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The Science of Muscle Growth | Christopher Fry PhD

Episode 78, duration 1 hr 29 mins
Episode 78

The Science of Muscle Growth | Christopher Fry PhD

Dr. Christopher Fry is a tenured Associate Professor in the Department of Athletic Training and Clinical Nutrition at the University of Kentucky, and he serves as the Associate Director of the Center for Muscle Biology. Chris completed a BS in Biology at Baylor University, PhD in biomedical sciences at the University of Texas Medical Branch and postdoctoral training in muscle physiology at the University of Kentucky. His research is funded by several grants through the National Institutes of Health (NIH), and he has received several awards for his research. Over the course of his career, Dr. Fry has created a focused research program that bridges targeted mechanistic approaches to clinical translation. Specifically, he seeks to enhance the regenerative and regrowth capacity of skeletal muscle when it is compromised following an acute musculoskeletal injury with the purpose to support patient recovery.

The Science of Muscle Growth - Christopher Fry PhD

In this episode we discuss:
– Why you should care about your satellite cells.
– What can you do to increase your sports performance?
– The future of muscle physiology research
– How to improve your muscle growth and recovery.

00:00:00 – Introduction

00:05:31 – Enhancing Physical Function

00:10:56 – Muscle Regeneration and Exercise Adaptation

00:16:33 – The Role of Satellite Cells in Muscle Health

00:28:02 – Exercise Planning for Older Adults

00:33:43 – Muscle Stem Cells

00:39:21 – Epigenetics

00:45:06 – Age-related Muscle Decline

00:50:33 – Blood Flow Restriction Training

00:55:59 – Concurrent Training and Diminishing Returns

01:01:16 – Enhancing Muscle Recovery and Joint Health

01:06:47 – GDF8 Antibody and Muscle Growth

01:12:43 – Myocellular Adaptations to Exercise

01:23:32 – Understanding Exercise Response and Muscle Health

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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, I sit down withDr.Christopher Fry. He’s a tenured Associate Professor in the Department of Athletic Training and Clinical Nutrition at the University of Kentucky. He serves as the Associate Director of the Center for Muscle Biology, which, of course, is something we find fascinating. Chris completed a BS in biology at Baylor University, PhD in biomedical sciences at the University of Texas Medical Branch, and a postdoc in muscle physiology at the University of Kentucky. His research is funded by several grants through the NIH, and he has received several awards for his research. He has created a focused research program that bridges targeted mechanistic approaches to clinical translation. What does this mean? This means he seeks to enhance the regenerative and regrowth capacity of skeletal muscle when it is compromised following an acute musculoskeletal injury with the purpose to support patient recovery.I know that was a mouthful. It’s really important to understand that in this episode, we do something very unique. We take bench research, mechanistic and animal model research, and Dr. Chris makes the bridge to human research, and then finally, to clinical application; very unusual and very important research.

In this episode, we discuss the concept ofmuscle plasticity and it’s important in understanding muscle adaptation and recovery, particularly in the scenarios of muscle wasting or injury. We also discuss what a satellite cell is, why it is so important, and how that impacts both injury and sport performance and hypertrophy. This episode was packed with scientific information with questions as to where we are in muscle physiology research, what we know, and what are some therapeutic applications of his personal research. This probably was one of my favorite episodes. As always, if you enjoy this podcast, please take a moment to share it with your friends, with your family, with your trainer, with your health care provider. This is how we spread the word on muscle-centric medicine.

I’m so excited to announce that I am having the first ever Forever Strong summit on January 13th and 14th for a transformative in-person experience where I will share cutting-edge insights on optimizing health, performance, and longevity, empowering you to unlock your full potential. My friends, I cannot wait to meet you in person. Please don’t miss this exclusive opportunity to learn from some of my best friends, renowned experts in the field. Secure your spot at drgabriellelyon.com/foreverstrongsummit. That’sdrgabriellelyon.com/foreverstronsummit. See you there.

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Dr. Chris Fry, welcome to the Dr. Gabrielle Lyon Show. I am thrilled to have you on.Just before we started recording, we were mentioning the list of the who’s who in the muscle protein synthesis world, and not just the muscle protein synthesis world, but the muscle world, you are certainly on that list. I am ecstatic and excited to talk to you about your research. Tell us a little bit about your current lab.

Dr. Christopher Fry [0:07:26]

Oh, fantastic. Thank you for the opportunity to be on the show today,Dr. Lyon. It’sa pleasure to meet you.I’ve been a big fan of the show for a long time. I’m currently an associate professor at the University of Kentucky. I helped direct our Center for Muscle Biology. We have a very interdisciplinary group of researchers that have an interest in all things muscle, be it cardiac or skeletal. Right now, my lab employs a variety of research trainees and scientists spanning from undergraduate level to PhD-seeking students, postdoctoral fellows as well as research-level faculty, those who have completed advanced training such as a postdoc fellowship looking to really make that next step to their career. As you said, we have an interest in all things muscle. We’ve got a variety of projects looking at how we can adapt our muscles in instances where we’re challenged in terms of weakness or atrophy. That’s our primary interest.

Dr. Gabrielle Lyon  [0:08:21]

Which is incredibly relevant to an aging population and also a population that has medical issues related to skeletal muscle, so I’m sure that we will go into detail there. But before we do, I always like to understand a little bit about the researcher. Why skeletal muscle?

Dr. Christopher Fry[0:08:41]

I’ll try and keep it relatively brief. I always enjoyed exercise and athletics growing up.When I was an undergraduate, I had friends in various kinesiology or exercise science graduate programs. I really fell in love with a lot of the molecular biology courses I was taking at the time. Some of my graduate student colleaguesadvised me to look at programs where I could bridge those two passions, where I could study on a molecular basis how muscle adapts.That’s what led me down to the University of Texas Medical Branch in Galveston, reaching out to some of the investigators there who study a lot of protein metabolism in response to nutrition and exercise. I thought that was the coolest thing ever, studying patients, taking muscle biopsies, understanding how we build muscle on a day-to-day basis. From there, my research interests continued to broaden. I really became interested in how we can leverage and harnesspreclinical models using rodent study to try and understand more mechanistically how muscle adapts to the various stimuli with which it’s exposed. That’sdovetailed into ourcurrent research paradigm where we try and bridgevery targeted mechanistic trials but then not losing sightof the patients we work with.Our goal is to identify therapies to enhance their physical function. That’s the principle thatguides our research program.

Dr. Gabrielle Lyon[0:10:11]

It’s so fascinating. I’ve reviewed a handful of your papers, and it’s exactly what you’re saying.Some of it is incredibly mechanistic, and it really points towards clinical relevance, which is very unique. We will link some of those papers, and we will talk about some of them.In regards to what we believe as truth, so science, muscle physiology, muscle mechanics, etc., health is an ever-evolving field. I often wonder the things that we agree upon, the working hypotheses that we agree upon when it comes to muscle plasticityversus are there things that we disagree upon?

Dr. Christopher Fry[0:11:00]

It’s a loaded question. I feel that’s part of the fun of science is we continue to uncover new evidence.Our hypotheses or theories, what becomes known as ground truth as you so well put it, I think adapts and changes much like muscle does. I think, too we try often to challenge paradigms more so because historical studies may not have been collected or analyzed in the most rigorous light with the bevy of tools we have at our disposal today, so it’s often helpful torevisit some long-held beliefs to see if they still hold water. I feel so much of the historical precedent and research guides our current clinical practice and making sure the veracity of those findings holds up to current studies, current designs, I think it is critical, not just a revisit for revisit’s sake, but always trying to keep in mind that these are guidelines we’re giving patients or advice to try and maintain function and vitality throughout the lifespan. I think it’s incredibly important tocome back to some of those ideas that we have held as truth.

