in the muscle fiber whenever we want. We can turn it on or off at will.

Dr. Gabrielle Lyon [0:53:46]

Is this the power mouse model?

Kevin Murach [0:53:47]

No, this is a different mouse. Power is an exercise model that we use in conjunction with our mice. The mouse I’m talking about is one that has been genetically engineered so that we can basically say, okay, we’re going to age the mouse to four months, which is an adult mouse, and we want to turn on Myc. but we only want to turn it on for a few hours, and then we want to turn it off. A couple days later, we’ll turn it on again, and then we want to turn it off.

We can do that with this mouse. It’s a very powerful tool. So it’s like I was saying, like when you want to study mTOR, a lot of times, you just turn it on, and then it’s always on, and then you study what happens. But that’s not how it behaves in response to exercise. It goes up and then it comes back down, goes up and then comes back down, or, with aging, maybe just gradually starts going up, up, whatever. But it’s a dynamic process. It’s not just on or off. With our Myc mouse, for instance, we want it to be able to turn it on and off because we know that if we turn it on for a long period of time, A, that’s probably not going to be good for muscle, and B, that’s not what happens with exercise. With exercise, we know it goes up, then it comes back down. It goes up and comes back down. We’re interested in trying to create a model that can replicate that, so we’ve done that.

When we turn it on, we can harvest different muscles from the mouse. We turn it on for, let’s say, 12 hours, then we harvest the muscles. We harvest the soleus muscle from the mouse, which is more oxidative. It has more slow twitch as well as—well, oxidative profile and fiber type don’t always go perfectly together, but it has more type I and type II fibers. Whereas the plantaris or the gastrocnemius, which are other muscles of the leg, may have a higher proportion of the more fast-twitch fibers like the 2X and the 2B, like the super-fast-twitch type of muscle fibers. Muscle fiber types differ between mice and humans.

Dr. Gabrielle Lyon [0:55:35]

I was just thinking, you guys, I don’t think humans have type 2B.

Kevin Murach [0:55:41]

I think we have the gene for it, but we don’t really express it except maybe in some really odd muscles. But for the most part, we only have 2A and 2X. But then it’s a debate whether 2X even really exists in pure form in humans.

Dr. Gabrielle Lyon [0:55:58]

I didn’t realize this. I’m curious; there’s a lot of talk right now about DNA methylation and aging. This is now the hot topic: DNA and methylation. Please tell me how this relates to skeletal muscle. What does it do? What can we learn from it? I know that your lab is doing a lot of work investigating methylation in skeletal muscle, specifically in the context of exercise.

Kevin Murach [0:56:26]

I can certainly talk about it. Real quick, with makeover expression, we see more genes being turned on in the soleus than in the other muscles. It’s more of, I guess, a slow-twitch type of muscle. It could be that it’s more influenced by that, but that’s just in the mouse and using a genetically modified mouse model. There are a million caveats, but that’s all I can say about that. As far as a human being, which muscle fiber type is more responsive, which has more Myc responsiveness, I don’t know. Hopefully, we can figure that out.

But as far as methylation goes with aging, basically, as we age, a lot of things change. The composition of our muscles changes. Sometimes we might get more fat infiltration. We may get more fibrosis as we get older, so the muscle may become less contractile material, less muscle fibers, and more other stuff. As our stem cells start to die off, a lot of different things happen. But in our DNA, though, the epigenetic profile of the DNA changes over time, too. So we’re not talking, well, the DNA does change over time because of mutations. That’s how cancer a lot of times happens; it’s a mutation that then starts driving a gene like Myc, for instance, and can cause cancer. But for most of the DNA, you still have the same set of genes that you had when you were born. It’s just that some of them might be a little different due to mutations in various environmental things and what have you.

