A

Is it then fair to say there are a subset of people who just simply cannot grow muscle from strength training?

B

I think the percentage of folks, when you look across different studies, the non responders are pretty low. So that is to say that most people will see at least some growth. But I'm always devil's advocate. Yeah, okay, so they grow, but some people see a lot more growth than those people. Right? So I mean, there are clusters, there's. You call it turtles, you have low, moderate, high, like there is that. But that is to say that maybe less than 5% of the population, if not even smaller, that will not grow.

A

The science and practice of enhancing human performance for sport, play and Life. Welcome to Perform. I'm Dr. Andy Galpin. I'm a professor and scientist and the executive director of the Human Performance center at Parker University. Today I'm going to be speaking with Dr. Mike Roberts. Mike has a PhD in muscle biology and and has focused his research in his laboratory at the University of Auburn, mostly on how skeletal muscle responds to strength training and resistance exercise. Mike is by far my go to reference when I wanted to talk about, understand, or learn more about how and why skeletal muscle grows in response to exercise. In this episode, you're going to learn a lot about that. He will cover many practical applications, such as what do we know about the style of exercise, how many repetitions, and how much volume is needed to maximize muscle growth. He'll also give you an extraordinary insight into the biology, molecular mechanisms and cellular components that go into understanding why and how muscle grows in response to resistance exercise. So with all that in mind, I hope you enjoy Today's episode with Dr. Mike Roberts. Dr. Mike Roberts, it is amazing to have you here, man. I really appreciate you flying halfway across the world to come hang out for a day. It's been a long time.

B

It has.

A

If you've ever seen any of my videos or conversations on muscle physiology, there's a strong chance it's Mike's work that I'm talking about. So I just had to have you in. We're going to spend as much time as we can today on muscle. And I'm really excited because your lab has done such tremendous work in this area, covering everything from responders versus non responders to exercise. Right. So why are some people growing muscle and other people having a really hard time? Sure, you guys have done a lot of work in aging. So how does this process change with age, with sex, with different nutraceuticals and nutrition and supplementation, but mostly what you guys have focused in on what I'll just call the molecular side in the equation.

B

Right.

A

What's happening in the cell. So with that in mind, actually, I don't think I could think of another person in our field who I've seen their science misrepresented and misquoted more than yours.

B

Oh, wow. Yeah, thanks.

A

People love to use your stuff as fodder for whether it's a training recommendation or something else. And so I would really love for you to maybe set the table clearly on what some of your work does, what it suggests, what it doesn't suggest.

B

Sure.

A

And otherwise. So that's the playbook in large part. And I think it would be best for us to actually just start with a broad understanding of how does muscle grow? When we say that, and we say this word, hypertrophy, one of our muscles, presumably our biceps, because that's what everyone cares about, Right. When it got bigger, how, why? And then that, of course, will lead us into. If you wouldn't mind giving us an overview of what we'll call the molecular mechanisms of how that muscle grew, why it grew. And then that'll give us the table to get into all the nuances of how do we optimize that, how do we alter it and change? So I'll set. Set you up that way, and I'll let you lead from there.

B

Okay, Sounds good. So how does muscle grow? The simple answer is mechanical overload. You will see that in the literature time and time again, which is to say that weight training for humans or very, very intricate models in rodents will allow the muscle to grow. So when we say mechanical overload, if any of your viewers read that, we're referring to resistance training in. In the human. Consistent resistance training. And we'll get into programming. Not my forte, like we talked about. Everybody. Brad Schoenfeld, who is very well versed in that, But I have some ideas in terms of how to maximize hypertrophy sets per week, that sort of thing, if you consistently resistance train. We've seen this time and time again with 10 week studies, 12 week studies, 16 week studies, we'll call it two to three days per week, full body. What you're seeing in terms of hypertrophy is mainly radial hypertrophy, which is saying that the cross sectional area of the tissue is increasing in size. How do you measure that? Right. So you can do muscle imaging. We do ultrasound in the laboratory. We have a panoramic, so we can actually look at the rectus femoris, the. The vastus lateralis, and we can see Something to the tune of, we'll call it 15% increases in the cross sectional area of that, of that muscle tissue. And then from there we can take muscle biopsies. That's mainly from the vastus lateralis. Our lab does the vastus. And we'll see probably, I would call it 20 to 25% type 2 fiber cross sectional area increases. So at the cellular level, those type 2 fibers, fast twitch fibers, are increasing 20, 25%. And it's preferential for type 2 because type 1, sometimes, depending upon training status, we won't see any hypertrophy. Or in the untrained individuals, we'll see something like a 10% increase in cross sectional area. Interesting. So you say, okay, the tissue's increasing in cross sectional area, the cells are increasing in cross sectional area. What's going on inside of those myofibers or muscle cells? Until recently, we frankly didn't know. And you had mentioned, you know, some of our research gets sort of misquoted a lot of times or misapplied. There are different modes of hypertrophy that we think exist. The conventional realm of hypertrophy would be that as your fibers, your muscle cells, as they increase in size, you are having a proportional increase in myofibrillar protein content, which are your contractile proteins. They allow the muscle to function. Right. So, and then the question became, all right, well, is it the pre existing myofibrils within those myofibers that, that increase in size or do you have an increase in the number of myofibrils? And luckily we were able to work with a very smart guy, professor at Wisconsin, Troy Hornberger. He had a fluorescent microscope technique where he did a really neat sort of resistance training model in his mice. And then we sent him some muscle from a training study that we did across species. What we see with mechanical overload in the mice and in the humans is that when you see this increase in fiber cross sectional area, it is due to the increase in the number of myofibrils. So those myofibrils, in terms of their size, sort of maintain the sweet spot that's relatively conserved. And so applying, you know, resistance training, you're just going to see a larger radial increase in cross sectional area of that cell. And that's due to the addition of myofibrils, if that makes sense. Other things that happen with resistance training, of course, is sort of this proportional increase in everything else in the cell. So we have the mitochondria. People conventionally look at it as like this is the powerhouse of the cell. They, you know, this is Xphys101 that produces the lion's share of ATP, which is certainly true. There are other roles of the mitochondria in terms of, you know, molecular signaling, Ross handling, things like that. But as you resistance train, that's been kind of one of our questions as well. What happens to mitochondrial content? Because some of the studies would indicate that you have a dilution effect, which is to say as the cells increase in size. Certainly we have this proportional increase in myofibrils, but that comes at the expense of not expanding the the mitochondria. We took different approaches throughout the years. One of the markers that has been conventionally looked at is citrate synthase activity. And a lot of studies showed that with Gen Pop, you take them through 10 weeks of resistance training, pre to post training, you see a decrease in CS activity, which would then reflect the dilution of mitochondria, which is to say the myofibril. Sort of the growth of the cell and expansion of the myofibrils outpaced the the expansion of the mitochondria, you know, reticulum or whatever. But looking at it from immunohistochemistry, we have a 2021 paper by Brad Ruppel. We were convinced that there is this proportional expansion of the mitochondria with hypertrophy, which sort of makes sense because you need that to produce energy for the growing cell, right? So we think that everything with conventional hypertrophy as it relates to fiber expansion, everything in that cell is going to expand proportionately.