I know that was a major part of some of the work I was involved with several years agowhere we were looking at how muscle stem cells themselves, helpgovern this intrinsic plasticity you speak about in muscle. I feel that’s one of the things that keeps me coming back to the tissue.It adapts so robustly when you expose it to stimuli, you begin lifting weights, muscle can hypertrophy, you’re faced with casting or bed rest, muscle atrophies. Understanding the cues thatgovern that adaptability are critical to devise more efficacious therapies. Part of what we sought to do in those prior studies was to determine the necessity of activating your local muscle stem cells tosupport what we would call hypertrophic remodeling, the building of muscle, andhow critical those cells are in governing those processes.

Dr. Gabrielle Lyon[0:13:06]

That is very eloquently put. I’d love for you to explain to the listener the concept of muscle plasticityand the importance of understanding muscle adaptations, recovery—I understand this is a very loaded question—within the scenarios of muscle wasting or injury, and I think, even potentially, before you do that, maybe explain to us what a satellite cell is, what a muscle stem cell is, because I have actually, frankly, questions of my own. One question is, are we born with the amount of satellite cells that we are destined to have? Is there a transcription limitation from– you’ve done research on this regulation of Pax, so I would love to hear your perspective.

Dr. Christopher Fry[0:13:59]

Definitely, happy to share and discuss.I believeyou’re the same from listening to prior podcasts, this concept of plasticity refers to how adaptable muscle is. It responds very well upon the initiation of physical activity or exercise. However, if we’re faced with an illness or periods of disuse, we’re just as likely to exhibitthose negative consequences within muscle whereby we are weak, we’re losing muscle mass. These arethe hallmarkconsequences we seek to avoid.How muscle responds to those stimuli is of critical importance so that we can try and mitigate those periods of weakness or atrophy. A lot of our prior work has focused on what Ibroadly termed muscle stem cells. There are probably a variety of stem cells or cell types that could fit under that umbrella. I use it most commonly to refer to what is termed as satellite cell that you described before.

Satellite cell was discovered some 60-odd years ago based on its anatomic location. If you think of a muscle fiber asa polygon shape, the cells were found to reside on the periphery ina satellite position. Thisled to its name and even six decades ago was hypothesized that those cells served as a critical source to support muscle regeneration following damage. We’ve continued to support those initial observations from scientists so many years ago, but satellite cells are the intrinsic stem cell within muscle. If you sustain an acute injury, the recovery process, that regeneration process is entirely dependent on satellite cells. They undergo a very well described activation. They increase the number dramatically, and they can directly fuse with damaged fibers torepair that process. Satellite cell activity has been best defined in context of damage-associated recovery.

But I feel many of those principles can be applied to how we interpret adaptation to exercise. Especially in the early periods of exercise progression, you can sustain a little bit of micro tears, micro damage to those muscles, as they’re exposed to something wholly new. We often perceive that as delayed onset muscle soreness or these kinds of feelings of aches and pains after a particularly heavy or new day in the gym. Satellite cells can therefore play a very similar role tofacilitate the remodeling, therecovery of those muscle fibers we damaged the day prior, the purpose being is we can build back the fibers better. The body is better able toface that same challenge again.It makes it being a little bit more robust to protect against subsequent injury from that particular stimulus.

Dr. Gabrielle Lyon[0:17:18]

I’m curious, are we born with a certain amount of satellite cells that some individuals are born with more,some individuals are born with less? Would that make an individual born with moremorecapable of recovery, regenerationperhaps for performance, protection against illness?

Dr. Christopher Fry[0:17:40]

Excellent question.The assessment of our satellite cell density is often based on direct tissue sampling, i.e., a muscle biopsy. It is a fairly invasive procedure. For that reason, there are rather limited assessments, at least from a pediatric or early adulthood standpoint, just the challenges faced with working with younger adults or children, it’s tough to know the exact amount of heterogeneity that exists within our population as far as stem cell abundance, satellite cell abundance. Butwe are born with a number of satellite cells. Again, that’s one of the challenges of working with a relatively long-lived organism like humans that we’re limited at times tosequential cross-sectional studies to look at how abundance shifts across the lifespan. In rare instances are we able to track the same person across their lifespan, but we can glean information by studying subsets of individuals ranging in age from early 20sthrough their late 80s. A number of studies have shown in the sorts of patient-derived outcomes that there is a loss of satellite cells as we age. This is thought to reduce thatintrinsic plasticity present in our muscles whereby we’re less able to respond to an injury or reap the benefits of exercise. To your point, it is an active area of research to try and harness that satellite cell or stem cell ability in an effort to bolster muscle’s ability to respond during periods of disuse, illness, or just during the aging process itself.

Dr. Gabrielle Lyon[0:19:30]

Do we know if it’s the aging process, or is it the inactivity that is often associated with aging?

Dr. Christopher Fry[0:19:37]

Yeah, you hit the nail on the head. It is very difficult, I feel, toparse those two separately giventhe adoption of a more sedentary lifestyle that tends to accompany aging across societies, cultures, and continents.I personally would like to think that aging per se has some effect there, but I likely and largely believe that it’s this loss of physical activity, this engagement and exercise that really exacerbates and accelerates the decline in satellite cell abundance.That’smy opinion, but I feel it’s one of those things, you definitely want to move it or lose it, so to speak.

Dr. Gabrielle Lyon[0:20:20]

In terms of nutrition for satellite cells, there’s a very clear indication of macronutrients that would feed skeletal muscle. We know that they have an amino acid trigger. We know their metabolic activity, and you do speak about the oxidative capacity of various fiber types, which we will discuss.Satellite cells seem incredibly unique to skeletal muscle. I’m curious as if we know what helps perpetuate,aside frommovement, but what helps feed the cells,or is there anything that we could do as people to ensure the health of the satellite cells?

Dr. Christopher Fry[0:21:03]

It’s an excellent question.Again, we’re somewhat limited because we are, as you very nicely pointed out, we’re chasing a pretty limited stem cell population in our muscle. You can assume satellite cells account for maybe 2% to 4% of all cells within our muscles. They’re by far and away a very limited subset of what we’re able to conceptualize when we think about muscle. Utilizing what we’ve learned from very basic studieswhereby you take the cells, expand them in a petri dish, there have been shown that a number of cocktails enhance their growth rates or doublingin those petri dishes, a number of essential amino acid derivatives, leucine, HMB, these things have been shown, at least in those cell culture-based models to be efficacious toenhance the growth rates of these cells.

If you think of a person at rest, satellite cells are incredibly quiescent. Their main goal at that point is tojust chill out and wait till the challenge comes. Now you go into the gym, have a really hard workout. Your body initiates a lot of reparative processes, some of which are occurring in time with satellite cell activation, maintaining just a diet enriched in protein,the samedietary guidelines one would give any individual ascribing to a new physical fitness regimen would be helpful tosupport their growth. As long as you’re not in severe caloric deficits, you’re able to then harness their true potential. But given their relative rarity, they don’t have large nutrient demands, like you think of your muscle accommodating 40% to 50% of your body size has a much greater pull on the calories we bring in following an exercise bout.