But what’s really changing a lot over the lifespan—and I say a lot; it’s not even all that much, but it is changing—is the epigenetic profile. DNA methylation is something that has been studied in laboratories. We’re talking about changes in methyl groups attached to specific nucleotides in the DNA. These can be added to cytosines, and they can be taken off of cytosines in different areas of the genome that can determine the function of different genes, whether they get turned on or turned off, spliced, or all these different things can happen with changes in DNA methylation.

That’s one of the epigenetic layers that my laboratory studies: DNA methylation and muscle with aging and exercise. We’d like to try and understand how these different methyl groups are getting added or taken away, maybe how that’s happening and how that’s influencing what genes get accessed, and how exercise adaptation does or doesn’t happen throughout the lifespan. but what’s been found, and there are a lot of people that have contributed to this field over many years. The most probably recognizable person is a guy named Steve Horvath who now works for Altos Laboratories, which is an aging startup.

Dr. Gabrielle Lyon [0:59:08]

Yeah, plucked away. They all left academics. I think that Jeff Bezos and these groups pulled all these highly academic minds away. I can’t be sure, but I think a lot of these people left academics.

Kevin Murach [0:59:23]

You’re right. Steve Horvath was one of them. He was at UCLA for a long time, and now he’s at Altos Laboratories. A lot of big names, like Shinya Yamanaka, are affiliated with Altos Laboratories too, including the guy who won the Nobel Prize. All these ideas are intertwined.

Dr. Gabrielle Lyon [0:59:40]

I have a question. I understand and appreciate that these are two separate things. Looking at methylation in blood work, for example, we might look at homocysteine, and there’s ways in which providers can potentially look in blood work and look at these methylation factors. Number one, is there any translation between skeletal muscle and aging methylation and something that we could potentially look at as a biomarker that you’re aware of?

Kevin Murach [1:00:16]

As far as something in the blood that would relate to something that’s happening in muscle with methylation, I don’t know if anyone’s looked at that. That would be a tough one. I mean, you could grab muscle samples and get some indication, but that’s probably not something most people are interested in having done. I don’t know if there’s anything; there’s other biomarkers in the blood that people can look at. But as far as epigenetically, I don’t know, like maybe there’s some microRNA, which is like a small RNA that gets out into the blood. That could potentially be a biomarker. But as far as the methylation age stuff, I’m not so sure. I don’t know the answer to that question. I feel like the answer right now is probably no.

Dr. Gabrielle Lyon [1:01:01]

I can appreciate that.

Kevin Murach [1:01:03]

What we can do is take a muscle sample, look at the methylation profile of the DNA, and get a fairly accurate estimate of your chronological age. That was a discovery that was made. We’ve known it for a little while, but Steve Horvath was the one who really popularized it, developed it, and turned it into something that people are really using now. But it’s this idea that as we age, all of our cells, not just the muscle—I mean, you could take a swab of saliva or a sample of blood and run a methylation aging analysis on it and accurately predict that person’s chronological age. So you can imagine that the uses for this could be numerous. You could maybe use it at a crime scene to figure out if there’s some blood and how old the person was, and that could maybe narrow down who the perpetrator was or whatever, but what it’s being used for now is to try and understand the aging process and whether it can be modified at the epigenetic level and whether that can lead to functional changes that are beneficial or not beneficial. For instance, if you had an unhealthy lifestyle, if you smoked a lot and were overweight or inactive, maybe we would take your methylation age analysis from your saliva, from your muscle, or wherever, for that matter. It may change from organ to organ, too.

Dr. Gabrielle Lyon [1:02:33]

I was just wondering, does it change from muscle to muscle?

Kevin Murach [1:02:35]

That’s a whole other conversation. Yes, probably is the answer, and more active fiber types and all these things might change or a lot of things. but we’ll just stay on track and talk about methylation and aging. Basically, the methylation profile will change pretty systematically throughout the lifespan for everybody. If you had an unhealthy person and you were to predict their age based on their methylation profile, that person might come back older than they actually are, and vice versa. If someone is healthy, you can predict their methylation age, which is younger than their chronological age.

