"Muscle Protein Synthesis and Response to Exercise & Nutrition" with Professor Kevin Tipton

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We Do Science Podcast

EPISODE 153

FEB. 04, 2021

"Muscle Protein Synthesis and Exercise & Nutrition"

with Professor Kevin Tipton PhD

[INTRODUCTION]

 [00:00:00] LB: Welcome to episode 153 of The Institute of Performance Nutrition’s We Do Science Podcast. I am Laurent Bannock. Today, I had a great conversation, if I do say so myself, with Professor Kevin Tipton, who you may recall was on a recent episode, only a few episodes back. We had Kevin talking to us about muscle protein balance back in December.

Well, since then, if you've been following our news via social media outputs, etc., you'll have learned that Kevin has joined the IOPN as our Director of Science and Research. You can expect to hear a great deal more of Kevin as our resident expert guest on this podcast. He will be featuring regularly, so I'm very excited about that, along with all the usual external guests that we have.

Also, we will be unleashing a wide range of additional projects at the IOPN, which Kevin will be spearheading, to include research and other outputs and inputs, if you like, to our diploma in performance nutrition, for example, where Kevin will be adding his considerable expertise to our world-renowned program there, as well as a regular journal club and various other things. Can't wait to tell you more about that in the future. 

Let's talk about today's discussion that we had, which was on the topic of muscle protein synthesis. Now, when we're determining nutrition and exercise recommendations, whether it's for optimal health and performance, it's important to understand the response of muscle protein synthesis, particularly as it relates to how we assess the quality and relevance, if you like, of our performance nutrition interventions or recommendations.

Now, despite what we may have thought we knew about muscle protein synthesis, there's actually a great deal of uncertainty still about muscle protein synthesis. This is something that we talk about in today's episode; particularly areas such as muscle protein synthesis, and its response to resistance training, or exercise and nutrition interventions, where we have a particular interest in how that relates to muscle anabolism and physiology.

We try and unravel as much as we can. As you can imagine, it's limited by the amount of time that we've got, and also, my ability to keep up with Kev on what is an immensely complicated topic. I did my best and I hope that you will benefit. We delved into topics that relate to muscle protein synthesis. Quickly delved back into muscle protein balance and areas, such as protein balance, or nitrogen balance, and the relevance that has to muscle protein synthesis and hypertrophy in general, and why there is actually a disconnect in this area, between what we thought we know and what we really need to know and are starting to know. 

Factors like muscle protein synthesis is not just about hypertrophy. It's also about remodeling and repair of this muscle tissue. Kevin takes us through a tour of some important factors, such as why training status matters, the various methods of measurements and why they matter, control of training variables in studies and why that is highly influential to how we should interpret the information that we're getting in the studies and papers and how that would impact our practice. Of course, why physiology matters. There are considerable differences between people, and we even delve into topics like, translational capacity and sarcoplasmic hypertrophy. 

Anyway, you can enjoy that in our discussion in a minute. Let me just quickly plug what we do at the IOPN. As I said, we've got Kevin on board, so we've got all sorts of things that we have been doing and we’ll be doing with regards to research. We look forward to over the coming months and years, really playing a much bigger role in the publications, etc., in this area, particularly, as it relates to sport and exercise, nutrition practice and information that is relevant to that, for you as practitioners and scientists interested in the applied aspects of sport and exercise nutrition. 

That really ties in of course, to what we've already been doing for a while, which is our practice-focused diploma in performance nutrition, which is complimentary to other training programs, degrees and whatnot in sport and exercise nutrition, and/or bridges the gap between sport and exercise science training programs and what is required to be a specialist in sport and exercise nutrition, and to upskill and upgrade the knowledge for those that are the personal trainer and nutrition coach, who really wants to get serious about their knowledge and get into this professional pathway. 

Well, anyway, look, you can learn more about that at our website, at www.theiopn.com, where obviously, you can find the link to this podcast, which will take you to the main website, where you can access the transcripts, the show notes, the various other things that goes with these episodes. 

I've only been getting the transcripts made for the more recent episodes, where you'll see an updated graphic for every episode, is how you can quickly gauge which ones do and don't have all those new upgrades. I am going back in time and cherry-picking a variety of episodes to have them re-edited, refreshed audibly, but also get transcripts. Please do contact us and let us know if there's any past episodes you'd love to see re-edited and get transcripts to and so on. I'll put them on the top of the list for you. If there's any topics, or anything you'd love for us to get into, please also, write to us, email, etc., and let us know.

Anyway, that's enough of that. I hope that you enjoy this conversation I had with Kevin today, as much as I did. You go and enjoy.
 

[INTERVIEW]

[00:06:19] LB: Hi, and welcome back to the Institute of Performance Nutrition’s We Do Science Podcast. I am Laurent Bannock, of course. Today, I'm particularly excited to bring back Professor Kevin Tipton. Now, you might go, “Oh, we just had Kev on this podcast only a couple episodes ago.” That is true. There are a number of differences between then and now; one of which of course, is that was December 2020 and it's a completely new year.

Also, as many of you will no doubt know, if you've been watching our updates and so on on news. Our big news of the year is that we are delighted to welcome Kevin as our Director of Science and Research at the IOPN. Kev, we are now colleagues. Welcome back.

[00:07:04] KT: Very excited about that.

[00:07:06] LB: Yeah. Well, we're upping our game. That's an exciting part of our mission this year. I know that we've got lots of plans. The things that we do at the IOPN are constantly growing and developing. I'm particularly proud of our team in general. Of course, having you onboard, Kev, is just even that more exciting. I'm so grateful to have you here. 

One of the many reasons why we want to have you on the team, is you've amassed over the years, many years of knowledge and research experience. Of course, we're going to want to be tapping into that, as much as we can for our work at the IOPN. Today, we're actually going to talk about something that you came up with as an idea for us to get into today. Kev, I'm going to let you introduce this topic and what it is that we're actually going to get into today. 