Dr. Gabrielle Lyon[0:23:06]

Thatcertainly makes sense. I don’t know if this has been studied in humans, but what about medications or other things that we could potentially be putting in our body that would be toxic to a satellite cell, and then thus not allow recovery of skeletal muscle?

Dr. Christopher Fry[0:23:27]

It’s a good question.I’m definitely not a medical provider, so I try and make sure I’m not doling out advice that’s outside of my scope, so to speak. But especially as we look towardstrying to enhance adaptation with aging, as we get older, there just tend to be more medications that we are on. It is difficult to parse out how individual medications might influence the activity of satellite cells. I don’t want to demonize any particular class of medications. It’s hard to study them in isolation, to speak to anyspecific notion that one per se is having a more detrimental effect than another.Apologies, it can be a little challenging. We have limited insight right now. These satellite cells, as important as I may feel they are, they’re not driving medical decisions, so we’re often not able to engage in thecontrolled randomized trials we would need to truly understand the effect of drug X or Y on how these cells function in our body. That’s what it would take, and they’re just unfortunately not driving the boat when some of those decisions are made from a medical perspective.

Dr. Gabrielle Lyon[0:24:48]

Not yet, anyway. Not yet, my friend.But we’re changing that because more and more individuals are recognizing that the survivability of an individual is largely dependent on their skeletal muscle.Regardless of the insult, regardless of the disease process, having healthy skeletal muscle will put an individual in a favorable position. Why would you say that satellite cells are so important from a recovery from injury and hypertrophy? To separate,and if I were to say injury, let’s say, disuse oron the other end of the spectrum from hypertrophy?

Dr. Christopher Fry[0:25:35]

That’s a fantastic question. I couldn’t agree more with your point. Our motto here is that muscle powers health and should be at the forefront of all of these discussions. But to your question, we look back to some of those preclinical studies, and the power of genetic research allows us to manipulate how certain cells function in different organisms.In one of those particular studies, we’re able to genetically delete satellite cells from the muscles of adult mice.When those animals are challenged with a direct muscle injury, in the absence of satellite cells, the muscle does not regenerate or regrow at all andbecomes afibrotic scarlosing all functionality. In animals with a full complement of those stem cells, you’re able to achieve meaningful regeneration.Again, speaking to the ability of the muscle, it can recover wholly denovo in three to four weeks in these animals,a truly wild sight to see. But that is a very supra physiologic injury model.We’re not tasked with being bitten by snakes with venom across our limbs.

Dr. Gabrielle Lyon[0:26:53]

I don’t know. I live in Texas.

Dr. Christopher Fry[0:26:55]

I hope that’s not the case. Butwe’re tasked with recovery after exercise, which still does inducea fair degree of micro damage to the muscle necessitating the activity of satellite cells. As the fibers seek to respond to those individual bouts of exercise, your satellite cells activate. They receive signals from those damaged fibers that cause them to increase in number.Theyexit that quiescent, dormant phase, and they dramatically expand in number. They’ll undergo a very clear proliferative phase whereby they increase several magnitudes of order. Then some of those cells further undergo a process termed differentiation whereby theycommit to a muscle fiber lineage, and they can either fuse with damaged fibers torepair those micro tears, if you will. Or if the damage is severe enough, individual satellite cells can link up, fuse together to form completely new or de novo muscle fibers if the damage is severe enough to warrant thatreparative process.

Dr. abrielle Lyon[0:28:09]

That is so fascinating.When you talk about the differentiation of skeletal muscle fibers, once that satellite cell fuses, so if it’s a type I or type II fiber, and that fiber goes through a transition, if in fact it does through aging, etc., or through change in training, does that affect the effectiveness of the satellite cell? Does it have any implication on the satellite cell?

Dr. Christopher Fry[0:28:41]

It’s a fantastic question.We’re very much just beginning toparse out any fibertype specificity that may underlie satellite cell activity patterns. Again, lookingin a very cross-sectional manner across participant biopsies, we see that there tend to be more satellite cells associated with your slower, more oxidative type I fibers than thosepowerful, fast-twitch type II fibers. Does this inherently mean that type I fibers have a greaterregenerative capacity. I think a question we have right now in trying to parse out experimentally how to test those paradigms iswhere the research field is. How can you more strategically target one fiber type or the other to test those theories? At this point, I don’t think we have sufficient evidence to say that there are very clear differences between fiber type, but that may be a very oversimplification just given the knowledge we have at this time.

Dr. Gabrielle Lyon[0:29:53]

It seems somewhat counterintuitive. One would think that the type II fibers that are undergoing power or hypertrophy would be shown to have more damage over time from the goal of the training, that they would have more satellite cells. It just makes me think, do they have other ways of regenerating? Which leads me to another question, do we know what would potentially augment the effectiveness of a satellite cell post training?For example, if an individual were to do some type of aerobic or endurance exercise, and we know that this has now stimulated these satellite cells, these satellite cells have fused, they’ve become very active, and they’re doing what satellite cells do, would it be safe to say that a period of muscular rest would be important to amplify the effectiveness of the satellite cell? Or is that totally in my field?

Dr. Christopher Fry[0:30:58]

No, these are exceptionally deep questions and things I think about on a daily basis.

Dr. Gabrielle Lyon[0:31:05]

So you’re saying we could be friends?

Dr. Christopher Fry  [0:31:07]

I think so. It’s one of these interesting concepts. I think for a younger adult, it is very difficult to overtrain.We have a very robust system to accommodate thedemands exercise exerts on the body. As we age, some of those processes may not be as robust as they were. There’s been a few recent studies that has looked tomodify exercise programming in older adults; one group of adults might engage in a relatively high-volume exercise training session. Their next bout might be relatively lower intensity, and then they have another high-intensity day. This would be compared to adults who had three high-intensity days back-to-back-to-back.Results of those types of studies where you’remodifying the intensity of your programming have shown thata moderate approach,a high-low-high day reallyfacilitated the recovery process in older adults. These were adults, I think, 65 and older in the study, in particular. I think we need to do a good job of listening to our own bodies and trying to avoid a onesize fits all. But definitely, when undertaking a new exercise program, just being mindful of your body’s cues andresponding in kind, but letting some of the literature and prior findings guide some of the decisions we may seek to make.

Dr. Gabrielle Lyon[0:32:44]

That makes just absolute perfect sense. For the listener, muscle biopsies, I’m assuming you did the vastus lateralis, is a very uncomfortable experience, I would say both for the participant and the individual doing the biopsy—I have done many—but it is only one small location. Again, vastus lateralis,we have many other muscles that are not easy to test. It would be very painful and difficult to do a tricep biopsy or a bicep biopsy, etc. This question might not have an answer, but I am extremely curiousas if there is a unified response to training. Obviously, it depends on training status, but overall, do individuals of similar cohorts respond the same?A fit 20-year-old may see a certain percentage of satellite cell activity versus a 50-year-old postmenopausal woman who is doing some type of endurance activity, we expect a satellite cell response to be as such.

Dr. Christopher Fry[0:34:05]

It’s an excellent questionI look forward to discussing. I will say I’ve had quite a few biopsies, both on the receiving end and collecting the tissue myself.

Dr. Gabrielle Lyon  [0:34:15]

You look like Swiss cheese.