What does that actually mean? It seems to align with a person’s health status. Does it mean they’re going to live longer or do any of those things? I’m not so sure. The other big question, I think, is: is it causative, or is it just a byproduct? these changes at these specific methylation sites throughout the genome, is it causative for that person becoming healthier? I don’t think we really know the answer to that yet. But these are things that people are trying to study and understand.

Specifically, in skeletal muscle, though, yes, we can take muscle samples from humans, and we can take them from our mice and submit them to this methylation aging analysis and predict their chronological age, and then we do stuff to them; it will change. For instance, like with exercise, we published a couple of studies where we exercise-trained our mice late in life. For the last two months of their lives, they exercised and trained. They were sedentary their whole lives, and then we trained them for a couple months, euthanized them, harvested the tissue, and subjected that to the methylation age analysis. The ones that exercised just for two months had a younger methylation age than the ones that were sedentary.

Dr. Gabrielle Lyon [1:04:26]

By how much?

Kevin Murach [1:04:28]

They exercised for eight weeks, and they were eight weeks younger from a methylation perspective. So essentially, from that methylation standpoint, their methylation aging stopped at the point that they started exercising. But what does that mean? Does it mean that they could turn back the clock all the way to zero and become infants again? Of course not.

Dr. Gabrielle Lyon [1:04:48]

Benjamin Button?

Kevin Murach [1:04:50]

Exactly. Are these Benjamin Button mice that we’ve made with our exercise models? No, I don’t think so. But I think it’s one part of a larger puzzle: What is exercise doing that’s beneficial that’s making older muscle appear like younger muscle, at least from this methylation profile? But this goes hand in hand with the change in fiber type that we saw that seemed like it was healthier, the increase in muscle strength that we saw, and all these things that coincided with that. It’s like, how is this contributing to this change in the methylation age? Or is it just a byproduct of something? I don’t know.

Dr. Gabrielle Lyon [1:05:26]

Is there any relation to the maintenance of power?

==========

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Kevin Murach [1:06:44]

I don’t know. People have asked me this before, and I’m trying to think because, I mean, the level of reversal varied across the mice. I’m trying to think because when we put our mice through these exercise protocols, it’s voluntary for them. We just put them on their wheels, and we weight the wheels, and they run in different amounts. Some run a lot. Some run less. I don’t think we’ve had a big enough sample size to really draw a correlation between how much they’re exercising versus how much reversal we’re seeing and things like that. I don’t think we’ve done enough. We need a pretty big sample size to tease that one out.

Dr. Gabrielle Lyon [1:07:19]

Their chow was all standardized. I’m curious how it would relate to humans. Again, we think about methylation, at least from a physician’s or nutrition’s perspective. You’re talking about DNA methylation from an exercise perspective. I wonder what influence, if any, nutrition plays on the DNA methylation of aging and skeletal muscle.

Kevin Murach [1:07:47]

I would think it would, and I don’t know the date off the top of my head, so I can only speak in broad terms. The reason I say that is because there’s evidence to suggest that a mother’s eating habits can affect their offspring. That’s mediated by epigenetic factors, and one of those is DNA methylation. So I would say that diet has probably played an immensely impactful role in determining it. the quality of the exercise and the recovery, but also maybe just the diet in and of itself. I think that being on a high-fat diet even for a relatively short period of time can change muscle DNA methylation, and it will stay different for a while. Methylation aging is an algorithm.

Dr. Gabrielle Lyon [1:08:36]

I’m just wondering how you’re looking at this. Is it a proprietary algorithm, or is there something that other researchers and providers can access to look at DNA methylation?

Kevin Murach [1:09:04]

To look at DNA methylation as a process It’s something where we have to start it in the wet lab and isolate the DNA in a certain way and enrich it, and then it needs to be treated. There’s a lot of steps. then with the actual methylation age analysis, there are what they call clocks, methylation clocks, and there’s a lot of different clocks out there. There’s a lot developed by a lot of different researchers. Steve Horvath has a whole variety of clocks that he’s developed that work across the entire animal kingdom, like conserved CpG sites and all this crazy stuff. But people have developed all different types of clocks. A lot of times, those algorithms are publicly available, but you have to know how to code, how to process the data, and how to do all these different things.