[00:07:54] KT: Sure. As many people know, a large focus of my research over the years has been on muscle protein synthesis, and measuring the response of muscle protein synthesis to exercise and nutrition. Over the years, an assumption that is most often made is that measuring that response, if you're measuring the response of protein synthesis between, say two interventions, two supplements, or two types of exercise, or whatever, that when you get the biggest response of muscle protein synthesis, it’s going to lead to the most hypertrophy.

Now, that assumption has been challenged, of course. A paper a few years ago, out of Stu’s Lab, Stu Philips Lab by Cam Mitchell, showed there was a clear disconnect between the response of muscle protein synthesis to exercise and protein feeding, resistance exercise and following that, the hypertrophy that occurred. That sent everybody into a tizzy about, “Oh, then what good is protein synthesis and all this stuff?” 

I think it's worthwhile to explore what is the physiological and practical relevance of the measurement of muscle protein synthesis, and how does it relate or does it relate to hypertrophy? Or if not, and what is it telling us? 

[00:09:03] LB: Yeah. This is, in many levels an important conversation, I feel. Because as the listeners know, I or we are obsessed with this translational component, finding the relevant science, or the quality science and then translating it into information knowledge, the information we discuss in these podcasts, so that people can take that home and literally apply it into practice effectively.

As performance nutritionists, or practitioners in some form or another involved in sport and exercise nutrition, it is important to understand that as a practitioner, it is about being effective. It's not about geeking up on scientific terminology and being able to recite information that one reads in books and papers, because that's all very well and good, but ultimately, we still need to get a successful outcome for our clients, or our athletes. 

That knowledge is only power if it's actually understood and translated and applied effectively, which of course, is the reason for having these types of conversations with people like yourself. Now, in reading up for this podcast, as I do for all my podcasts, it's not like I'm new to this, but it always blows me away when they use phrases in these review papers, and we'll talk about this today, things like, this concept of muscle protein synthesis and muscle hypertrophy is far from being in a position of we know everything. There's so much that we don't know.

Particularly, when we're thinking about all these journals, and all these papers, and maybe podcasts that we might listen to on these topics, a lot of assumptions have been made. Conclusions are arrived at in these various papers. There are opinions that exist out there on how certain nutritional strategies can influence adaptations to training. Ultimately, those strategies are used for athletes, for teams, for recreational sports, to a degree of what is this – it's something that’s done daily. 

We eat many times a day, and these nutritional strategies are used to influence those things. Whereas actually, a lot of these things that we take is given or a fact, are not necessarily as, well, fixed as we might like to think. Kev, I’ve thought a good thing for this discussion would be for us to, well, maybe start off with a few definitions, because not everyone's going to be on the same page, or the same level of understanding as to what some of these terms are going to be. I guess, in this conversation, today, we're going to use a lot of terms. This is one of these areas that could get very technical. There are things, like muscle protein synthesis, there's terms like, hypertrophy, like I've just discussed, and then protein balance and so on, nitrogen balance and such. Maybe you could just quickly define what some of those terms are, so that we understand what you mean by this as we get into this conversation today. 

[00:12:00] KT: Sure. We start with hypertrophy. Basically, what we're talking about is, ultimately, an increase in protein content of the muscle. In particular, the myofibrillar proteins, actin and myosin. The more that content increases, then the bigger the muscle can get. Now, that protein content increases as a result of a positive balance of those particular proteins. By that, I mean, proteins are constantly turning over. You constantly have synthesis of new proteins, and simultaneously, breakdown of proteins. 

Now, those are constant and concomitant. At the same time, and I used to always tell my students, “You don't want to stop breakdown. The only time you don't have any protein breakdown is if you died.” We'll probably get into this a little bit more than we did last time I was talking about the importance of protein breakdown, per se. 

You have a balance between those two rates. If the rate of synthesis is greater than the rate of breakdown over any given period of time, then you're going to get an increase in that protein. In the case of the myofibrillar proteins, that'll result in bigger muscles, ultimately. You have a resistance exercise bout that does increase protein synthesis, but it also increases protein breakdown. They both go up, it's just that synthesis goes up more. 

Now, if you haven't eaten anything, then breakdown is still going to be higher than synthesis and you won't gain any muscle. You need some amino acids there to provide that and to help build muscle. Over the long-term, each time you exercise, and you stimulate synthesis, and then that is further enhanced, because the exercise, per se, allows the muscle to utilize the ingested proteins to a greater extent. Then each time you eat for at least 24 hours after that, you get this enhanced response to the amino acids of muscle protein synthesis. It's greater than breakdown; you have positive balance and you're gaining protein. Then over a period of time, you get enough of that build up that you can measure it. 

Now, as we'll get into, that changes with training status. Those responses change. Now we have positive muscle protein balance. That's when synthesis is greater than breakdown over a given time period. You can think about that time period on minutes to hours. If you want to, you can try to sum those up over days and weeks. 

Now then, so you have protein synthesis, muscle protein synthesis, you have the balance between synthesis and breakdown, and that's either negative or positive, or in balance. That'll determine whether you're gaining or losing muscle proteins. Ultimately, muscle mass if those proteins are the myofibrillar proteins.

[00:14:42] LB: There's a lot of ifs, right? 

[00:14:44] KT: Well, different proteins are responding to those exercise bouts. You're going to have those. Its size comes in if it's the myofibrillar proteins, which it is and resistance exercise. We know that. That's typically what's measured nowadays, is you take a muscle sample, you take a muscle biopsy, and you can use a biochemical process to separate out the different types of proteins. So you can separate out the myofibrillar proteins. We know that those respond to resistance exercise. 

[00:15:10] LB: When we think about, there's a body of knowledge, which is not insignificant at this point in time on this topic. As you cast your mind back, or as we review the studies going back, I mean, how many – this is more than years. This is decades now. How far back does this body of knowledge extend back to your thing, as it relates to what is significant to sport and exercise science? 