Dr. Christopher Fry  [0:34:17]

You should be under relatively littlesharpphysical discomfort ifa local anesthetic is applied nicely. You don’t want todissuade any future research participants; we are dependent on the tissue samples from our subjects. But to your point, I think that’s a concept that has really come about, and I’d say the last 10 to 15 years, this appreciation on a verybasic molecular level, the heterogeneity, thatsort of response variantswe tend to see an exercise.Many studies or investigators have been able toretrospectively look back.In essence,every one might respond to some degree to a new exercise program. Everybody gets a little bit stronger, accrues a little bit of muscle mass, but there is a lot of variance between participants in the studies.

Understanding the source of that heterogeneity or variance is an active area of research. If we can do a better job prescribing exercise selection to benefit individual people, hopefully we could reduce some of that heterogeneity. But assuming a one size fits all training paradigm is often going to be wrought with a great spread in outcomes. Some will adapt, beautifully gain a lot of strength and muscle. Others might see very minimal adaptation and be frustrated and perhaps turned off by exercise. That’s the exact wrongtake-home message we want. What can we do as scientists to better understand that source of variance so that we can better prescribe exercise programming, so everyone hopefully can reap the benefit to a more similar degree?

Dr. Gabrielle Lyon[0:36:10]

That heterogeneity of exerciseand that exercise response is really of interest, especially in the medical community, and this idea of a quote, non-responder.This is a question I’m going to ask your opinion on. Do you believe that the non-responsiveness could be or if in such, you do believe that some people respond better, and some people will respond differently? Do you think that it has to do with potentially the influence of Pax-7 on gene transcription that may be that could be one area of focus?If you just want to explain briefly what that is and that influence in that target gene.

Dr. Christopher Fry[0:36:56]

Definitely, happy to discuss.Pax-7 is what we would term a transcriptional factor. It, in essence, turns on other genes. But for our purposes today, it serves as a fairly unique marker for satellite cells. It’s often how we are able to identify them in patient biopsies or in more basic studies, manipulate the expression of genes within satellite cells. It confers a great deal of specificity to those musclestem cells to satellite cells. There were a number of fantastic studies that looked at, especially inolder adults, their ability to what we would term accruemyonuclei. These are myonuclei derived from satellite cells. Older participants engaging in exercise continuing to increase the loads, they’re lifting, you’re activating satellite cells. Some of those satellite cells fuse into muscle fibers. When they do, they add nuclei to the existing fibers. The results of some of that research suggested that the individuals who are able to more efficiently accrue myonucleithrough satellite cell additionexperienced the more robust adaptation to that exercise program, lending at least some evidence to this notion that your ability to activate and mobilizeyour satellite cells could help dictate how robustly you’re able to respond to the various exercise stimulus?

Dr. Gabrielle Lyon[0:38:32]

Would you say that that’s a more of a hypertrophy with the increase in myonucleiversus an endurance-type activity?

Dr. Christopher Fry[0:38:40]

That’s exactly right. I agree completely with that.At least inmy realm, and I feel with most others, when you’re looking to engage in resistance training, you’re hopefully seeking to build muscle or hypertrophy the fibers you have. That growth of fibers is often accompanied by the sequential addition of myonuclei.Muscle is a unique cell type; you can see in the images behind me. There are a number of nuclei along the length of an individual cell or fiber, and I often think of them as different governing ordinances along the length of the fiber. You drive so far in the state of Texas, you come to another city, and then a city after that or a town after that. As the fiber increases, if a state were to increase, you would increase the number of local governments tooversee the running of that cell or that state. That’sthe analogy here is that as our fibers grow, we’re seeking to add nuclei via satellite cell fusion tomaintain the regulation of that muscle fiber, if you will. It’s more so a goal of what we tend to see with resistance training or more hypertrophic stimuli versus endurance-related activities, but there are a number of studies that have shown inexercise-naive participants, upon beginning to engage in more aerobic training, still do undergo some degree of satellite cell activation and fusion tofacilitate that early exercise adaptationeven when it’s of a more aerobic type.

Dr. Gabrielle Lyon[0:40:21]

That’s really important to point out because, again, this is science being translated to action for the every day. Is it safe to draw the conclusion that the healthier satellite cells you have, the more capacity, of course with the appropriate stimulus, the more hypertrophy one would be able to maintain?

Dr. Christopher Fry[0:40:45]

I do think there are a number of results from studies tosupport that notion.I think, again, the hope is to maintain as many healthysatellite cells as you can,so that way your body is in the best possible position to respond to anychallenge or stimulusyou throw at it, be it an unexpected injury or a more planned engaging in exercise or physical activity. I think those arecritical adaptations we’re seeking to enhance by maintaining a viable pool of satellite cells.

Dr. Gabrielle Lyon[0:41:21]

How would that relate to muscle memory?

Dr. Christopher Fry[0:41:25]

It’s been at the forefront ofexercise adaptation and understanding how muscle adapts for a while, and we’re just now beginning to parse out our understanding of the basis of this muscle memory. There are a number of theories as to what serves as the basis of that. But there are researchers that have shown that one’s ability to add nuclei through exercise training or other methods, and then engaging in a period of not exercise, sotaking more of a couch potato view on life, and thenre-engaging with exercise, they were able to rebuild that muscle faster. It was postulated that by adding those nucleiin a pre-existing exercise period, you are better able to harness muscle growth potential during that subsequentreentry into exercise training.

There are other groups, too that feel there is an epigenetic memoryof exercise.Epigenetics, without diving too much into it, is how we’re able to access various genes within our DNA, how accessible the expression of various genes can be, and how exercise might permanently open up the expression of certain genes. That becomesa means by which to continue to support that muscle fiber.Even when exercise stopsand then is restarted, hopefullythen you’re better able to increase back again the expression of those genes by having thatimprintingwithin the DNA of our muscle fibers.

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Dr. Gabrielle Lyon[0:43:18]

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Yeah, it’s fascinating. The message to me would be start training younger and start training often.When an individual goes through this period of disuse, do the myonuclei stay? Obviously you said that the satellite cells become quiescent, which means essentially, in my understanding, sleeping, not doing much, waiting, hanging around waiting, freeloading off your muscle. What about the myonuclei? Do they stay? Do they revert back to the original tissue? How does that work?

Dr. Christopher Fry[0:46:48]

Man, these are the most pointed questions I could have expected. I love the discussion. I feel that’s one of the biggest debates. I was part of a recent point counterpoint where we had two groups of scientists that were basically arguing either in favor of a loss of myonucleiduring a period of disuseversus those that argue the opposite, that there is amaintenance of myonuclear abundance during periods of unloading or disuse. I wish we had a very definitive answer as to the true nature, but I do think that there is good evidence to show that in certain situations, myonuclear number can become compromised. As such, perhaps what the actual consequence of that is, does it lead the muscle to be more susceptible to an exacerbated atrophy response, or does it require them a greater stimulus torecover? How does age, per se, affect these processes?Unfortunately, we have more questions than answers at this point. But I think there’s evidence to show that this concept of the permanenceof a myonucleus during periods of disuse is an incredibly important concept that we’re all very actively trying to understand and define within the field. I knowour lab has a great interest in it, and there are dozens pursuing similar lines of inquiry.

Dr. Gabrielle Lyon[0:48:25]

It’s very exciting to see what is going to come from that. I’d love for you to mention some of the myocellular changes that are characteristic of aging, and we’ll say aging because we don’t have a better term. I have three in mind.