A

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B

Yes.

A

That's your outside thigh muscle.

B

Yep.

A

Right here on out friends, we're going to call that the vl. Yeah, that's what we would always call it in the field.

B

Right?

A

Sure. So that's what we're talking about. It doesn't matter what muscle we picked up. We don't actually have any indication that any of these things would be different across most muscles.

B

I would agree with that. Yeah, yeah, there's nuance, but yeah, generally speaking that's fair.

A

Certainly if you look at like the gastroc versus soleus. Yeah, but close enough. Okay, so within that vastus lateralis you've got how many individual muscle fibers.

B

I think a good guesstimation is anyone off the street on average would have between. We'll call it 400 to 600,000 cells in the VL alone.

A

So one individual muscle there is actually, we will call it a muscle. Yep. But really we're looking at a half a million individual cells.

B

Yes.

A

That are comprised of that muscle. And so conceptually it's easy for us to think about this muscle as one thing.

B

Yes.

A

But when you get into this side of the equation, you actually don't even consider the VL really a muscle. Like you're actually just paying attention to the individual tissue, the individual cells, the mild cells. That's right, themselves. So you got 500,000, we'll call it individual muscle cells. Now within those individual muscle cells, if you wouldn't mind, give us just a really quick overview of myofibros, myofilaments, all that. So people can follow that jargon just a tiny bit. So then we'll come back to some of these questions.

B

So when we say myofiber, that is synonymous with a muscle cell. Think about an uncooked spaghetti noodle that you would pull out of a box. Right. That is what your muscle cells look like. So the diameter is relatively small when you look at the length of the, of the fiber. Right. So they are very, very long cells.

A

And these are huge cells in all the biology for the record.

B

Yeah, yeah, sure, sure, yeah. They, I mean, uncommonly large. Yeah, uncommonly large. Right, right, right. Because of that, very unique to the muscle cell. Although there are other cell types that have multiple nuclei, but they are multinucleated. Which is to say that, you know, when you look @cell bio 101 books and you open chapter one, you're going to see this sort of organic, and it's going to have this centrally located nucleus which contains really a copy of the human genome, right? So all 23 chromosomes, over 20,000 genes that are protein coding, et cetera, inside of that nucleus, inside of that cell, muscle cells. And you've done a lot of work in this, right? If you image them under a microscope, individually, you will see very, very long cells and you will see that the nuclei are on the periphery of the, of the cell, which is unique. And one of the sort of predominant theories in our field is we have this myonuclear governance of cell size. And so in order for that cell to grow, right, we need to add more myonuclei to regulate certain areas of that muscle cell in order to make MRNA's, which then are translated into proteins. And then you can have the deposition of those proteins, be it into the contractile apparatus. You can have metabolic enzymes residing in that area of the myonucleus, et cetera. But if you close your eyes and just think spaghetti noodle, and you take a sharpie, a fine sharpie marker, and just draw dots on that, those would be each of the myonuclei, right? As you lift weights, right, Just imagine the diameter of that spaghetti noodle increasing in size, and you draw more dots on that, on that spaghetti noodle, right? So people then ask, well, where do those nuclei come from? Is a natural question. And by and large, they come from muscle stem cells or satellite cells. One good stimulus to activate satellite cells so that they fuse to that growing fiber is resistance training. Just tried and true. Certainly a conserved mechanism, whether it be a rodent or human. We're going to activate satellite cells to eventually fuse to those growing my fibers with resistance training. Now, inside the cell, you had said, you know, what are the sort of nuanced components? You're going to have 80 to 85% of that cell volumetrically occupied by myofibrils. I'm trying to go back to the spaghetti noodles.

A

So, so imagine several more spaghetti noodles inside your spaghetti.

B

Now what we're talking about is like imagine the muscle cell at this point being A round cylinder that holds uncooked spaghetti noodles.

A

It's the package. So imagine if you got, you know, 50 noodles in a package.

B

Yes.

A

And then you got a bundle of 50 of those packages. And that whole bundle is the muscle.

B

Yes.

A

I'm working with your analogy.

B

There you go.

A

Doing my best I can.

B

So, yeah, we have this long can. That's a cylinder within the cylinder. Now we have spaghetti noodles that are uncooked.

A

Yeah.

B

Now what we're saying here is we're looking at one muscle cell again, and we're sort of zooming in where this cylinder is a muscle cell. Those spaghetti noodles inside those are the myofibrils.

A

Yeah.

B

All right. And if you pull out one of those spaghetti noodles, what you're going to see in series. Right. Z line to Z line is sarcomeres, which contain your main myofilament proteins, actin and myosin.

A

Getting back now to the very place you started, which is the mechanical tension.

B

Yes.

A

Idea. Right. So what you're saying is. And please interject if I don't do this perfectly, but you've got that vastus lateralis. It's got a half a million cells.

B

Yes.

A

Each cell has a bunch of. If you want to think about them as sub cells within them, like a bunch of individual kind of little circles within it. But on the outside of that cell are these nuclei.

B

Yes.

A

The nuclei are what hold your DNA. They control the cell's activity. Grow, shrink, die, repair, anything in between.

B

Correct.

A

And when you mechanically stretch that tissue, those nuclei effectively understand the fact that they can no longer control enough of that region. It's kind of like having a bunch of managers and you're growing and you're opening too many stores.

B

Yes, Good analogy.

A

And you have to say, hey, we have a new store opening. We need a new manager there.

B

Correct.

A

That manager is the nuclei. The way you do that is you recruit satellite cells, turn those into nuclei, and now you've got more of these manager centers is the stem cells. These satellite cells are what eventually turn into that. Is that a fair, perfect breakdown? Okay. I know we've gotten a little bit deep early, but this is Mike and I's passion, so I don't apologize to what we love to do.

B

Yes.

A

But this stuff is important because it will help us understand how we mitigate unloading.

B

Yes.

A

Aging, muscle wasting. This stuff is all predicated on us understanding how the muscle is even growing in the first place.

B

Sure. Yeah. Yeah. So I've heard. In the field, I don't. You'll have to Tell me the third. But basically, and I know Brad, and I think maybe Jeremy Lennecke had spoken to this a few years back, mechanical tension and then this sort of metabolic perturbance.

A

Yeah.

B

That could.

A

Damage would be the third one.

B

And then damage. That's fair. Yeah. Damage. Do you need damage to grow? Right.