[00:15:35] KT: Probably go back to well, Mike Rennie did a study in the late 80s, was one of the first studies. I think it was the first study to measure muscle protein synthesis with exercise. Then there were a couple of studies done in Canada. Chesley was the first author. Those were the first studies with FSR, fractional synthetic rate. We go back to the vocabulary. Again, fractional synthetic rate is a specific method to measure muscle protein synthesis. We probably will have to touch on a little bit differences in the methodology in a few minutes. 

[00:16:05] LB: Definitely. Yeah. 

[00:16:07] KT: Chesley did those studies in the early 90s, 1992-1993, a couple of studies. That was with Mark Tarnopolsky and McDougal. Then, that's about the same time I started in this field in Texas in Bob Wolf's Lab. Then we published a study in ’95, where we did measure FSR, but we also used an arteriovenous balance method to measure muscle protein synthesis. That was the first time that method was used. You can measure breakdown with that method as well. That was the first study that we measured both together with resistance exercise in ’95. Gianni Biolo was the first author of that one.

[00:16:44] LB: The reason why I’m mentioning this, Kev, is because, and I've gotten into this in many – well, not many, but in a been a number of podcasts in the past, where there's an evolution of the body of knowledge. In this case, we're talking about muscle protein synthesis. 

As I mentioned earlier, there's an assumption that we know almost everything there is to know. By we, I mean, more in the basic journalism that exists on this topic. Of course, as I said, as you start reading deeper and deeper into this, you start to realize that this is far being in a place where we can definitively say, we know everything. Of course, we don't. 

On this particular topic, although we're using terms that are familiar throughout that timespan, such as muscle protein synthesis, there have been different ways of measuring responses to training and nutrition and its impact on muscle protein synthesis, which is also influenced the interpretation of that information over time. I mean, maybe we should get into that a bit, because I feel that that does alter this body of knowledge. Although, there is a tendency to just bag it all in. You see people doing reviews with all this information, but they they haven't all used the same techniques. Perhaps, if we do look back at some of that information, we would interpret it differently now, knowing what we know now, back then if that's not too confusing. 

[00:18:08] KT: Basically, we measure muscle protein synthesis and we do that primarily, using stable isotopic tracers, so metabolic tracers. You have an amino acid that's labeled. It's labeled, usually, by having extra neutrons, which makes it heavier. Biochemically, they act exactly the same as the regular amino acid phenylalanine, for example. They're heavier, so we can detect them. We use those in different ways to measure muscle protein synthesis.

As I mentioned before, you can measure muscle protein synthesis on different levels. Ultimately, what we're talking about here is taking – a ribosome will take, will bring in the separate amino acids and make a polypeptide chain. That's what we're talking about as muscle protein synthesis, right? Ultimately, that's what we're measuring. Now we can measure it in, like I said, in a couple of major ways. One is arteriovenous balance and one is what we call the precursor-product method, and that's fractional synthetic rate. 

Now with arteriovenous balance, and early on, we were measuring mixed muscle protein synthesis. We're measuring all of the – We would just take a muscle biopsy and we had representing all the proteins in the muscle. As I said before, nowadays, we can and for the last 15 years or so, people have been taking and they can separate out using a detergent separation method to get the different classes of proteins. 

Then, there have been a handful of studies now that are starting to look at even individual proteins using proteomics, which is exciting. We can get a lot more detailed, more resolution of the information. That's with the FSR.

With the arteriovenous balance methods, you can divide those into two types. One's called a two-pool model, where you just measure the artery, what's in the artery, what's in the vein. Three-pool model is artery, vein and the muscle. The three-pool model gives us a little bit more detail on muscle protein synthesis, or making less assumptions, basically, without going into too much boring detail. 

Like I say, with the arteriovenous balance method, we can also measure protein breakdown. Again, it's all the mixed proteins. As we talked about on the last pod that I was on, you really can't get much more resolution than that, not with any valid methods. You’re stuck with just the mixed, as opposed to with protein synthesis, you can get more. Now, there are some limitations with the methodology, that it's much more difficult to measure feeding-related responses with the arteriovenous balance method. You really need a steady-state. 

If you take in a bolus ingestion then those models fall apart, now people have done it. I'm a little bit dubious about some of those. Because what we did in the early days is we would just infuse the amino acids, so we'd get a steady state of amino acid levels in the blood to represent. The arteriovenous balance methods, as you might guess, you got to have an artery. Back in the 90s and early 2000s, we were able to do that with, usually, a femoral artery stick.

Nowadays, ethics committees aren't really allowing that, except in clinical situations. In healthy volunteers, probably not going to be able to use AV balance that much. We can do the precursor-product method, which is the fractional synthetic rate and the fractional breakdown rate. The precursor-product method is a pretty intuitive method. Basically, you take a muscle sample, well, you started an infusion, or now, you can do it orally with deuterated water. You introduce a labeled amino acid. Usually with an infusion, or it used to be always with an infusion. Then, you take a muscle sample.

Then, the amount of label inside the muscle tissue is low. Then you keep infusing, and then that synthetic rate is going on. Then you take another muscle sample an hour, two hours, six hours, whatever, later, and you measure how much of that label is in that protein in the second sample. The difference between the two represents the rate. The greater the increase in that label in the muscle tissue, the greater the rate of protein synthesis. Then you have to worry about what the precursor levels are and stuff like that. I don't think we need to get into those details. 

Essentially, it's pretty intuitive. The greater the increase in that level inside that muscle tissue, the greater the rate of protein synthesis. Then you compare that between two types of exercise, or two types of proteins, and then you can get a difference. 

[00:22:24] LB: Kevin, even though we're only just starting to delve into this topic already, one gets the impression that this is actually – I mean, it's obviously, for those of you who know, and those that research in this area is obviously, a deeply complex area. We're going to tease out some of these things. Now, but it has been reduced into very simple levels of understanding, where people use terms like, muscle protein synthesis and hypertrophy. Look, it's quite simple. You just resistance training, or resistance exercise and the result is muscles will grow. Is it as simple as that? Or is it more complicated than that? Or is there a lot of ifs and buts to that statement? 