Dr. Christopher Fry[0:48:45]

I’d be interested to your three. One of the bigger things that tends to jump out when we’re looking both on a very specific biopsy basisor looking at more broad imaging of the musculature are deficits inwhat I term muscle quality. This is perhaps an infiltration of fatty tissue in the muscle or fibrotic tissue. I unfortunately go back to a lot of food analogies with students in the lab, but if I’m out shopping for steaks, I tend to favor a ribeye, something with a fattier profile. It tastes better.It’s a richer cut of meat, but I argue for the opposite for how I want my own muscles to look as I get older. I’d much rather bea leaner sirloin. Again, not being able to attribute it directly per se to aging but this concept of how our muscles lose more of the muscle-ness, if you will, and perhaps have a little bit of replacement by fat or other tissues, they have less of an ability to produce force per unit muscle size at that point. Deficits in stem cells are another one, and I think we see two of the biggest ones are shifts in fiber type as well as just age-related muscle atrophy. We can discuss any of those, but I’d love to hear your top three.

Dr. Gabrielle Lyon[0:50:10]

Those were my top. I have one more that I’ll throw in the loop here, and that is potentially the decrease in capillary density and perfusion we see all over, just in general, in agingand the potential distance between the satellite cells

Dr. Christopher Fry[0:50:31]

I couldn’t agree more; one of the concepts near and dear to my heart. I wasn’t sure if that was perhaps too into the weeds, so I left it off my list. But that was a big research interest of ours is this concept that you speak to. We deliver nutrients, oxygen and remove waste from our muscles via our capillary bed, thatterminal site whereby arteries and veins meet, and the magic happens, if you will.Seeing less capillary density or a reduced perfusion ability of the muscle, that ability to deliver nutrients or oxygen to the muscle, definitely can compromise its adaptation. These were studies that we undertook when we looked in older adultsand westratified them via a biopsy into how many capillaries they had in their muscle.

All adults then underwent a progressive exercise training program, and then follow-up measures were taken. The individuals that had the most dense capillaries, the greatest number of those micro vessels in their leg muscles, underwent the most robust changes following exercise. They were better able to harness the ability of that exercise to build both muscle and strength. We argued at least that it was the ability to deliver nutrients, remove waste from that exercising muscle thatgave them a leg up, whereas individuals with fewer capillaries were at a relative disadvantage. They had toreestablish that functional capillary bed to then begin the more positive adaptation to exercise. I definitely agree with you wholeheartedly that maintaining adequate perfusion of our muscle as we age is a critical factor that could determine how well we respond to exercise.

Dr. Gabrielle Lyon[0:52:31]

Are there strategies to increase capillary density? Would that be something equivalent to blood flow restriction? What are what are strategies that potentially we could begin to think about incorporating?

Dr. Christopher Fry[0:52:46]

It’s a fantastic question. I feel there are a number of approaches you could take. It’s something that I might lecture in class and trying to provide practical advice. But if I were a relatively sedentary adult looking to engage in some resistance training, I feel a period ofan aerobic preconditioning—this may be walking outside, some stationary bike riding,jump starting, hopefully, that process to build back or restore some of that capillary density, and then moving intoyour progressive exercise resistance training, you may better then reap the yearly benefit.

Another way is exactly as you said, this concept of blood flow-restricted training. This is one of those exercise paradigmsthat itlooks funny if you see people doing it, but they’ll wear what amounts to a blood pressure cuffvery proximately or high up on a leg or an arm. The cuff is inflated to a degree whereby you are restricting arterial flow into the working muscles, but then completely obstructing venous return. This createsa pooling effect in the muscle; you feel like your muscles are very full. You’re, I don’t want to say, like causing a true ischemic event, but you’re limiting local oxygen delivery for a couple of minutes. This triggers the muscle to think that it needs more capillaries. So then it begins stimulating these processes to expand and grow the capillary bed because it senses there’s less oxygen due to that cuff being inflated during these acute bouts of exercise.

Perhaps the incorporation of a training program that included some blood flow restricted might be another way to help with that.It’s one of those exercise programs, I think, that needs to be taken a little bit with cautionif there’s any underlying vascular issues or anything like that, but definitely, you can consider it a tool in your toolbox that may be something to help jumpstart that exercise response.

Dr. Gabrielle Lyon[0:55:01]

That’s really good advice.For the listener out there, blood flow restriction is incredibly uncomfortable, shouldn’t go and get bands and do it by yourself. It should be something that is done with a highly trained professional, certainly, at least at first. As Dr. Fry was mentioning, anykind of pre-conditions like hypertension or other things within that category, it should be used in caution. That being said, there is evidence to support.It is very good for exactly what Dr. Fry is discussing, as well as injury. It makes me think, well, maybe one of the benefits of blood flow restriction is in fact due to that increase in capillaries. What timeframe would we see an increase in capillary density in humans? Is this a slow thing? Or is this something that would take six months to a year?Do we know

Dr. Christopher Fry[0:56:03]

It’s not as rapid assome of the more responsive processes to exercise. We think of completion of an acute bout, your muscle will start to build proteins within minutes after exercise cessation.The ability toexpand that capillary bed, as you say, takes a little bit longer. We’re limited, again, by the assessment of tissue samples from patients that are fairly invasive. But a number of studies have tried to add some clarity to that and have shown that at least in younger adults, your ability toexpand your capillary bed actually precedes or falls right in line with the ability of your muscle fibers to grow or hypertrophy. We’re talking, I’d say with a regimented exercise program, you can start to see changes maybe within a few weeks to definitely a month. It’s one of those things that again, like many things muscle related, is fairly plastic, which is good for us.

Dr. Gabrielle Lyon[0:57:02]

Yeah, it is interesting to think about how quickly skeletal muscle changes from a mass perspective as a result of that incorporation of amino acids as opposed to, for example, thyroid tissue or cardiovascular tissue. The turnover and the influence that we directly have is quite unusual. Basically, if we could take it a step further to a practical level, which is exactly the road that we’re going on, it sounds as if you believe, and the literature would support, somewhat of a preconditioning program, not just for capillary density, but there’s also potential for a preconditioning program prior to resistance training and increasing the outcome of that training goal. Could we agree that the goal of resistance training, would we say that it is strength or hypertrophy? We should probably define that. I don’t know if it changes, the preconditioning program.

Dr. Christopher Fry[0:58:08]

I think whether you’re chasing strength or hypertrophy, many of those changes should hopefully occur hand in hand.What comes to mind is recent work out of McMaster University whereby theyrandomized adults to that exact program, or actually they randomized their respective limbs. One limb underwent a—I know it sounds funny—unilateral cycling program,this pre-exposure to aerobic exercise, and then both limbs engaged in the same progressive resistance exercise program. The limb that had the early exposure to that unilateral cycling exhibited better adaptation. It accrued more muscle, had greater expansion and satellite cells, and I believe ended up producing greater strength improvements as well. These were younger adults, very healthy, not actively engaged in exercise, but I do feel there is mounting evidence to support that concept.

Dr. Gabrielle Lyon[0:59:13]

I wonder what that would look like for a trained individual. Again, obviously, training status matters. Age matters. Do you think that it could be a 10-minute warm up at a comfortable pace, just a zone 2 chatting pace, to really get the blood flow increasing?