A

So in other words, translate right now, do you have to break muscle down to build it?

B

Right.

A

Great. So you're gonna. You're gonna answer that question for us, but.

B

Oh, God, I hope I can.

A

So. Oh, I think you're gonna be fine.

B

Yeah. I am of the persuasion and keep in mind, a group of us across the world, Karen Esser and I, she's at the University of Florida. She was more or less the godmother of the field of skeletal muscle hypertrophy. She trained Troy Hornberger, Gustavo Nader, John McCarthy, Kentucky Lab for many years. CMB. Exactly. So we got together in 2022 and we were looking to collaborate and I said, we need to write sort of this update on mechanisms that we think contribute to skeletal muscle hypertrophy with mechanical overload. So 2023, publish a paper with people across five different continents, all of whom specialize in certain mechanisms that we talk about in that paper. And it's pretty evident that mechanical overload or mechanical tension is the prevailing mechanism. We didn't even speak to the metabolic aspects in terms of lactate accumulation. Is it involved? I've had conversations with Brad. There are a couple of studies, some rodent studies, in vitro work. So petri dish muscle cell stuff where they put lactate, they either injected into rodents or put lactate in a petri dish with muscle cells showing. Oh, yeah. You know, we see this uptick in muscle protein synthesis, which is needed for hypertrophy. But there was a human study done in. It was in Europe. I apologize for forgetting the. The location where they infused people, participants with lactate peri. Exercise versus like a buffered saline as a placebo, showing that, you know, when they did the lactate infusions, they didn't see this. This enhanced post exercise muscle protein synthetic response.

A

This is mimicry of blood flow restriction.

B

Yes, Right.

A

Very similar idea. If you guys are heard of that, that style of training, that style of exercise, very effective. We know that it works.

B

Yes.

A

The quest was why is it working?

B

Right.

A

And the basic idea was if you block blood flow, you eliminate the ability to get waste out of the tissue.

B

Yes.

A

So that waste should accumulate.

B

Yes.

A

One of the primary. We'll just call it waste. Right now you're referring to as lactate, lactate.

B

Right.

A

So then the next step would be oh, what if we then induce the buildup and just inject it straight in.

B

Right.

A

Shouldn't that then result in muscle growth?

B

Yes.

A

And it turns out I don't think so. It didn't work very well.

B

Yeah. I mean again you're going to see there was this Japanese group that did it. I think it was in rats or mice. I apologize. And they, they, they did lactate injections, IP injections and showed a little bit of an increase in hypertrophy. But the human study that was peri exercise did tracer work. Looking at the mps response after the exercise bout didn't show anything if that makes sense.

A

So they're directly sampling muscle, looking to see is protein increasing at all muscle protein synthesis and at the molecular level. It just wasn't.

B

It didn't enhance the post exercise response after, you know, sets of leg extensor training. Which reiterates the point that mechanical tension was the driver and we didn't see the enhancement with the addition.

A

So if you induce the metabolic damage without the actual strength training component, I don't buy it. We don't see the growth.

B

Yeah.

A

Okay. You, you said at the very beginning the contractile portion of this mechanical tension is.

B

Is king.

A

80%. Yes. 90%.

B

Yeah. Of the driver royalty.

A

While we're here, let's touch on the damage side. So what do we know about the adage? Of course you've got to break it down to build it. You have to, you know, do all that side of the equation. True. Not true. Summer Moutain. What do we know about that side?

B

I don't think it's true. Now I'm going to say this based on what's in my brain cells right now recalling information, but I do have one close friend at ucf, Matt Stock, that has done concentric only versus, you know, mixed contraction model type stuff showing concentric, at least according to ultrasound, is just as effective. I'm almost positive there are meta analyses on this. If Brad hasn't done one, I know someone else has done one. It does not seem like the eccentric portion is for hypertrophy to occur.

A

We certainly see almost no relationship between muscle soreness and relating growth.

B

Yeah.

A

Right. So more sore does not equal more growth at all.

B

Right, right. Which you know, growing up we were going to the gym as teenagers, you and I probably like, oh, you have to be sore. Yeah, that's a like prerequisite to look like Ronnie Coleman, right?

A

Yeah, yeah, yeah, yeah, yeah. Not necessarily the Case. Now, when you do something that requires mechanical tension, that can often result in some soreness and some damage.

B

Yep.

A

But that looks like more like a byproduct of doing the. The king queen than it is an independent mechanism itself.

B

Yeah.

A

So if we were to go in. I guess another way to think about this. If we were to go in and isolate a tissue, a muscle cell, and you were to just damage it.

B

Yep.

A

You would not see any of the signaling cascade, any of the other stuff you've mentioned probably kick on to an extent to where it would result in the muscle growing.

B

That's fair. Yeah. And they've done that. There's certainly signaling that overlaps when you compare it to exercise, but it's a. It's a different signature. Practically speaking, I've had this conversation with people that train. You know, coming to Auburn and asking, how should I train students? This and the other. I. I wouldn't. Unless it's something for, you know, stabilizing the joint. I don't think that doing pure eccentrics is going to maximize hypertrophy.

A

If.

B

If that makes sense.

A

Yes.

B

Do it for something else, you know, optimization purposes, but don't do it thinking that this is the way forward to. To get muscle growth. Right.

A

Another area that you've spent a lot of time on is this idea of responders versus non responders.

B

Oh, yeah.

A

If you can give us a basic overview, we'll start there. And then I've got a lot of specific questions within this. But the overview of what do we know about why some people. Again, the responder phrase is some people will grow muscle. You mentioned at the very beginning, kind of an average, rough number. If you were to do 10 to 12 weeks of strength training, 20 to 25, increase in muscle size. Is that fair? What would that number be? We'll just start there and I'll get in my response.

B

Yeah. I think at the tissue level, it's fair to say 15.

A

15.

B

Yeah. And then at the cellular level, and this is another topic we can get into. Right. But you. You have a little bit larger increases in cell size.

A

Okay. So if you were to take an individual muscle cell, that cell might be 20 or 25% larger. But if you're looking at your leg, your vastus lateralis, after three months, 10 to 15% increase. Yeah. Depending on lots of variables. And I'm just trying to give you a rough idea of how to picture this in your mind.

B

Yes, right.

A

Of course. Much lower. So the fundamental question of responders, non responders is if you say the group average was 15%. And then you start looking at every single person.

B

Yeah.

A

Somebody was probably at 25%.

B

Yes.

A

And somebody was at five.

B

Yes.

A

So again, the question, yeah, what do we know about why some of these people are these hyper responders? Why people are these non responders?

B

Yes.

A

And then ultimately I want you to tell us then what do we do training wise?