[00:23:06] KT: It's certainly more complicated than that. As I'm sure, everybody will understand, there's a great deal of heterogeneity in the response of muscle hypertrophy. You can get three different guys and you're going to get three different levels of hypertrophy, even though they do exactly the same thing. There are all sorts of reasons for that. You can start with genetics. You can go to feeding. You can go to rest, and all sorts of things. 

That, of course, complicates it. Then the question is, well, why do we even do protein synthesis, when we can just do studies and measure hypertrophy, and then we know what's the best nutrition or whatever to support that? Well, like I say, you get this heterogeneity. You have to have larger sample sizes. You also get that some of that heterogeneity is genetic, and you can't do anything about it. Some of it's because of various variables that you need to control in those studies for a long period of time. How much sleep they're getting? Are they all eating exactly the same thing? Did one of them break up with his girlfriend and go on a binge for a week? 

You can't control free-living individuals who are lifting weights, and so you get a large variability. You spent lots of time. Then how long do you need? Are you going to go for six weeks, eight weeks, 12 weeks, 16 weeks? The longer you go, the less control you have and the trickier it is. It's problematic to do that. That's one of the reasons that we've gone to measuring protein synthesis, because we can get a snapshot of an acute response over several hours. We need to get into that a little bit later. How long and why? You get a snapshot. Then the idea is, is that predictive of that hypertrophic response over a longer period of time? That is the key controversial question. 

[00:24:44] LB: That's exactly why we're having this conversation, because there is that assumption that muscle protein synthesis is going to result in somebody – Yeah. I mean, it's the holy grail. “I'm going to do this and I'm going to be bigger and stronger.” Is that necessarily the case? Of course, it's not as simple, obviously, which we can get into.

[00:25:09] KT: Just to avoid burying the lede, the bottom line is sometimes. If you're careful and you do it under the right circumstances. But not always. I think, to make that assumption is a mistake. It's certainly not predictive on an individual basis. If I were to measure your response of muscle protein synthesis today, I could not predict what would happen. It is on a group basis. There are plenty of studies, where there is a link between the response. Now it's not quantitative. If I get a 50%, larger increase in protein synthesis with this intervention versus that one, you're not going to have one guy looking like the Hulk and the other guy looking a little bit bigger. You're not going to get a 50% difference. That's a function of what that protein synthesis response actually is, which is what we're going to get into. The lede is not buried now. We can then crack on with why it does sometimes, and what else it could mean, kind of thing, which I think is interesting and important. 

[00:26:09] LB: It is. Just before we go down this path, because this would be an eye-opener for quite a few people, I would imagine, is why has muscle protein synthesis being used to predict hypertrophy? What has been the most common ways in which people have predicted hypertrophy and how is that impacted the overwhelming bulk of that knowledge that we see out there and that we adopt as a bible, so to speak? 

[00:26:32] KT: Well, the metabolic mechanism for changes in muscle, as we've said, is muscle protein synthesis. Now, why isn't protein breakdown involved? Well, it is to some extent, but like I said, in response to an exercise bout, you get an increase in both. It's not like, breakdown goes down and you get bigger. Also, as I said, breakdown is more difficult to measure. We know that the majority of the response to interventions is a change in synthesis. It changes much more than breakdown. 

It was used as a proxy. Based on the metabolic mechanism and the assumptions, that's when protein synthesis was first started to be used. Then, we did it and Sri Nair did it, in 97-98, showed some correlations of protein synthesis with muscle mass and muscle strength. That's again, associative data, not cause-and-effect. Again, that's a problem, or it can be a problem. It doesn't have to be. 

This was back in 20 some odd years ago. Seeing an association of protein synthesis response and muscle mass and strength. Then the assumption was always just that, protein synthesis does represent predictive value for muscle hypertrophy. That was pretty well accepted. Although, I got challenged quite often at conferences about that. If you read the papers back from the late 90s and early 2000s, almost all of them are going to say something about how this is the metabolic mechanism for muscle hypertrophy. 

It is. We keep coming back to the question is, does that measurement in protein synthesis really give us predictive value? Not always. That's for many different reasons, both methodological and physiological. 

[00:28:11] LB: Yeah. Also, muscle protein synthesis, isn't just about hypertrophy, is it? There's more going on than that. 

[00:28:17] KT: That's right. That's where the physiological aspects come in. Stu Phillips and the first author was Felipe Dumas, did a really nice study a few years ago, trying to address this a bit. What they did was they measured muscle protein synthesis at three different times in a training cycle. They started with untrained males. Then they measured protein synthesis in the first week, the third week, and I want to say, 10th week. 10th or 12th week. 

What they saw was that when they measured protein synthesis in the first week, that that wasn't associated with the change in muscle mass over that 10-week period. When they measured it in the third week, it was associated with it, and even stronger in the 10th week. Early on in the training cycle, you're seeing this increase in protein synthesis in response to the exercise, but it's not associated with hypertrophy. 

What they also did in that study, which was really nice, was showed, they measured Z-line, or zed line streaming as a measure of muscle damage. Of course, the muscle damage was much greater after the first bout of exercise, than it was after three weeks, and it was after 10 weeks. That muscle damage was much more greatly associated with the protein synthesis in the first week. The notion is that early on in training, a lot of that response of the muscle protein synthesis is more about remodeling and repair of that damage that's occurring, than it is hypertrophy. Later on, once you get past that damaging stage, you start doing – it's more focused on the hypertrophy. 

The other factor that's complicating in there is probably, there's some of that protein sets, especially if we measure mixed muscle protein synthesis. Some of that response is going to be to rearrange, if you will, the types of proteins that are going in there, you're trying to build the capacity to build more muscle. You have to build different proteins as well.

Yeah, it's much more complex than just hypertrophy, but especially early on in training. Later on, in the training, it is more predictive. If you want to do say, look at different nutritional things, then you probably want to do that in trained individuals, more than in untrained. 