It has been commercialized, though. You can send out a swab of DNA or a cheek swab or whatever and have a methylation age done based on one of these algorithms, and it’ll give you a number. but I think the ones for muscle, for instance, there haven’t been that many that have been optimized for muscle, so that’s been a little bit of a challenge. We’ve had to work with Steve Horvath and some people trying to sort that out. But these are specific cytosines, and the change in methylation throughout the lifespan is very small, but it happened systematically. There are a lot of different clocks. There are clocks that have hundreds of thousands of CpG sites that are included in their algorithm, some that only have a few, and how well they perform based on tissue, species, and all these things.

Dr. Gabrielle Lyon [1:10:38]

You haven’t mentioned that, but I do have a question. Does muscle myonuclear CpG DNA methylation change with exercise training? You brought up CpG DNA. In all fairness, I had not heard about it before you. Does that change with exercise training? Then I think the ultimate question is, what can we learn from your research? How is it translatable? Because I think your ultimate goal is to bring some of this work to the bedside. What does it mean to further an individual’s life? How can they address aging? So number one, what the heck is it—that CpG DNA methylation? How does exercise affect it? What was your research? What are some of the things that if your mom called you and was like, Kevin, I need to de-age myself, what do I need to do?

Kevin Murach [1:11:37]

Right, let’s take them one at a time. With myonuclear methylation, when we study muscle, muscle is really interesting and unique for a lot of reasons. It’s difficult to study, but that also makes it fun to study.

Most cells in the body are mononuclear, so they have one nucleus, like your skin cell, an eye cell, or whatever. Almost any other type of cell in your body has one nucleus, and the whole tissue is made up of single cells with one nucleus in them. Muscle fibers aren’t like that. Muscle fibers are these really long cylinders. They contract, so they get shorter and longer. They’re very adaptable. They get bigger and smaller and change their phenotype from type 1 to type 2, and all these different things are fascinating.

They’re very long tubes, like spaghetti, and within them are hundreds to thousands of nuclei. They’re multinuclear, which makes them really tricky to study. What we’ve had to do is think up some new techniques so that we can pull out the nuclei from the muscle because, for certain assays, you can just put a tissue through a machine, and it’ll give you the cells you want. You can’t do that with muscle. The cells are just too big. We have to pull out the nuclei if we want to study them. So we made some models that now enable us to do that.

What we did was use our mouse model. We can look at the myonuclei and the methylation in them, and we looked at it before exercise training and after exercise training to look at this CpG methylation. DNA is made up of A’s, T’s, C’s, and G’s, and what happens is that when you have a C that’s next to a G, that C can get methylated, and then it can change the function of that gene that it’s associated with. In front of the gene, if there’s a promoter region that allows the gene to get expressed, methylating that promoter region may shut down gene expression. or vice versa, if you remove those methylation signals, it may increase the gene expression of that gene. It has an actual, tangible function. Sometimes there’s methylation all throughout the genome, and we have no idea what it does—no idea at all, not yet, at least.

In any case, what we did was, after exercise, pull out the nuclei from the muscle fibers. Then we isolated the DNA just from those nuclei, and then we looked for methylation changes in the DNA and found that yes, the exercise training specifically targeted the muscle fibers, so the DNA of the nuclei of muscle fibers was different than before training. We think that certain genes are being changed in order to facilitate adaptation. That was something that we published a couple of years ago, and we have been building on that story ever since then. That’s an ongoing project that we’re doing.

But as far as what do we hope to gain from all this? What’s the ultimate outcome here? For me, as I mentioned earlier, we need to understand the processes. If we’re ever going to design any sort of therapy, exercise intervention, drug, or anything, to be effective, it’s best that you know how it works.