B

Excellent. So I need to give, I need to tip the cap to Marcus Baumann, who really brought attention to this topic at the molecular level. Priscilla Clarkson and Monica Huebel, they published really the first paper in the, in the mid-1990s on this just showing after resistance training, when they're looking at hundreds of people and you plot the individual responses, what happens is exactly how you described it. Right. You're going to have this sort of mean response where 70% of these individuals fall, you know, 60 to 70, or right in the middle there, sweet spot.

A

It's a bell curve, right?

B

It is a bell curve, yeah. And then you have, we'll call it 10, some odd percent, maybe 15, that respond quite well. And then on the other side you have people don't respond at all. It's almost like they didn't train when you're looking at the hypertrophy response. So Marcus Baumann also presented in Finland. He, he was the first into, in the mid-2000s, him and J. Kim, his postdoc showing, and I still think this holds true, that the highest responders hypertrophy wise to resistance training, this would be 16 weeks in their study, had this very exaggerated satellite cell activation response. And not only that, but they started training with more satellite cells. Which is to say that if you were somebody that has never trained walking into a gym and for whatever reason, genetically, that you have more satellite cells in your muscle tissue, that could be a huge advantage in terms of gaining muscle mass when you activate those satellite cells. Right. So you're, you're sort of primed with more satellite cells. You train for 16 weeks, you activate a sub population of those to fuse to myofibers, adding myonuclei, which we talked about being important, and then those cells can grow. I think in his paper, the extreme responders saw like a 60% increase in fiber CSA.

A

That's crazy.

B

That is nuts. Yes, yes. So satellite cells are critically important, a B. We think that ribosome content and the response to training is important. So ribosomes are macromolecules, some people call them organelles. They reside inside of the cell. They themselves have 80 proteins glommed together. You have this large small subunit. When the large and small subunits sort of coalesce around messenger R, it. It translates that messenger RNA into protein. So that's muscle protein synthesis. When you talk about that inside of a muscle cell. We published a paper, Brooks Mobley in the lab, part of his PhD work, showing that in our hands, the high responders to 12 weeks of resistance training saw the greatest response to training in terms of increasing muscle ribosome content. So now our theoretical framework is if you have the muscle ribosome response to training, and if you walk into the gym with more satellite cells, you should be primed if you train consistently to be a relatively higher responder. Okay. Other mechanisms we've looked at a lot.

A

I was gonna say give me the.

B

No. This is where the null hypothesis comes into play. So there has been some back and forth as to whether or not the androgen receptor inside of muscle cells.

A

Walk us through what that is.

B

So the androgen receptor is a protein inside the muscle cell, and it is activated once testosterone from the blood diffuses into the muscle cell, binds to the receptor. The receptor then is activated. It can translocate into that nucleus or myonuclei across a cell, and it can turn on a gene program that is anabolic. Hence why you take, you know, 600 mgs per week of test and anthate. You see hypertrophy when you resistance train. Shali Basin did those studies back in the day.

A

So can I pause you right there?

B

Yeah.

A

I want you to continue on the story, but actually, people are going to jump off the roof right now if I don't stop you. Let's actually go in order, if you don't mind.

B

Yeah.

A

With testosterone. And then we'll get into receptors and we'll kind of follow that pathway through. If you want, we could actually even go into fiber type as a thing. But we'll kind of go up the chain. Another way of saying this is, is one of the things that determines a responder versus a non responder or super responder. Testosterone. Let's walk me there. And then we'll get to the receptors.

B

Okay. I'll give you the short answer. So people. It'll stick. So when we look at the younger male and we look at the younger male that doesn't supplement with testosterone, that physiological range is not a predictor, which is to say somebody walking in the door and has, you know, 500 total

A

testosterone, 5, 600 milligrams per deciliter. Right.

B

And then you compare that to somebody that has 900. If we train them the same way. That variable difference between those two did not drive the differential. We want to know who will get

A

bigger or smaller based on total testosterone nor free testosterone.

B

Yes.

A

And can I go ahead and just assume the same answer would be the case if we looked at estrogen in women?

B

That is correct.

A

So the total amount of circulating hormone at normal physiological levels, this is in the young adults? In the young, yes.

B

And when I say young, I'm saying we're talking about 18. And we'll call it up to peak muscle mass, which is 35, 40. Great.

A

So if that caught you by alarm, it's actually, that's been pretty well established, in my opinion.

B

Yes. Now, here's the deal. There's a caveat there.

A

There's several.

B

Yes, yes. So there have been aging studies in the Northeast, I think Baltimore aging studies a good example of this. Whereas when you look at the lifespan in the male and you track from the age of 18 to 90, there is a relationship with testosterone in the blood and muscle mass and people just walking around that's tough to disentangle because you're like, okay, well, it matters, obviously, but when you look at resistance training, it doesn't matter. And the answer is it's just not a predictor of the hypertrophic response. Which brings me to the most important point here. And it comes back to mechanical tension.

A

Yep.

B

The driver is mechanical tension. And then there is about 20% of the recipe that has to deal with perhaps metabolic byproducts, perhaps hormones, et cetera, et cetera. Right.

A

Yeah.

B

Yeah.

A

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B

I agree 100%. Yeah. And that again assumes normal physiology. They're within range, right?

A

Yeah. Now if they're using exogenous testosterone.

B

Oh, they're going to hypertrophy or it works and then that becomes its own question. Okay, well, you know why. And this gets to the engine receptor.

A

What the time right there. That's where I'm going to walk us to. The opposite could also be true if you are subnormal.

B

Yep.

A

So if you are a 20 year old male walking around with a total testosterone of 100, we would anticipate much less hypertrophic response.

B

Yeah. Because at that point you're hypogonadal and they've, you know, there's studies done subclinical. Yes. And Phil Atherton over in England, they, they've inhibited testosterone production endogenously through pharmacokinetics and they show that. That does.

A

In non humans, I assume. No, in humans.

B

Yeah.

A

Woo.

B

And this is published. Right. So when you bring levels way, way, way down. Right into that like. Okay, we are certainly happy to add, almost not producing anything then we, we do have somewhat of a blunted hypertrophy response. But there's still hypertrophy. Bingo.

A

Do you remember how low they brought them?

B

I want to say it was like under a hundred. Yeah, we could look that up. But yeah, this, this is through pharmacology. Right, of course, yeah, yeah. Wow.

A

Amazing. Irb. Good for you. So those are the things that, the part of the story that gets missed if you are again way above or below, especially if you're above because of pharmacology, we'll just call it that or below. Getting back to a normal range will likely impact, but it's not like you go to zero either. Right. So if you're subclinical, we're not going to zero muscle growth.

B

Yeah. You, you still have muscle growth. Yeah, yeah.

A

It's still there because 80% of the

B

driver is attention mechanical tension in the mechanisms.

A

Testosterone in this case would be folded into one of those subparts whose subpart at best explains up to 20%.