[00:30:34] LB: Yeah, because as those various reviews have mentioned, and I know you want to get into training status in a bit more detail, and we will in a second. I think, just to go back to some basics for those that aren't physiologists, or you're describing this process where initially, the resistance exercise, the resistance training actually exerts a level of stress, that as long as you're training halfway decently, will actually result in some degree of damage. Although, that word damage sounds – it's a necessary part of the process. It isn't necessarily a bad thing.

The response to that might well be, or what we now see is that there's a – as you have with damaged tissue, there's going to be – there’s an inflammatory process, potentially an increase in water, and so on, which some people have assumed is just – that there's a hypertrophy process going on here. Of course, there are modifications that occur maybe after four weeks, relative to what happens maybe 18 weeks of consistent training. Yet, and where I'm interested in this is, a lot of these studies have tried to justify a nutritional strategy, a supplement, for example, based on very short timelines for the study, using very basic ways of observing what's actually going on. 

In fact, they might just do it on the basis of body composition assessments, where they're looking at the size of the muscle, or an estimate of the increase in muscle mass. When actually, that's quite misleading, isn't it? Could you just quickly explain what was going on there?

[00:32:11] KT: I didn't really understand exactly what the question was. 

[00:32:14] LB: It was not so much a question. It’s just that there's a process there that you've already gone into. I think for us as practitioners, or sports nutritionist, it’s quite useful to understand that there's a bit of a timeline that's going on here in terms of the response to resistance training and exercise, and what's actually happening to, if you like, the body composition, that we're able to measure on a basic level, i.e. through skinfolds, through bioimpedance, and so on. 

Actually, those changes in the architecture, if you like, to that muscle isn't necessarily hypertrophy. It was assumed to be hypertrophy, maybe in the first very early stages of this process. Does that make any sense? 

[00:32:56] KT: I think so. Partially, what we're getting into a little bit here is methods of measuring hypertrophy. I'm going to keep saying that the American way. What are we really measuring when we're measuring body composition? That depends on the method, of course. Partially, what we're getting into a little bit too is there's this concept that people talk about called sarcoplasmic hypertrophy, which could be fluid infiltration and other things as well, as opposed to protein gains.

Now, on one level, the assumption is that every time you have an exercise bout and a feeding, you get a little bit more protein built there. As I was saying, early on in the process, that's probably not true. Well, maybe a little bit, but not that much. It's not until three or four weeks in that you're really starting to build that protein. 

Now, we know we can measure increases in muscle mass as early as say, two and a half, three weeks into a training program. The trouble is, what is that that you're measuring? Is that actually increased protein? Or is it more other things, like fluid and connective tissue? Which would be protein, but not myofibrillar proteins. That confuses the issue, especially early on in the training. 

That also leads to another reason why there might be a disconnect between your measurements of synthesis, protein synthesis, and hypertrophy is because of the method used to measure hypertrophy. If you do a DEXA and you don't control for fluid status, you're going to get a different reading. Louise Burke did some studies on that. Then Nidia Rodriguez did some in Stirling when I was there, with different fluid status indexes. 

You’ve got to think about, what are you actually measuring and what does that mean? That's more or less, the whole theme of this whole podcast is measuring protein synthesis, but also measuring hypertrophy. Both of those have their assumptions, and you’ve got to be careful about how you're doing that, or how you're thinking about those.

[00:34:57] LB: Of course, that's why when you're reading this research, you must not just read the abstract, or the conclusion of the paper. You want to get in there and say, “Well, how did they even run the study and how did they arrive at those conclusions?” 

[00:35:13] KT: Right. Yeah. I mean, I tell my students, if you're going to read about hypertrophy and they're using DEXA, for example, you want to see, have they actually controlled for fluid status, or other factors? When they've done that DEXA. Are they fasted when they come in for the DEXA? If you want to do it properly, and there's some guidelines, and Louise wrote a set of these guidelines on how to do this. To get the best control of that DEXA, so it is actually measuring, or giving you answers about that you think you're getting, as opposed to not.

Bioimpedance is the same way. That's even more sensitive to fluid status. Skinfolds have all their various and sundry assumptions and issues. In the old days, I don't know how many people do it anymore, but we used underwater weighing. That was always fun, because you had to account for residual lung volume, for example. Using Archimedes principle, which – I guess, people use Bod Pod nowadays still, don't they? That's roughly the same. 

Anyway, you got all these different techniques of measuring hypertrophy, and they all have their assumptions too. This is why if you're not careful, then you can't use FSR to predict hypertrophy. It's possible, just because you've made mistakes with measuring the hypertrophy, that you've introduced this error that makes the FSR hypertrophy not match up. When they might really be telling you something. I think, you've got to keep in mind all these things. I think, discerning listeners, that's what you want to do as a practitioner is you don't want to just accept, like say, that abstract. 

[00:36:50] LB: Yeah. That's why I bang on about context all the time. 

[00:36:54] KT: I used to tell my students that what you want to do with when you're reading a paper, the main question you want to ask, and this goes back to what we were just talking about, is you don't just accept the conclusions that the authors give you. You go and you look, and you read the paper and you evaluate and ask yourself, are the conclusions supported by the results, given the limitations in the methods and the design, and within the context of the literature? I think, when students are first trying to learn how to read papers, that's not what they do. They just accept what the authors say. 

[00:37:29] LB: This is something that we've talked about this, and we will do a podcast for everyone to get into this more. Of course, we're going to be doing a journal club soon for our students at the IOPN on our program, where you're going to really take them through this stuff. Because it's so important to understand, what does this all mean, and the context. It’s not just a buzzword. It is incredibly important to get your head around it. It takes a bit of training to understand this stuff, because of course, some of the readers are going to be going like, “Very well for Professor Kevin Tipton to be saying this, but he knows what he's talking about.”

That's what I meant at the beginning is, at the very least, we're increasing the awareness that not all this information is as strong as you might like to leave. That's why the contextual considerations are important factor. Which brings me to something you mentioned earlier, and about training status and why that's important.