For us, what I’m trying to do with my laboratory and the team that we have here is just try to get a basic understanding of these different processes so that hopefully, maybe we or someone else in the future can help to design drugs that maybe we don’t want to target specifically because it’s an oncogene, or maybe we do in muscle and it’s fine; I don’t know. But maybe we don’t want to design a drug that would have an off-target effect. That’s bad.

But maybe if we turn on Myc in the muscle and then we see all these genes change, and we see this change in muscle strength and change in muscle size, well, maybe we can isolate it down to just these genes that are being turned on by Myc, and then we can focus on those because if we target those, then there won’t be off-target effects. Those types of things are what we’re interested in trying to do. A lot of this is some of this pie in the sky idea, but some of it is just generating basic knowledge on how muscle works and how muscle adapts to exercise.

Dr. Gabrielle Lyon [1:15:42]

Do you think that we are far behind in understanding skeletal muscle?

Kevin Murach [1:15:51]

Skeletal muscle is a field that sometimes still lags behind a little bit. I think the cancer field probably leads the way as far as technology and things like that because it’s cancer. I mean, we need to figure out how to solve that one. A lot of that technology does trickle down. But I’ll tell you what, though: there’s a really big initiative at the National Institutes of Health right now, the NIH, which is the main funding body; they fund my research, they fund Chris Fry’s research, and probably everyone you talk to has NIH funding. They support the work that we do, which is fantastic, but they have this huge initiative called the Molecular Transducers of Physical Activity, or MoTrPAC, and I’m sure someone has spoken about that.

Dr. Gabrielle Lyon [1:16:27]

Blake was talking about MoTrPAC.

Kevin Murach [1:16:31]

I think he’s involved in that. It’s this huge initiative, and it’s rodent studies, and it’s human studies, and it’s getting human tissues like blood, fat, and muscle before and after exercise and different types of exercise. We’re talking about thousands upon thousands of people where we’re getting all these samples, and there’s all these data analysis scores all throughout the US that are analyzing these samples and doing methylation; they’re doing proteomics, transcriptomics, and every sort of omic you can imagine to try and understand why exercise is good, and are there things that we can target based on this huge sample size? So if we do these huge studies and see every single person having an upregulation of Myc in their muscle with exercise, okay, well, that tells us something is probably important for adaptation. What is it doing? And that’s where I’m coming in and saying, “Okay, I’m trying to figure out what it’s doing so that we can get together and maybe figure out something that we could target.” That is or isn’t Myc.

These types of huge datasets and studies are really coming on board now. The first papers from MoTrPAC will be out in the new year. We’ll learn some really cool things, and the human papers will be a couple years after that. The first papers will be the rodent papers, I think, but they are really interesting. Are we behind? No, I don’t know that we’re behind. I think we’re just still trying to adapt to all these new technologies. There’s so many different types of technologies that have come on board in the last five years that are just mind-blowing, that aren’t as publicly available yet, and we’re still trying to grapple with that and understand how to integrate them into our research programs because there’s so much you can learn, but at this point, you can generate so much data, and then you have to have someone to analyze it, and that’s a task unto itself. I’m not a bioinformaticist.

Dr. Gabrielle Lyon [1:18:28]

I’m going to let your lab know. If you were to make a recommendation, would you say that there is a difference if we were trying to affect aging? I’ll say aging, or, quote, longevity versus performance. If you were to, again, make a recommendation, for example, would it be that perhaps 20% of your activity would be high-intensity intervals and 70% would be resistance training? Have you thought about a translatable way to give it to the population or what you would consider ideal? Or even what you do for yourself, and if you’ve thought about the percentages?

Kevin Murach [1:19:14]

I’ll preface it by saying that I’m not a medical doctor, and I’m not in a position to give really strict advice. If you’re going to go out and begin to exercise, I say, make sure you’re healthy enough to do so. Make sure your medical doctor clears you; I’ll say that. I don’t know if there’s any sort of lawfulness thing going on.