B

Sure.

A

So the other 80 are still driving some growth.

B

Fair.

A

Okay. Is there anything we need to add to this from the female side of the equation or is the answer the exact same in women? Because we, the example we've been giving are young men.

B

Yeah.

A

Same thing happening in young women as well.

B

Yeah. Hot sake. I think muscle growth is conserved across men and women at the younger age and across species, which is. There's beauty and simplicity in my opinion. Programming doesn't have to be complex. Mega complex. That's a topic that's becoming very, very, very hot. Brandon Roberts, Greg Knuckles, they probably have the best meta on this. The young female population can hypertrophy on a relative scale just as good, if not a little bit better than men.

A

Yeah.

B

Right. Same training stimulus.

A

I'm a little insulted you didn't mention my paper on that.

B

I'm saying that's okay.

A

It's fine.

B

No, no. And you guys published before.

A

That's fine. It's fine. It's fine. Give him all the credit.

B

Galpin also has a great meta on this topic crowd. Go read it.

A

Nonetheless. Yeah. The muscle growth effectively the same, right?

B

Yes.

A

Certainly strength on those estrogen. It's a similar story here.

B

Yes. And the receptor too does not predict in muscle.

A

So as long as you're in, we'll just globally call these anabolic hormone ranges.

B

Yep.

A

If you go below or above pharmacologically, the story changes.

B

The story changes, but they themselves.

A

You know, I'll come back to what I said earlier. I think the practical implication we want to take from this is we simply shouldn't alter training variables and how you're lifting weights. If you're intending to grow muscle simply by a blood test that looked at one of these. And really, honestly, you could pick any endocrine marker here.

B

That's right.

A

And I really don't care.

B

Yeah. No. And Stu Phillips, you know, he did this. They looked at, I think HGH in the blood. They looked at free tests, they looked at total tests, they looked at cortisol. We have looked at myostatin in the blood. None of these markers predict the hypertrophic response or the acute muscle protein synthetic response according to what Stu had published too. Right.

A

So if you look at the molecular mechanisms that happen immediately after exercise.

B

Yes. It's all inside the muscle cell. That's the magic. That is the Sizzle of the steak.

A

That's right.

B

That makes sense. Yeah.

A

Okay, so it's not the signaling from outside the cell. Correct. No matter how you cut it there, something is inside, secretly happening inside the tissue that determines how much it grows. And we could actually probably play this game for a very long time. And you have, across your career, you've looked at a lot of, we mentioned three or four, but you've looked at a lot of them. And it's just we're so confident here. You are. Particularly because it's. Nothing has stuck. Like nothing has landed.

B

Yeah.

A

Outside the cell.

B

Yeah.

A

So now let's move to the cell.

B

Yes.

A

On the cell membrane. And we'll be careful to not call it a cell wall. So you biologists.

B

Ah, yeah, yeah. Don't do that.

A

Biologists will kill us on that. We're humans, so we have a membrane, you have receptors. And in the example of testosterone, testosterone needs to bind to that receptor for that receptor to then move to the nucleus.

B

Yes.

A

To tell it to turn on its genes.

B

Yes.

A

To get the ribosomes moving to synthesize and make new proteins which ultimately makes those myofibrils larger.

B

Yes.

A

So then the next stop in the equation, and we'll just keep going this route, is, is there something unique on those cell membranes that is then predicting it? And I'll let you answer it, but I'll finish real fast here. Example could be maybe the amount of testosterone doesn't matter. What does matter is how many testosterone receptors you have.

B

It would matter.

A

And he just told you I'm gonna be a buzzkill. I know, I took all that.

B

That was really elegant though. That was beautiful. So yes to your question directly, what about the hormone receptors? Initially Stu Phillips said there is, there does seem to be a correlation with muscle biopsy, testosterone receptor content and the hypertrophic response to training. And that led us with Cody Hahn. When he was in the lab, we did a study in trained individuals. It was a secondary analysis of his main dissertation. We didn't see in trained individuals when they did a six week, very, very high volume training study that muscle androgen receptor content or testosterone receptor in the muscle. And trained men, college age, we didn't see it predict hypertrophy. Since then we've worked with Clayton labardi's lab, who's down in Brazil University, Sao Carlos and he had a really nice elegant study where we had 40 individuals, 20 men, 20 women, college aged, they did an acute bout of exercise. We took a pre intervention biopsy. Walking in the door, they did their first bout and then 24 hours later, we took a biopsy. That's T2 biopsy. T3 biopsy was after the 10 weeks of training leg extensor. And there was hypertrophy. When looking at the biopsy markers, be it the estrogen receptor in the muscle or the angina receptor, there was zero. I mean, not even close association with hypertrophy.

A

So that also answers our sex question.

B

Yes.

A

So this is not a male specific answer at this point. And not only is it not a receptor specific, but it's not gender specific.

B

Yeah.

A

At all either.

B

Right.

A

Strike number two. With even the anabolic hormones or receptors. You can answer both sides now.

B

Sure.

A

Does this story change in midlife or later in life or.

B

Yes. Oh, that's a great question. So I and Juha Tianen, he's a great colleague at Havaskala. He's the one that we did the conference with. He and I organized on the response heterogeneity to resistance training for background information. But he's also looked at this a lot. He has shown that across the age span and skeletal muscle, you do seem to lose androgen receptor content. And there does across the age span, young versus old, this is where we get outside that just young window. The relationship becomes a little bit more evident there in terms of less receptor could be detrimental to growing muscle. Which we'll get to that topic too, because so far this conversation has hinged upon when we're young and vibrant and trying to, you know, optimized peak lifetime muscle mass. It doesn't seem to matter. Things change at our age and beyond our future. Right. Proteins in the muscle may be a little bit more important. And we have some data that I'll get into on that.

A

On that front too, the fundamental question I'm getting at here is again, if we're trying to get better programming, the concept, whether this is supplementation, recovery or the actual exercise intervention itself, if we understand who's going to be a better responder, if we understand who's going to be a worse responder, if we can preemptively give different recommendations. And so the quest here is to figure out, well, what's causing that to begin with, then theoretically this could lead to potentially a screening process where we could run some tests on somebody. Obviously very few people have access to a muscle biopsy, but at least we had to figure out what we're trying to do in the first place before we can come up with a screening tool. And let's say magically one was possible. We could Say, okay, you've been flagged as a non responder because of xyz. Whether this is you or whether this is now you because you're aged.

B

Yeah.

A

Then we could say, okay, start this way. And we'll get into what those this way versus that ways are pro protocols. But that's ultimately we're getting at. So with the aging question, if we're still just figuring out and kind of what it sounds like is there's something there. There's potentially something there with the testosterone story across the lifespan.

B

Yeah.