I remember you, and Stu talking about this quite a few years ago now. I think it was on the first podcast we ever did with you guys on protein nutrition. You guys were talking about the fact that there are so many studies done on people, where their training status is they’re novices. Of course, that has a certain influence on what's going to happen after they start resistance training, relative to someone with some experience and an elite athlete, and of course, how that influences the data and subsequently, the interpretation of that typically, to potentially arrive at a very pro supplement narrative, which can be very misleading. Bringing it back to this conversation, Kev, why is training status such an important factor in this? 

[00:39:09] KT: Well, I think as I mentioned before, because protein – the response of protein synthesis changes with training. It's a variable response. Partially, that's due to what we talked about before, which is that it's responding to this, for a different reason. Also, it seems that protein synthesis – Okay, so let me – I will do that just now. I'll just say this, then we'll get into why. 

Basically, you're seeing a change in protein synthesis. Stu and I did a study back when we were in Texas, and Stu is the first author on this paper. I think it's ’99, we published it. It was a cross-sectional study. We took trained and untrained individuals and measured protein synthesis and protein breakdown. This was mixed. Showed that the response is different in the two, and protein synthesis goes up with training and protein breakdown, the response isn’t as great with training. That was cross-sectional, so then you have all the complication of the different individuals and all that. That was what we found. 

Then subsequently, there been other studies and Stu’d done a couple of these. You see that the response to feeding changes with training. In that study, that original study that ‘99 was fasted, the fasted response. These things complicate this ability to predict. Like I said at one point, now, if I were going to try to judge an intervention, I certainly wouldn't measure untrained individuals and their response to try to predict whether an intervention is going to be better or not. I think that that's been fairly clearly shown to be a problematic, and maybe just a guess, at best if you did that.

[00:40:49] LB: Of course, with you saying that, though, there is still plenty of data out there, plenty of papers that have done that, though. Again, this is why you need to go into that paper and have a look, because that in your filtering system is like, that's probably not relevant to what I'm trying to achieve here.

I know you've mentioned about methods of measurement. Because we're on this theme of things like training status matter, we talked about from a measurement perspective, things like body composition methods matter, when we're trying to determine the changes to that person's physique, muscle mass, and so on. Actually, I did a podcast on that a few years ago now, with Shawn Aaron, Professor Shawn Aaron, who's coming back on the podcast very soon, as it happens. That will be worth listening to. Obviously, the actual methods of measurement itself for determining muscle protein synthesis, just take us through that a bit more. 

[00:41:47] KT: Okay. Let me start with saying, to expand on what I said a minute ago, which is we know that the peak magnitude of muscle protein synthesis is greater after training. This may increase the complexity here. The time of the peak is later in untrained and trained. That's going to get into the methods a bit, so keep that in mind. The duration of the response seems to be greater in untrained than in trained. 

You got different aspects of the response here. Now, that's important, because of the way that we measure protein synthesis. I'll just dispense with the arteriovenous balance quickly. Because what that relies on is, let's go with the three-pool model to make – just to get that out of the way. You take an arterial sample and a venous sample at the same time. Usually, the way that we used to do it was, you'd sample over about half an hour. You’d take five samples, or four samples over half an hour, and take a muscle biopsy at that half hour and assume that that muscle biopsy covers all four of those. You average those together, because what you get is each individual time you do it, you get a bunch of variability. If you average them, then the assumption is you get a pretty good number. 

That means you're getting a snapshot over that 20 minutes, 15 minutes, half an hour, however long you've taken those four samples and averaged them. You could do one in the first half hour after exercise One, two hours later and one – so you can see some different snapshots there. Now, but of course, you can't keep those arterial catheters in, for a huge amount of time.

We did one study with 24 hours. We did that one and published that in 2004, I think with three. Again, you're not going to see too many of those. Most of the studies you're going to see are fractional synthetic rate. Now with that, as I said, you have to take two biopsies and look at the difference between the two. The trick is how long between those two biopsies. 

If you think back to what I just said about the differences in the peak value versus the duration of the response and when the peak occurs, you can miss that if you take the samples at the wrong times. Then, if you're comparing untrained to trained, you're going to have to decide when to take those muscle biopsies to try to get the best response.

Now, you can do a little bit of time resolution by taking multiple biopsies. For example, Stu and Dan Moore did a study probably about 12 years ago or so now, where they took a sample at one hour after exercise, three hours after and five hours after. Now you can do a one-hour response, or a zero, one, three and five. You can do from zero to one, from one to three and from three to five and you see a difference in the pattern that way. 

The shorter you do this sampling, the more problematic the measurement is. The mass spec methods are much better now than they were back in the day when we first started doing this. You get much more noise, the shorter you do that sample. Zero to one hour, that's tricky. Just having an hour of incorporation, that gives you very low signal, and you’ve got to be good. You’ve got people who have good mass spectrometers, the analytical people who are really good that can do this, but it's tricky. 

The longer you do it, the better, the cleaner the measurement is. You tend to see a lot of studies where there's four hours from zero to four hours after exercise, or something like that. You're missing time resolution in there. You don't really know what's happening, because essentially, what you're – This is where like, we were talking before we got on air, about needing a whiteboard here to show this. Let's see if I can do it verbally. 

If you adjust when that biopsy is taken, what you're really looking at with FSR is ultimately, is integration. It's really the area under the curve of that response of muscle protein synthesis, of that rate of muscle protein synthesis. If it changes over that time, which it does, then you've got to know when to take that biopsy. Some people don't even take a biopsy until half an hour, 45 minutes after exercise for the first biopsy, because they think that there's a delay in that response. They don't want to start it until it's actually started. 

You really got an area under the curve during that time of whatever timeframe you choose, or the investigator chooses to take those biopsies. The problem is, of course, whatever that intervention is doing, that you're trying to test, it might change that time course. For one intervention, you're better off taking a biopsy from zero to three hours to really encapsulate that response properly. Whereas, it might be zero to four hours to really encapsulate another response. 