Dr. Gabrielle Lyon [1:19:30]

No, we have you covered. We have many disclaimers. Everybody knows that I am not their physician, and you are not their physician.

Kevin Murach [1:19:38]

I’m not even a physician at all.

Dr. Gabrielle Lyon [1:19:41]

What I really try to do for the listener and even the providers is: how do we get experts like yourself on, and as you’re doing the research, oftentimes, you’ll see things or you’ll have flashes of insight that, again, take years for the papers to come out in the teams and in the labs? You get it out there. What I’m always looking to do is, how can we initiate some of this from an evidence-based perspective, or at least have the inclination to make these recommendations to allow people to become the best versions of themselves?

Kevin Murach [1:20:16]

Well, I’ll start by telling you what I do, and then I can maybe give you a little bit of insight from some studies that we’ve done. My exercise evolved over the years, but there was a period of time where I was almost exclusively lifting weights when I was younger, when I could afford to eat what I wanted and not put on a ton of weight. But nowadays, though, it’s a combination of both. I lift three days a week, upper and lower body two days of the week; one day I’m doing squats; the other days I’m doing deadlifts and bigger compound movements. But those are things that I enjoy doing, and then the other stuff, of course, is working my arms and chest and all these things too.

Dr. Gabrielle Lyon [1:20:56]

Universal chest day is Monday.

Kevin Murach [1:20:58]

Actually, it is. Its chest and back are Monday with legs. Those are heavy days. Those are hard. But then the other days, I’m doing some form of cardio. I’m either riding my bike outside when the weather’s nice, or I have a road bike I like to ride. then I have a rower that I love. I love rowing. I row 10k. I’ll probably run 20k or 30k a week; I love doing that. I spend some time on the treadmill too. But I think that combination is so important. That’s what the American College of Sports Medicine recommends: doing a combination of both. I believe that that’s the right thing to do.

But I think the real answer for most people is to do what you can stick to. I think adherence is something that is really important because if you don’t like it, you’re not going to stick with it. If you enjoy endurance training more, then if you try to do resistance training, you’re not going to adhere to it. Do what you enjoy. But I think from a health and wellness perspective, it’s good to be strong and to have good cardiovascular endurance because both independently are predictors of mortality. having high aerobic capacity or having a low aerobic capacity is predictive of mortality in a bad way, and being weak, not having good strength or power production is also predictive. Having both of those things at the highest level you can get them, I think, is really important, especially as you get older.

As we get older, we’re naturally going to start declining in muscle mass, and so I would say, try to put on as much of that as you can when you’re younger so that when you’re getting older and it becomes a little harder to maintain it and to build it, you have a bigger reserve. I think that’s really important. I feel like a lot of people focus on endurance training, and that’s wonderful. I’m not an endurance athlete, but I will go ride my bike for two or three hours at a time. It’s something I enjoy. In the summer, I do that. But it’s like, if you saw me in person, you wouldn’t say that guy’s an endurance athlete. I don’t look like an endurance athlete; I’m pretty bulky. But I see the value in it, and I know how important it is. But also, I think resistance training is really underrated. You’re going to lose muscle mass as you get older, unfortunately. I would say to try to put on as much as you can as early as you can so that you can maintain that muscle mass as you get older.

Dr. Gabrielle Lyon [1:23:23]

That’s really good advice. I would leave the listener with something else: that, again, we’re not training to become better at exercise. If you continue to do the same routine, you don’t challenge yourself, and there’s no growth; you have to be. From my perspective, if we know that at some point there’s this natural decline in strength and power in skeletal muscle, then we have to begin thinking about skill acquisition and ways in which we can get better, whether it is a new movement, or, I don’t know, a kettlebell carry, a swing, or improving your balance, whatever it is, rather than doing the same thing that you did in your 30s and 40s and then just continuing that but getting less effective and weaker. We have to think about how we can really offset that.