A

100 something there with the antigen receptors potentially across the lifespan.

B

Instead of 20% in that young, vibrant, you know, we're saying up to 20% of the variance could be related to the receptor thing when you become older. That explains more in terms of the response.

A

Still not a single point variable while we're here. Actually, I've seen these done, but how do you feel about direct to consumer commercial genetic testing and similar things that will say you're an xyz, therefore you should train this particular way. What are your current thoughts on those?

B

We are totally not there yet, dude. Like, that scares me that because we. We actually have us in collaboration with Stu Phillips and Chris Van was the lead on this. He's at Duke. Post docking. We did the first GWAS study. So looking across the entire genome to see if any gene or genes predicted muscle fiber hypertrophy or DEXA lean mass changes to 10 or 12 weeks of resistance training. And we found one gene sort of weekly did. It's called. It's called Glee 3. Now that needs to be validated because for a GWAS study, it was only 110 or 20 people. But what we showed was people that had a certain GLI3 genotype. Right. So a T, C, G. I think if it was like a CC, meaning that mom and dad's copy of Glee 3 at that locus spot in the Glee 3 gene had a cytosine. You were a good responder. And it dealt with the satellite cell response. So that's kind of cool.

A

Okay.

B

Because now we have genetics satellite cells and response heterogeneity before we put that and package it into a genetic test. Though I do want to see it validated.

A

Okay. So I'll. I'll translate that in my own brain.

B

Yeah.

A

Humans have. We'll call it 20,000 unique genes.

B

Yep. That code for proteins. Right.

A

And of those 20,000, you ran an analysis of people where you. The Gwass. Right, the genome wide thing. So you looked at all them, basically?

B

Yeah, we looked at all. And of the 20,000 and as well as non coding regions of the genome too. So that's a difference larger number. 100%.

A

And of those, one of them potentially explained 1%.

B

Yeah, I would say it was under 10%.

A

Under 10%.

B

If I were to do the math on that. Yeah. Yeah.

A

Okay. So hopefully that answers at the current state. If you're buying direct to consumer testing that tells you how to train to optimize muscle growth from a genetic perspective, you've wasted 96% of your money. Maybe.

B

Yeah. It's fair.

A

Yeah. Okay.

B

Yeah.

A

Okay, great. We'll just, we'll just move on from there then.

B

Yeah.

A

Continuing back to some of our null hypotheses.

B

Oh, another, another null hypothesis, by the way. Sorry about that. Yeah.

A

Oh yeah, yeah, we missed that one too. Presumably we'll get better at that. Yeah, you mentioned. Needs to be validated. There'll be other things pop up, but there are some things gene testing can tell us and we can infer for. But simply whether or not you're gonna respond well to strength training from a muscle growth perspective. It's such a nuanced question. It is that single polymorphism or site mutation. I'm not sure what it was. Rear mutation.

B

Yes. Snp. Snp.

A

Yep, yep, yep. It's not going to tell you anything.

B

Right.

A

So don't use that. We'll call that intellectually interesting.

B

It is.

A

But not clinically relevant.

B

Correct.

A

Going back to our responder story, the androgen receptor concentration or density didn't seem to pan out. And that, that's actually really interesting because that's one of the things I was referring to at the very beginning when I see, when I say like people are misquoting your stuff so frequently.

B

Yeah.

A

This seems to be what. I don't know why, but in pop culture it's the receptors that get all the answer.

B

Right.

A

It's like, well, your total testosterone doesn't matter. And the reason it doesn't do ABC is because it's actually all about how many receptors you have. And so there's been a race for private companies to try to try to develop all kinds of assays where we can actually measure that in blood.

B

Yeah.

A

And the assumption is we're answer this. And I get like a little bit frustrated because I'm like, yeah, but like, have you seen the papers?

B

Yeah.

A

You're trying to solve a problem that we already know actually doesn't matter.

B

Sure.

A

It's like you're just way too far behind. So that part gets very frustrating. Relevant Interesting. Like I can say, but it's not the thing that's describing whether or not you're responding. Yeah, that's not. Yeah, let's continue down the chain then. So is it something in the signaling or gene side of the equation that is answering what do we know about that?

B

Long story short, I think the original question, it finally popped back in my brain was is there anything at the cell membrane? Yeah, yeah. Receptor, be it receptors. We talked about receptors. We don't think any of the receptors play a big role. I had a student, Josh Godwin, did a very elegant two year project Deep Dive where we took it was a small cohort of humans that we had trained already. We had sort of biobanked the muscle biopsies and pre post training we isolated the cell membrane from the tissue and interesting. And we did proteomics on it. Okay, so resistance training in these folks, you know, the aggregate numbers were what they were in terms of VL hypertrophy, fiber CSA growth looked pretty average, but there was response heterogeneity. We then did proteomics pre, post intervention on the cell membrane proteins. The total cell membrane protein pool significantly increased, which I thought was cool. I, I looked at the literature and said, oh wow, this is kind of the first time that we're saying things that happen at the cell membrane may be important to know. By the way, from cell membrane down to signaling to muscle protein synthesis is important. Right. The transduction of the, of the mechanical tension down to the ribosome in terms of increasing protein synthesis. So Josh did proteomics on that and we found a couple of proteins, one of which was called vimentin V I m that we saw small sample size regression seemed to be associated with mild fiber hypertrophy. We did some elegant studies showing that vimentin seems to, it's an intermediate filament, meaning that it should exist in cells. But what we found was it seems to be deposited in the extracellular matrix and it seems to come from satellite cells. Like I don't know if the satellite cells secrete it. We didn't answer that question, but we saw using John McCarthy's PAX7 DTA model of satellite cell ablation or getting rid of satellite cells in a mouse. We got rid of satellite cells and applied mechanical overload. We didn't see vimen in the extracellular matrix hardly at all. And they didn't hypertrophy as well. Now there's other factors that play into that mouse model. The lack of satellite cells prevents myonuclear accretion so that certainly is also driving that lack of hypertrophy, but it is coinciding with the loss of VIM being associated with hypertrophy. So we think more research needs to be done from vim. There's also some other studies, and I want to say they're in like petri dish, embryonic fibroblasts. But VIM has been linked to stimulating MTORC1, which we know is needed for bolstering MPS or protein synthesis in any cell. And so there's that linkage between this protein and mtor. So we're really excited. That seems to be part of the mechanical tension story that we think needs to be further investigated, if that makes sense. Other than that, Marnie Bopard does elegant work with the integrins that are spanning the cell membrane. The notion being you have this integrin protein that sort of communicates with. With the extracellular matrix and then once tugged upon, will start this phosphorylation cascade that can transduce the tension signal into anabolic signaling in muscle cells. And so that's always been in the backdrop, I'd say, for the past decade, in terms of potentially being a driver of how we get tension into anabolic signaling. Right. Other candidates, and we talk about this stuff in the. In the review that we wrote in 2023, Karen and I's review. Other candidates would be calcium. So stretch activated calcium channels. When you contract muscle, you have this influx of intracellular calcium. Now, some of that is used to activate cal pain, which are calang proteases. And you see this, you know, proteolytic response. But in addition to that, there's a tie in with the influx of calcium and MTOR activation. So there's a little bit of that going on as well. But all of this sort of, you know, mechanisms aside, this is cool stuff. This is. These are academic questions. These are just sort of reinforcing the notion that it is a mechanical tension. Right. That is feeding into this anabolic signaling, which is then bolstering MPS muscle protein synthesis, which is then leading to the deposition of more myofibrils, which is then leading to the expansion of the myofiber. And once we reach a critical threshold, call it like a 10% increase in myofiber size, we have the stem cells fusing, starting to tether additional nuclei so that more proteins can be produced and so on and so forth. Right.