Dr. Christopher Fry[0:59:36]

I definitely agree.I think somethingvery accessiblemakes a lot of sense and would be much easier to engage with. It can be very daunting to begin exercising. I think something of that nature is a nice introduction.It’s fun; you could bestill conversing with friends that you’re engaging in this new exercise program with. I think that’s very applicable but then would hopefully reap benefits, too, as you move into more resistance type exercise modality.Per your point is, as someone who’s actively engaged in exercise, I guess they’d want to consider what their goal is.If they are actively exercising, I assume they have sport or performance-related goals, or they’re training for particular types of competitions.Maybe they’re chasing a 5k PR or a marathon or engaged in the local CrossFit community, so trying to understand what their current training program looks like and how to help them better reach whatever performance goal they may have. If it’s more general health and wellness, there’s obviously greater flexibility there to try and achieve those results versus chasing a specific goal or target.

Dr. Gabrielle Lyon[1:00:53]

That’s a really good point. Do we have a timeframe where there could potentially be diminishing returns?For example, if someone is doing 30 minutes of cardiovascular activity in this goal of preconditioning prior to a resistance training program, that may be a little bit too much versus stopping at a 15-minute mark, 50% of that would be ideal.Do we have any sense of timeframes?

Dr. Christopher Fry [1:01:21]

This concept of concurrent training whereby you’re seeking to harness both aerobic and resistance components to hopefully reap maximal benefit is obviously ideal. We all want to have the cardiovascular benefits of aerobic training, but hopefully build muscle and strength through resistive training as well. It’s difficult. I guess, at the end of the day, we all have to choose a path where we’re more focused on achieving benefit. To me, at least, if I’m looking to maximize my ability to build muscle and strength, I would be more concerned with a more taxing aerobic bout of exercise preceding that resistance training. As you move into that30-minute window—again, speaking just anecdotallyfor myself—I no longer have the requisite energy to lift as much weight as I feel I should to try and build strength and muscle. Personally speaking, I may keep it at more of a 15 to 20-minute aerobic window at the beginning of a workout. But again, I think a lot ofconsideration to individual goals and thenyour own perceived enjoyment, if you favor one or the other, should help.Exercise should be fun at the end of the day.Wanting people to enjoy what they’re doing is important.

Dr. Gabrielle Lyon [1:02:47]

I would joke and say if you guys are liking it, you’re probably not working hard enough.

Dr. Christopher Fry  [1:02:53]

I suppose that is one approach.

Dr. Gabrielle Lyon[1:02:53]

But we want to be fit.Every morning, I say to myself and my trainer, Carlos, this was the worst idea I’ve had all day. Now you’ve done actually some very interesting research on specifically ACL injury. This is something called a growth differentiation factor-8.Can you describe a little bit about what you were seeking to investigate and what your research showed?

Dr. Christopher Fry [1:03:18]

I’m happy to. Exercise has been an overarching passion of mine since as far as I can remember.One of the concepts we explore in the lab is exercise can take many different shapes. We often seek to implyexercise principles and the recovery from injury.Think of rehabilitation as exercise.You’re lifting weights. You’re training. You’re seeking to get back to where you were, but it’s employing much of the same programming and concepts that exercise physiology leans on. Much of our lab’s research portfolio seeks to enhance recovery after a pretty common knee injury or an ACL tear, as you say, Dr.Lyon. It’s sustained at a relatively high rate in a lot of sports-specific activities. The recovery process can be daunting. It’s often a lot of younger athletes who really want to get back to their prior level of activity, reengaging with the sport that they were participating in. Our lab is very interested in identifying techniques and treatments tofacilitate that trajectory. Can we accelerate that recovery process?

Work that started in the lab a few years ago, we did some screening of patient samples. We observed that this growth differentiation factor-8, GDF8 or myostatin was an early factor upregulatedin the limb, in the muscle of the ACL-afflicted knee, the knee that sustained the injury. Further work from us continued to follow patients across time and show that those individuals that had the most robust elevation in that growth factor had relatively worse outcomes longer term. They showed greatest atrophy, the greatest weakness, and it extended beyond muscle. They had greater detriments in bone loss surrounding that injured knee. We thought that this may represent something modifiable, something we could target in an effort to enhance recovery.

That’s where my labtakes this concept, what we like to think of reverse translation.We take observations gleaned from patients, from research participants, and then we seek to move back to the bench. We develop models where we can test out therapiesin preclinical studies, try to find out what works in the hope to then translate back out to the bedside to enhance patients. We developed a model of ACL injury in little furry subjects, and then we gave some of them different drugs. Some of those drugs were meant to completely inhibit that growth differentiation factor-8.The animal that was lucky enough to be randomized to those drugs, they showed a much stronger recovery rate, almost complete restoration of muscle size and strength. But more importantly, looking at the overall concept of musculoskeletal health, they saw a far greater preservation of the bone surrounding their kneeand then better integrity of the cartilage in between the joint space there, thatsoft tissue that helps bolster the impact of your limb when you run, when you participate in sports. Looking ahead, it helped both accelerate recovery, but then hopefully also better protect the long-term health of that joint to enable activity, sport participation throughout the lifespan.

Dr. Gabrielle Lyon [1:06:50]

That’s so interesting. Typically, when the body has a response to an injury, it is trying to protect itself. It is trying to do something to facilitate regeneration. Why would the body release growth differentiation factor-8?

Dr. Christopher Fry [1:07:08]

This is a bit of my theories, my pet theories, but I like to think and if I’m imagining a caveman running from a sabertoothed tiger, they sustain an ACL injury, and they’ve managed to crawl off into a cave. Our body has a great healing ability. If given enough time, a partial ACL rupture will heal itself, but you need to protect that joint while it’s healing. My thought is that the joint itself helps promote this GDF-8 release to weaken the surrounding muscle in an effort to not tax the joint while it seeks to build back that injured ligament. With the advent of modern reconstructive surgery, these evolutionary mechanisms no longer serve the purpose they once didand may, as you say, be more of a hindrance in the context of modern medicine. What once may have been a key for our body topromote self-healing in today’sattack mode response to recover, it may justserve as a further barrier limiting that recovery, something that we may be able to knock down effectively torestore and take advantage of modern reconstructive techniques as we have them today.

Dr. Gabrielle Lyon [1:08:36]

Is the growth factor released systemically?Is there a systemic response versus a localized response?

Dr. Christopher Fry [1:08:44]

I believe it is released more locally based from that injured limb. But we’re able to detect upticks in levels found inblood draws taken from the arm. I think you probably see a gradation whereby it’s locally produced, but it ends up systemically within our bodies and so could serve perhaps as a biomarker of sorts to try and better deliver care in patients who might show an elevated response in that particular growth factor.

Dr. Gabrielle Lyon [1:09:13]

Do we know that injury is the only time that it’s released? Are there other injury tissues or other aspects of the human body in which it’s released?

Dr. Christopher Fry [1:09:26]

You’re exactly right.I think during periods of disuse, a number of studies have shown that GDF-8 is elevated. Periods whereby you’re in bed, if you are subjected to a cast after an injury, an acute fracture, I think a number of periods compromising normal health of the muscle will exacerbate the release and production of this growth factor.

Dr. Gabrielle Lyon [1:09:53]

Do you think that there’s any indication or any relevance clinically to routinely test this, perhaps once a year, for an individual? I know that might be outside your comfort zone. I’m just asking for your opinion because it would make sense that if we were to really think about this concept of muscle-centric medicinethat we would begin to look at alternative lab values, that we just begin to enhance and broaden our perspective.