Maybe, it's come back down to zero by the three hours. If you take four hours, and you're really, you're cutting off part of that response and you have to try to think about all this when you're designing these studies. I can tell you, we would spend many hours. I mean, the post-docs, or post-grads or whatever, debating. Okay, do we take the biopsy now? Or do we take it this time? Go back and forth and try to make the best decision you can before you know.

These factors, along with the measurement of hypertrophy and the variability you get there, those also contribute to some uncertainty with the responses and whether you can predict hypertrophy. Now we have physiological reasons and we have methodological reasons. Why? You might not get this nice predictive value of muscle protein synthesis with muscle hypertrophy. 

[00:46:53] LB: Kev, we've been getting to this for about an hour now, and there's still so much for us to talk about. People can see, this is clearly a complex area, or at least, it shouldn't be oversimplified. I think it's clear that there's a need to not have this oversimplified. We talked about measurement issues and methodological issues. You've talked about things like, heterogeneity, and factors like that. Of course, individual variability. 

One's physiology is also a factor there, and there's a number of areas that I know you wanted to get into, including the translational capacity, which is something that we don't read so much about over the course of all that literature. Just tell us why physiology really does matter. 

[00:47:40] KT: Well, like you say, that physiological response, the magnitude and the duration of that response is different, or can be different, for different interventions. As you just mentioned, you've got, well, as we talked about earlier, you’ve got the physiological responses adding protein. Also, the physiological responses is remodeling and repairing proteins. It's not really gaining any. It’s tearing them down and then building them back up again or building new ones up. 

Also, as we talked about, we got to translational capacity and translational efficiency. By that, what I mean is, it's based on the number of ribosomes. Everybody thinks back to their protein synthesis, as I said, you got the ribosomes and you're building on – the ribosome’s building the polypeptides. Well, you have a certain number of ribosomes in the muscle. Translational efficiency is what we're actually measuring. That's how much of that protein is being synthesized, relative to the number of ribosomes. Efficiency. It's efficient. 

The more it's doing based on a certain number of ribosomes, the more efficient it is. That's what we’re measuring when we're measuring FSR. Now, later on, and there's a thought that you actually increase the number of ribosomes with training. You're getting greater translational capacity, because now you have more ribosomes that can be used. Even if each individual ribosome isn't as efficient, you can make more protein later on. 

That's what's thought to happen. There're some pretty good arguments. There's some indirect measurements of ribosomes. Also, more recently, Phil Atherton’s lab, Brooke was the first author, I think, they actually did some isotopic tracer methodology to measure ribosomal synthesis. That complicates it even more. Now we got, are we talking about ribosomal capacity, changes maybe later on in the training status. Now you're getting all these, again, all these variables that are related to physiology, like the ribosomes. You get the variables, whether it's repair, or remodeling, or hypertrophy, or adding protein. Then you’ve got the methodological variability, and you have all this and the methodological variability of measuring both protein synthesis and hypertrophy.  

Also, then like we said earlier, the complications from individual responses of muscle protein synthesis, which can be highly variable. If I get 12 people, in fact, you can look at some of our studies, we in the last few years, we started showing individual responses in our graphs, because we thought it was giving a lot more information, because you can see the difference. Also, the variability of hypertrophy, if you get some training. Everybody knows that. You see in a gym, some guys just walk into a gym and they blow up. Some people like me can’t. I can lift forever and I just don't get big. That was before I was old.

[00:50:17] LB: We might be to find you some illegal juice that might have some effects about that. 

[00:50:22] KT: Yeah. Anyway, it complicates things. I know we're probably going to have to wrap it up in the not-too-distant future here. Again, the bottom line is to go back to what we talked about earlier, the bottom line is yes, you can use FSR to predict muscle mass under the right conditions. I would urge listeners to be careful about those assumptions, or think about those assumptions when they look at some of these papers. 

Now FSR, or muscle protein synthesis, is also useful from a mechanistic standpoint. Mechanistic data do help us evaluate interventions. I certainly, and of course, my whole career would be ruined if I did believe this, that FSR, I do believe, is a valuable tool to assess nutrition interventions. You’ve just got to be careful about the interpretation, as with almost every – well, as with every measurement that you're doing. 

I don't want to throw it out by any means. It's just that, there's some thinking that needs to be done about what it actually means in some care with the interpretation. I think that's where people are let down often. 

[00:51:27] LB: Well, Kev. That's why learning is an ongoing process, isn't it? We need to learn forwards and we need to learn backwards. By that, I mean, it's like this business of people talking about the only research you should be reading, and/or citing is recent research. Actually, some of that historical stuff is immensely influential in understanding where all this has come from, and the journey of that body of knowledge is profound to how we learn how to understand it, and obviously, apply it. That's a rabbit hole we could go down, which I can't let us do right now, but we will in another podcast, Kev. 

I just wanted to quickly, just come to something where when we talk about skeletal muscle, or muscle hypertrophy, it's a fairly simplistic term that actually, in some of the papers I've been reading more recently, they start talking about things like, sarcoplasmic hypertrophy. Why is that term important to this discussion about why physiology matters, Kev? 

[00:52:28] KT: Well, because sarcoplasmic hypertrophy is not gaining of the muscle proteins that lead to increase size. It's gaining of other factors, like I said, fluid or connective tissue. Actually, connective tissue wouldn’t technically be sarcoplasmic. You can get increase in protein synthesis and connective tissue does have to grow, if you're going to get bigger muscles, right? 

I haven't studied sarcoplasmic hypertrophy myself, but there seems to be a core group of investigators, which really think that this is a big deal, and others who don't think it's that big a deal. Especially in an acute response to exercise, if you get some edema and you get bigger muscle – when you go and you get your pump, get your pump on for – go do your biceps before you go to the beach, get your pump. That's basically what you're talking about. You're getting increased blood and stuff in the muscle. 