Kevin Murach [1:24:17]

No, it’s a great point. Just quickly, a quick anecdote: during the pandemic, I set up a gym in my garage. It wasn’t anything fancy. I had my rower. We had a treadmill, and I had a rack with some dumbbells and barbells, but they weren’t very heavy. I lifted that way for three years. I decided I’m never going back to the gym; this is fine. I’ll just do this. I don’t have to deal with people or whatever. I’ve always been on college campuses too, and so I was like, I’m a professor. I don’t think I want to work out with the students. I’m just going to stay at home, so I worked out in my garage.

But I recently found that there’s a gym just around the corner for me, Anytime Fitness, and nobody’s really ever there, especially earlier in the morning. They have all the equipment I need. It’s a very grungy gym, but I love it. So I was like, you know what? Nobody’s here. it’s easy. It’s not even a two-minute drive from my house. I’m going to give this a try. It 100% reinvigorated my passion for lifting weights again. I used to lift all the time heavy when I was younger, and I gave that away, and then now that I’m back at this gym, I’m like, wow, I get really excited for my workouts again in the morning, and I get to do all these different things I wasn’t able to do in the garage because they have more stuff. but it’s been transformative for me, and I just love it, and I just forgot how much I enjoyed it. It was not something new, but it is new to me now because I haven’t done it in a while. I think it’s really important to keep it fresh, as you say, and to try new things, if only just so you don’t stop doing it.

Dr. Gabrielle Lyon [1:26:00]

I think that it’s wonderful advice. It is wonderful advice. Well, Dr. Kevin Murach, we are really excited to continue to do your research. Where can people find you? Are you accepting graduate students? Are you looking for people for your lab? Tell us a little bit about where people can find you.

Kevin Murach [1:26:19]

Yeah, I mean, you can obviously email.

Dr. Gabrielle Lyon [1:26:23]

No, you do not want to give out your email. If they are motivated enough to find you, we will put your lab website page and your Twitter account there.

Kevin Murach [1:26:37]

It’s easy to Google me. But yes, I have a lab website. I have a Twitter account, @KevinMurachPhD, and the same for Instagram. Those are social media ways that you can get in touch with me. I’m always looking for students and trainees. If you’re interested, we have a master’s program and a Ph.D. program, and I hire postdocs at any level. We have an undergrad program here. That’s great, too, of course. University of Arkansas, check it out.

Dr. Gabrielle Lyon [1:27:10]

Hey, do you know Jamie Baum?

Kevin Murach [1:27:12]

I do.

Dr. Gabrielle Lyon [1:27:14]

I trained with Jaimie. I think that she’s wonderful.

Kevin Murach [1:27:20]

Gosh, so many people bring her up when I go places. I’m like, I don’t see her that much, but everybody seems to know her.

Dr. Gabrielle Lyon [1:27:26]

Yes, she’s wonderful. I was at the University of Illinois. We say we were both in Don Layman’s lab.

Kevin Murach [1:27:33]

Okay, because I have some colleagues, Nick Burd is in Illinois, and Martin is there. They have a wonderful thing going on there, so that’s awesome.

Dr. Gabrielle Lyon [1:27:42]

You know what? I’ve got to get Nick on the podcast. I really appreciate one of his papers. He was talking about the blunted muscle protein synthesis effect in obesity. Maybe you’ll make an intro for me.

Kevin Murach [1:27:56]

Yeah, mental note, get him on here.

Dr. Gabrielle Lyon [1:27:59]

Kevin, thank you so much for spending your time with us. We really appreciate you and all the work that you’re doing. I think it’s very meaningful; it’s extremely well thought out. I will link some of your open access papers with a nice summary that we’ve put together, and again, thank you so much for all the work that you’re doing.

Kevin Murach [1:28:18]

Thank you for having me. This was really fun. Hopefully it wasn’t too dense and made sense.

Dr. Gabrielle Lyon [1:28:24]

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