Dr. Christopher Fry [1:10:24]

I love that perspective. I guess I would try and think of it two ways. If it were me who had sustained the injury, I would probably be testing my own values just because I have a problem.

Dr. Gabrielle Lyon [1:10:40]

Hey,everybody, where’d Chris go? Well, he’s in the lab, just taking his own blood.

Dr. Christopher Fry [1:10:46]

I think in terms of routine care, it may not be at that level yet. ButI do hope that with current research findings, what they are, greater credibility is given to that conceptand thisroutine testing to modify care or perhaps just try and have a very musculoskeletal-centric approach, especially with an injury like this that compromises the musculoskeletal system, albeit very localized. But I do think that in certain instances, it could be useful. But I think with within the confines of having sustained an acute injury or period of disuse, I’d be most interested in understanding that about myself.In the day to day, I’mjust writing the status quo, it may not be as useful there. But anyacute perturbation, I would personally be interested in that information.

Dr. Gabrielle Lyon [1:11:48]

I know that the that these were done in mouse models, so the mouse model findings, you administered a GDF-8 antibody, which is interesting, and that really reduced atrophy, weakness, and fibrosis, which, again,it’s something that we do see in an aging population, although certainly takes time. Is there any future use for or do you knowof that GDF-8 antibody use in humans?It seems like that would be really important.

Dr. Christopher Fry [1:12:27]

I agree. I think there has been a lot of interest over the years in translating anti-GDF8 therapies. I think of it like a huge molecular break for muscle growth.It basically is able to shut down our ability to build muscle.Youremove your foot from that brake pedal, and the muscle can grow far more easily. In micewhereby you delete this GDF-8, they look like superheroes. They’re hypermuscular little critters thatclearly show unchecked muscle growth.

I think there’s a number of challenges related to the translation of those therapies. Especially within the context of aging, it’s so difficult to understand when best the initiation of a therapy would need to occur.At least within the context of our study, I have a precipitating event.The injury was sustained, and I have a clear point where I’m trying to enhance care thereafter. Looking across the lifespan, there are risks associated with any medication. At what point would it need to be more clinically viable to start moving into treatment to enhance muscle?There’s a lot of redundancy, I feel, just because anyoff-target effect, if you’re looking at a pharmacotherapy agent that you’re giving perhaps across decades, you get into some murky water, so to speak. But I love this concept, and I do think there’s much more consideration given these daysnot just to promoting lifespan, but healthspan and what it takes to have functionalityinto our later years.There are high-impact research groups looking at differentcocktails that could enhance this concept of healthspan and what that would look like. But one of themore difficult concepts I always try and wrap my head around is when would initiation need to begin with something as chronic as aging, as you so well put it?

Dr. Gabrielle Lyon [1:14:36]

I’m hoping we’re going to get there. For the listener, or the viewer, the paper is GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury.This was in ScienceAdvances. I will link it. It’s a very interesting paper. You’ve published some papers that I think are just so well done. I would say one of my favorites is the Resistance exercise training promotes fiber type-specific myonuclear adaptations in older adults. I don’t know if you remember this paper, but it was a 12-week program, and they did full body resistance training. If you remember it, I’d love for you to just mention a little bit about it. I want to point out for the listener that when a really respected and a real expert in the field like Dr. Fry, not to make you blush or embarrass you, will tell you the limitations of the information, what his opinionversus what the data would support. If you go back and you listen to this episode, you will see that he chose his words very carefully. Not to embarrass you, but well done, sir.

Dr. Christopher Fry  [1:16:01]

I appreciate that.

Dr. Gabrielle Lyon[1:16:02]

Anyway, onto the resistance exercisetraining.

Dr. Christopher Fry [1:16:05]

There was a favorite study of mine. It was back when I was faculty in Texas myself.We were looking to try and understand, I think the word you used previously,myocellular adaptations to exercise and what occurredunique to different fiber types during resistance training in older adults. It did require biopsies from participants who underwent then a 12-week progressive program. We saw some unique differences as it relates to adaptation. Your more glycolytic or powerful fibers don’t have a fair amount of fat within the fiber. But we saw that it was actually reduced with training, so perhaps seeking to improve, per se, the quality to a greater extent in those fibers. We also saw some unique findings as relates to the capillary bed interacting with satellite cells topromote further adaptation in those type II fibers.

It’s tough. One of the things I often try and think about is how more susceptible were those type II fibers to a new stimulus than the type I that may see greater basal activity, walking up and down stairs or to the end of the driveway, that this exercise really represented a more dramatic stimulus to those type II fibers that may not have seen as much activation in the preceding years. But it definitely showed that those type II fibers, both work from our lab and others, have shown that it’s not all doom and gloom, that you maintain a lot of that adaptability as you age. Just by beginning to engage in exercise, you’re able torejuvenate some of these pathways and restore a great deal of adaptation and functionality to your muscle.

I feel like there’s a lot of negativity painted in the adaptation to exercise as we age. But time and time again, there are a number of studies that show lifelong exercisers show just fantastic-looking muscle that’s more akin to a person in their 30s when they’re in their 70s. Just our own work has shown that you definitely have the ability to reap benefit if you go out there and participate. That’s, I guess, the take home I always seek to do is anything is better than nothing. Just getting out and being active is the best advice to give.

Dr. Gabrielle Lyon [1:18:32]

I think that it does highlight that, that it is truly never too late. The average age of the participant was 71. We hear a lot of individuals, a lot of women and men in their 40s and 50ssaying, is it too late for me? Do I have to do hormone replacement? Do I have to do X, Y, and Z? Is this where I’m stuck? The literature would say that is quite frankly not true.

I do have a question regarding that infiltration of fat. There’s the athlete’s paradox whereby we see endurance athletes see an increase in triglycerides within skeletal muscle. The flux is quite frequent, so we don’t see some of the more negative byproducts build up. But for a more sedentary individual, when we see the increase in intramuscular or intramyocellular fat or lipid droplets, how fast do you think it takes to see turnover or remove them?

Dr. Christopher Fry [1:19:34]

I think with regard to the athlete paradox, they’re able to mobilize and utilize those droplets as sources of energy because they’re chock full of little powerhouses within their muscle fibers, the mitochondria.In the context of a more sedentary adult, mitochondrial density tends to be lower, and so they’re less able to utilize those fatty acidstoreswithin the fibers.One of the earlier adaptations to exercise that occurs is this mitochondrial biogenesis. Hopefully, you do begin toincrease the abundance and functioning of those mitochondria toput those fatty acid stores to use. I’d like to think that’s what we saw in the participants in our research study. I do think that is one of the more early swarms of adaptation to exercise that occurs. Butdefinitely, in terms of the fat you see in the muscle of a sedentary person, it’s easy to maybe conflate with that of an elite marathon runner, but they’re definitelytwo different species in terms of their ability to use that fat. Like you say, that flux is very quick in those elite-trained athletes. They’ve trained their bodies to rely on those sourcesbecause they provide such prolonged energy during long runs or lengthy cycling bouts. It’s just it, for sure, a byproduct of theyears they’ve put into their respective sport training.