A

Okay. Are there any other major candidates? Myostatin I threw out there.

B

Yeah. Okay. So golly, myostatin. John Petrilla, was a PhD student with Marcus and that. That early landmark again, landmark hypertrophy molecular paper by J. Kim and Marcus showing modest low extreme responders to 16 weeks of training in terms of muscle fiber CSA increases. One thing that they showed was that myostatin signaling pre. Post intervention. I believe I'll have to go back and look at this in detail. There were differences between extreme and low responders, which is to say that the myostatin response seemed to be partly diminished in those extreme responders. We have since taken an interest in myostatin. I mean, golly, right? If you overexpress follistatin, which inhibits myostatin in a mouse, or if you knock out myostatin genetically, or if you have this selectively bred dog or Belgian blue cow that has a mutation myostatin and therefore doesn't have a functional myostatin protein, they are jacked. They are completely yoked.

A

If you don't know what we're talking about, go just google the word myostatin and hit images you're gonna see. You mentioned the cows, the bull weevils. There's humans.

B

Yeah, the German, I think, child that. Yeah, we've all lost touch of. There was like a cool pub and

A

then there's actually did a little update on him in one of my shows last year.

B

Is he yoked?

A

I'll save it for the surprise.

B

Okay. All right. All right.

A

So this can happen, as you mentioned, naturally. This is just a lucky part of the job. But you can also induce this.

B

Right?

A

We can cause this.

B

We can gene block this in mice, to be clear. Yeah.

A

In humans.

B

Yeah, humans too. You have CRISPR Cas9.

A

Nonetheless, because myostatin is what we call a negative inhibitor.

B

Yeah, Right. It's a backwards.

A

So it blocks muscle growth. So if you block the blocker, it can take off. So what you're indicating here is if you presumably have a lot of that, then you would be a lower responder to growth. Right.

B

And I think even though you're going to hear me say this, I always couch things on. We. We always need a little bit more data.

A

Yeah.

B

Just to be more certain.

A

Yeah, Right.

B

Because I want to speak truths and I don't want to, you know, spread falsehood based on the John Petrella data as well as just data showing that when you resistance exercise, you are down regulating myostatin at the MRNA level. You are upregulating follistatin, which is the inhibitor of myostatin at both the MRNA and protein level. We have a 2023 paper, Mason Macintosh, showing that the pathway is certainly a conserved response to a bout of training. You are certainly working on that pathway.

A

Yeah, I mean, this is a way of saying this is a natural biological phenomenon not specific to humans. You're going to see this as a general physiology. Why that matters is that gives us more confidence to say it is a thing. This is not a random thing we saw in a human. It is a real biological phenomenon.

B

Across multiple labs, you'll see this. Yes.

A

So I think we've done a pretty good job of that. I could go more, but we'll kind of progress now because just I have a lot more areas to go. It's a fundamental problem. Let's round out this responder versus non responders. You've clearly done a lot of work in this area. We're starting to learn more. We've crossed some things off the list. We've added some things, some things in your data, some things you're really excited about that are coming to interest. But let's go to the implications of this stuff. Is it then fair to say there are a subset of people who just simply cannot grow muscle from strength training in, again, normal humans without clinical medical conditions? If that's the case, elaborate. If that's not the case, elaborate that side as well. So how do we overcome that? What do we do about it if we are a non responder? I just think there's a lot of questions in the implication side, so I'd love to go there.

B

I think the percentage of folks, when you look across different studies, is getting honed in a little bit more now that our lab has done a lot of this work. Abby Mackey's lab, Marcus Baumann obviously has done a lot of this work. Yuha Tianen's done it. Clayton labardi's done it. Like you said, we're a small community, we're all friends. So Stu Phillips. Right. So I think Stu wrote a recent review and I think the indication is this, the, the non responders are pretty low. And same with Abby's data. So that is to say that most people will see at least some growth. But I'm always devil's advocate. Yeah, okay, so they grow, but some people see a lot more growth than those people. Right. So I mean, there are clusters, there's. You call it turtiles, you have low, moderate, high. Like there is that. But that is to say that rarely would you see the person maybe less than 5% of the population, if not even smaller, that will not grow. And oh, by the way, Clayton labardi did this with Marcus and they published this maybe a year ago, showing that the lower responders to lower volume training actually could respond to more training volume. So there's your practical implication. If you're not growing, then you may not be training either correctly or you may not be having enough volume implementation to maximally stimulate hypertrophy, if that makes sense.

A

When you and I were in school, I feel like the number we would always hear all the time is, you know, 30 to 40% of people are going to be low responders. And I remember thinking that sounds crazy. I hear this in the outside world really often. Right. A third of people won't respond. Or like some wild numbers, to be really clear, probably looks more like less than 5%.

B

The people that just show minimal growth.

A

Animal.

B

Yeah, minimal growth.

A

Really, really uncommon.

B

And, and oh, by the way, they get stronger for sure. Because we've done that study. Right. We said we've, we've done the. Okay, this is what happens at the VL level in terms of ultrasound. And now let's look at their 1 RM changes. Well, the low responders got stronger.

A

Yeah.

B

Neurological adaptation, whatever you want to call it. Right.

A

Yeah.

B

There was a, there was a positive response to resistance training there.

A

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B

Sure.

A

First stop on that train to solution is probably then saying maybe this is a volume issue.

B

If you can tolerate it.

A

Right, if we can tolerate it. And then the next stop we'll get there. But with that we've said this a number of times. Would you define what high volume is here? Can you give me some bumpers as to how someone know if they're up high, up low? Like what are these things? I think you guys actually put this out in one of your papers some we did.