Well, that wouldn't be sarcoplasmic – sarcoplasmic is actually in the muscle cell. All that comes from just an acute response and not necessarily, gaining muscle protein, which is ultimately where you're going when you're increasing mass and to some extent, strength. 

[00:53:41] LB: Thanks for that. That's perfect. Just one of the final points, before I wanted to get into a more summarizing of this topic, just so we can bring it all together for people are going, “Oh, my God. My head's just exploded, basically.” Would be the very topic of our last podcast last December, where we talked about muscle protein breakdown in response to nutrition and exercise. Yes, people should listen to that podcast. Just quickly, why is that also relevant to this topic? 

[00:54:08] KT: Well. I mean, again, we don't really understand it as well, as we talked about ad nauseum last time. Breakdown has to play a role here. If we're only measuring synthesis, and this is a common criticism of a lot of these papers, if we're only measuring synthesis, then we're missing a little bit of the story, even if we think that it's 80/20, or something like that. The response of hypertrophy is related 80% to synthesis and 20% to breakdown. Well, it's still 20% that we're missing. 

It has to play a role here. Now, we do know, again, as I mentioned earlier, from our cross-sectional study that we did all those years ago, the response to protein breakdown was less in the trained people than the untrained. You're getting a difference in these responses. Again, we don't know what proteins those were, so it's a little bit of a black box mystery there. If that is true with the myofibrillar proteins, then that has to be part of the factor, or part of the reason that you're getting this hypertrophy later on.

It also could be true that it would intuitive anyway, it would fit that lack, or that lesser response of breakdown after you're trained, could be because you're not getting as much damage and you're not having to break down and repair and remodel a lot of those proteins. You're now just adding them on. The breakdown is partially in response to your breaking down those damaged, if you will, proteins. Or, and I almost hesitate to get into this, because it adds another piece of it here. When we're measuring these fasted, you get a stimulation of the pathways that lead to protein synthesis, the mTOR pathway set. Those exercise itself does that. 

You get increased synthesis. Well, you have to get amino acids from somewhere to provide that amino acids for the synthesis, so you’ve got to break down proteins to provide that increase in synthesis, so you’re breaking down others to provide it. As you train, it gets less, because now you don't have as much of that going on, and especially if you're feeding, but we're talking fasted.

The breakdown has to be playing a role here. We just don't know what it is, as well as we do with the synthesis. That also adds a little bit of that uncertainty in that when you're trying to say, are we going to predict hypertrophy from protein synthesis? 

[00:56:12] LB: Thanks, Kev. Listen, I think we should park it there. This is not the end of this type of conversation. We'll be doing regular podcasts. I hope everyone's enjoyed our conversation today. I always learn a huge amount out of these. Well, every podcast I've ever done with everyone, it just blows my mind how much there is to learn in this body of knowledge that is forever growing. That's why it's so easy to get lost in it all as well.

Like I like to say, we just need to stay with what's relevant to influence effective practice, which is my area of interest. Just by way of just summarizing a little bit, Kev, this is an important topic. In fact, it's not just important, it's incredibly popular. 

[00:56:59] KT: Well, okay. Just to summarize. Obviously, I'm not going to argue that muscle protein synthesis is not worth paying attention to - or measuring. I definitely think there's a role to play for measurement of protein synthesis to different interventions. What I would argue, and other smarter people agree with me on this is that, in order to save – a good first step is to measure muscle protein synthesis to different interventions. Maybe that's not the end all be all to say, okay, now that we know that this intervention gives us a 50% greater response to protein synthesis than this one, that we definitely want to jump on the first one. 

What we then do is we can use the protein synthesis studies as a starting point to give us a little bit more ability to decide what we're going to do next in a longer-term training study - or feeding study. A combination of the two, I think, is the way to go to really get the best information. Of course, with all the various and sundry things that people want to test, that's going to be a long-term process.

Like you said earlier on, it means that we don't really know as much as we think we do. We have to be careful about the interpretations. As always, as a practitioner, people are going to have to make the best decision that they can, given the information that they have at the time. That unfortunately, is what it is. We're not an all-powerful being that we know everything. We have to make the best decisions that we can and we have to be willing to learn more and change our mind. 

As you know, my favorite thing to say is to be skeptical, but open minded, and to learn so that we can improve all the time and improve the information that we get, but the information that we then pass on to our clients and athletes and exercisers, etc. Again, I don't want to throw out protein synthesis at all. I think, yes, we have to be cognizant of the limitations as with anything else, we're measuring. Cognizant of the limitations in the methods of the hypertrophy measurements as well. To think about that and to keep it in mind when we're making decisions. 

[00:59:09] LB: That's great, Kev. Thank you so much. There's a huge amount to absorb there from today's discussion. I know that the benefit of this being a podcast is people can rewind and fast-forward and read the transcript. There will be a transcript as well, which you can get via our website. You just go to www.theiopn.com. Click on podcast and then follow the links to the website there, where you can get not only this podcast, obviously, but all related podcasts with Kevin, but also with some other researchers and experts and so on, that I feel are relevant to this episode. 

We will be back with Kev. We will be back. We'll have other topics that we want to get into. Also, it's worth me putting out there if you as listeners, if there's topics you would specifically like me and Kevin to get into, or for me to find some other experts, then please do let us know.  

You can contact us via The IOPN website, or through the Contact Us page on the wedoscience.com website, specifically for this. Do do that. I will link to Kevin's other podcasts and research and all his contact information, should you want to. Have you got any parting words for us, Kev beyond that? 

[01:00:28] KT: Well, it’s just exciting to be the first pod as a full-on IOPN team member. 

[01:00:34] LB: Fantastic. I'm really excited too, Kev. I'm sure the listeners are as well. Huge, huge amount of plans going forwards, which includes many podcasts like this. I hope everyone remains safe and well, and we look forward to bringing another IOPN podcast back to you all very soon. Take care, everyone. Thanks again, Kev.

[01:00:53] KT: Thank you.

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