Dr. Gabrielle Lyon [1:21:07]

When I was doing my geriatric fellowship, we would look at sarcopenic patients.The thought was that, yes, they can always get stronger, and yes, there was always improvement. But once the tissue becomes somewhat infiltrated with fat and fibrosis, that there was no going back. I would say it’s probably on a continuum, just like the liver and other tissues, that as long as you’re not too far gone in one direction, that you probably can begin to deplete some of thoseintramyocellular fat stores and have a positive usage.The length of time, I have no idea. Is it one bout of exercise? Is it two weeks? Certainly we see an influence in insulin sensitivity and glucose utilization quite quickly. But the actual tissue change and utilization, I don’t know. I don’t know if you have an answer to that.

Dr. Christopher Fry [1:22:13]

It’s a fantastic point of debate.That point taken though, that yeah, you’ll see improvements in glucose disposal, insulin utilization with a single bout of exercise. We may not have the sensitive enough tools to where we can speak to those changes on an acute bout basis, but I do think within just a few short weeks, you would be able to observe those changes. They’re definitely, I think, visible from more metabolic-type parameters, like you speak to. Looking at that glucose disposal, the muscle will really start serving as a store for that glucose to be uptakenafter acute bouts of exercise very quickly upon initiation of training. I’d be hard pressed, I’ve seen a lot of human biopsies thus far in my career, and I don’t think I’ve seen one where I’d say, that person’s too far gone, and they’re not going to reap any benefit. I think as different all shapes and sizes that our muscles may come and how they’re affected by our life paths, I think every one of them could definitely experience a significant degree of improvement with exercise. I definitely would caution against anyone thinking that they’re past the point of no return.

Dr. Gabrielle Lyon [1:23:34]

I second that. I think that is so important for the listener to take away.So far, we have covered what you do, your current research. We’ve also talked about this concept of muscle plasticity, which is so important in the adaptation of recovery, muscle-wasting injury, as well as hypertrophy, the critical nature of a satellite cell, which, again, I find incredibly fascinating, especially considering it is so important, and yet it makes up only 2% to 4% of the cells, which is wild. What else that we spoke about that I absolutely love is this idea of preconditioning for the goal of increasing capillary densityand just overall performance and adaptation to exercise. I would love to talk about this, but we’re not going to because I’m going to let you get out of here on time. Eventually, I’ll have you back for around two, most certainly. The point of conversation for that would be really the difference between humans and rodent models because I think that it’s important to highlight.Especially, and maybe even if you have a few minutes, when it comes to muscle physiology, muscle health, it is different.

Dr. Christopher Fry [1:25:06]

Agreed. I can take just a short little approach.

Dr. Gabrielle Lyon [1:25:08]

Wonderful. I’m just trying to honor your time. I know how people are changing the world.

Dr. Christopher Fry [1:25:13]

It’s tough. I feel we occupy a unique niche.We perform clinical research, and we perform preclinical research. There tend to be more scientists on either side that then don’t see the respective contributions of their colleagues. If you’re very mechanisticallyoriented, human research might not seem interesting enough for you, and those that are more clinically oriented think maybe preclinical models have zero translation. I think we use animal models to support our clinical work. They’re serving a purpose to try and understand betterwhat does go on in a personwhen we don’t have the ability to sample every tissue under the sun or any time point we want. We’d have to be considerate of participant burden and getting poked and prodded with needles.

But mice and rats are incredible critters. If I put a wheel in a mouse’s cage, it’ll run 10 to 12 kilometers a nightjust by choice. I don’t know many humans that would do that. Their intrinsic drive to just get out and run vastly supersedes most people, and they are very active creatures by nature. I always task our lab with thinking that we put an animal in a small box, we’re likely forcing it to be more inactive than it would by nature. How does that change your interpretation?

But I do feel that adaptation to exercise, there are a number of conserved pathways that span mouse to human. We can understand a fair deal about how we do recover from exercise from using rodent models.Our lab employs that to a great degree. There’s just frankly a lot of information that can be gained through the power of genetic studies to understand what then specific genes or gene programs might do to govern that exercise response. Having an appreciation for species differences is key, but then understanding the power that the data could provide to help better prescribe exercise or understanding how to improve muscle health across the lifespan, I think there’s lots to be learned from employing preclinical models.

Dr. Gabrielle Lyon [1:27:40]

Yeah, I absolutely agree with you. Do you think that we are going to get to the point where we’ll be able to, very specifically, based potentially on someone’s genes or various other factors that we determine,be able to say, for your muscle health longevity, here are the things that you should be doing? You should be doing a variable high-intensity interval training because your satellite cells are really robust in their recovery and their spacing and their density, versus potentially another individual may be more geared towards some type of endurance. I’m just curious if we’re ever going to get to the point where we can really understand a dose response based on various factors just as we are able to say, you have a blood pressure of 140 over 90, we’re going to trial you on hydrochlorothiazide, or based on your genetic profile, we’ve done DNA genetic snips, we know that this medication for depression is going to work best for you.Do you think we’re going to ever get there?

Dr. Christopher Fry [1:28:58]

I definitely do. I think you can see the signs right now. I mean, many people have a 23andMe report that speaks to their athletesubtype based onalpha-actinin-3 snips and how predictive that is for performance. We’re stillat the at the cusp, so to speak. Butbetween a genetic screening and understanding certain other biomarkers, I’d like to think withinour respective lifespans, we’d be at that point where you could harnessthe multitude of knowledge about one’s own body to then better try and think how to approach sport exercise, what have you, to reap maximal gains or just maybe avoid injury.You could then avoid perhaps falling into overtraining pitfalls or just being more purposeful in thinking about how we go about physical activity. I’m very hopeful that I’ll have that information at my disposal as I continue to get older.

Dr. Gabrielle Lyon [1:29:58]

Well, I’m calling you for that. I am definitely calling you for that. As we wrap up this interview,first of all, it’s such an honor to have you on. I’m a huge fan of your work. I think that you are really making inroads and doing such importantwork and providing clinicians as well as researchers with just valuable information. What is on the horizon for you that you’re excited and can share?

Dr. Christopher Fry [1:30:28]

Thank you, first, for the opportunity.I’ve been a big fan of the show for a long time. Like I said, it’s a daunting list of speakers you’ve had in prior sessions. So I was gulping pretty hard looking forward to today among their ranks, but this has been a fantastic opportunity to chat with you.What we’re doing to look forward, I’d say aging and exercise have been passions of mine since my career began. We have some exciting data I hope will be in a publishable format soon, looking to reallyenhance that growth response and studying a couple of key factors that we stumbled across with some screening. We’re doing a few studies to really try and target them to see how much we can restore that growth response with age to that of a younger animal in this case.It’s some of the work that I’m very excited about. Then two, just in line with our recovery after ACL injury, we’ve got a number of ongoing clinical trials all the way down to preclinical research, always looking to devise new therapies to get athletes back to what they were doing before injury.

Dr. Gabrielle Lyon [1:31:41]

Well, that’s all very exciting. When those papers come out and you are ready to share, I will bring you back on the show to talk about it. If you want to tell people where to find you?

Dr. Christopher Fry [1:31:53]

Please know that we’re on Twitter as a lab at@ChrisFryPhD. I think it’s where we’re most active toshare and disseminate our work to the public, and then happy to take emails, too if anyone has specific questions; christopher.fry@uky.edu.

Dr. Gabrielle Lyon [1:32:10]

That is very generous of you. Dr. Fry, thank you so much. I look forward to our part two.

Dr. Christopher Fry [1:32:17]

Thank you so much, have a great day.

Dr. Gabrielle Lyon [1:32:20]

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