B

This is Cody Hahn and he really, you know he's, he's doing great. He's. He's in Alabama running his own company. But he really, I mean opened my eyes to this world. He had trained with Mike Stone at etsu. Masters came in, he was into programming. He taught me his professor. This is what a deload week is. And I'm like this sounds so stupid. Why are we like letting them sort of rest for a week? Sure enough it seems to work in terms at least psyche and you know, we're not getting aches and pains throughout a 12 week intervention. Okay. So Cody comes along long and one of his sort of sub questions to his dissertation is look, if we take these well trained individuals, these are all college age men and we do six weeks of training with them where week one is something that they would do typically in the weight room. Three days per week. You know, three sets per exercise, maybe four sets per exercise every week was an increase in volume. So by mid study it was like 20 sets per week per exercise. By week six it was like 32 sets per week per exercise. Oh by the way back squats, you know, all the way down, all the way up. Think about 32 sets per week of that. 32 sets per week as well of bench press, 32 sets per week of deadlift, 32 sets per week of cable pull down.

A

Very easy program.

B

Awful.

A

So sorry before we go on.

B

Yeah.

A

Intensity was I'm assuming reasonably high. Like you're. They're trying very hard. So it's not like they're lifting light weights.

B

Yeah. So we try to keep it within a 10 RM. Which is to say that the typical hypertrophy programming. 10 reps. Yeah. Right. Plus or minus two reps.

A

Okay.

B

Okay.

A

So they're lifting at. We'll call 80% effort. At least.

B

We had said 60 to 65.

A

Okay. Yeah, yeah, sorry. When I say 80% effort, I don't mean percentage of one or max. I mean reps in reserve or RPE kind of thing. Like, they're trying.

B

Really? Sure, yeah. So the reps and reserve, I would predict after every set. Once. Once you get in last week was like one or two. So.

A

Yeah. So RPE is nine out of ten. Yeah, yeah. This is RPE is. You know, how hard was this?

B

Yeah.

A

Just emotionally. Right. So you're. You're really trying hard.

B

Yeah.

A

For 32 sets per exercise per week.

B

And we did some mood disturbance stuff, some validated questionnaire. I mean, it did. It affected their mood.

A

Yeah.

B

Which is a different. You know, I'm not a psychological person, but I was like, oh, yeah, they're starting to really. This is accumulation that's leading to.

A

And how many weeks was it total?

B

You said it was six. It was six. So we. We accelerated quickly. Yeah, we sell her quick.

A

The ramp.

B

It was. It was certainly the ramp. So. And we had done like 30 people in this study. But long story short, Andy, what we did was we took biopsies at, you know, pre intervention week three and week six, and then we had a deload week where half of the 30 folks did, like 25% volume, and then half of them did nothing.

A

So 25% volume or 25% drop?

B

75 drop in volume.

A

Okay, so they went almost all the floor.

B

Almost on the floor. Just sort of going through the motions. Yep. Yeah, we'll get to that week seven after the deload week later on, if you want. But to summarize, not only did we do biopsies, but we did DEXA and then we did total body water, intracellular water, extracellular water testing using bioelectrical impedance with Jordan Moon, who is one of the, you know, the thought leaders in this field on that. And based on number crunching to Our best guess, 20 sets per week per exercise seems to maximize hypertrophy. I gotta be careful. Without this extraneous increase in extracellular water, which gets into a different story, which is apparently hot topic right now.

A

Yeah.

B

And misrepresentation. Yeah, yeah. So that is to say, like, I. I am of the persuasion that, you know, Brad Schoenfeld would say it only takes six sets per week at minimum, perhaps to Stimulate hypertrophy appreciably. And then I would add to the other end of that and say, yeah, goes from six like he's saying, and work all the way up to 20. If you're a non, or I shouldn't say non. If you're a lower responder, not seeing results and you're at eight sets per week, why don't we try 12? Let's start there.

A

Six is enough to get something there. But that's not necessarily the same thing as saying optimal either.

B

Right?

A

Right.

B

I think optimal would be. Would be. And again, this is probably, probably response heterogeneity here, but I think it's safe to say 20. And you know, our, our Cody study wasn't perfectly designed to answer that because it was all those same participants that continued to scale. We didn't have like parallel groups. One group did 20 per week, one group did 32 per week, if that makes sense. I think Eduardo de Souza, though, at Tampa has some data, and I think they're landing around 20, if I'm not mistaken as well. In terms of optimizing, when we say

A

20, we're talking about number of working sets per week.

B

Yes.

A

Per muscle group.

B

Correct.

A

And do we have an indication about how that is best split up those 20 throughout the week? Can I do all 20 sets one day? Should I do four sets a day for five days? Any thoughts on how we should break that up?

B

I think practically speaking, two to three days per week just makes sense. Would be my thought. Again, Brad, would be a much better

A

question if you just think about this from a human perspective. If you gotta do 10 working sets per muscle because you're trying to split this up into two sessions per week.

B

Right.

A

Starts to get. That's a day.

B

Yeah, that's a day. So if you're optimizing hypertrophy, this goes back to the split routine where you do two upper too lower. You can. The math works out favorably in that regard where you're not spending three hours in the gym.

A

Right?

B

Yeah.

A

Alternatively, 10 working sets per muscle per day is doable.

B

Yeah.

A

Right. If you do three sets of 10 of three exercises, that's not completely off the stratosphere. And I bring that up because every time I mention these types of things, the comment section explodes.

B

Right.

A

Like, well, it's actually not. It is hard, but it's not that crazy of a thing to do. It's probably not that different than what most people are doing. And I'll also remind you, because this will be the next most popular comment not Every rep of every set is taken to maximum failure.

B

Yes.

A

You can't do that.

B

Yes.

A

It's just, you're not going to last to the 20.

B

And that gets into another interesting question, which is training 3 to 4 RIR according to the Zordo scale.

A

Here's my next question.

B

Yeah.

A

You have published on this.

B

Yes.

A

High load versus high volume. What do we know? We can take this from the responder non responder route or some of the other pathways. You guys have taken this. But how should we be appropriately thinking about if. If again, the goal is muscle growth. Yes, we'll get about strength adaptations and other things. Bone, you know, maybe a different time. But how should we, based upon the data you've seen, think about load versus volume?

B

When we talk about load, what, what we compared was the 30%1 RM training where if you go do squats, you know you're doing 40 reps. If you're.

A

Because you're taking them to failure, you're

B

taking them to almost failure. Close to volitional fatigue, as we would say it.

A

So if you're 30% of one rep max, you're going to have to do a lot of repetitions before you get to failure.

B

And they suck.

A

Yeah, they suck after up like 12.

B

Correct?

A

Yeah.

B

Or you can do your twelves. 10 to 12s of 80%. That right there gives you an answer. Yeah. Practically speaking, if you want a hypertrophy, according to our data, according to Stu's data, you can do 30%1 RM training close to failure, or you can do 80% close to failure, whatever you like. If you're Sadistic, you're a 30% person. Right. With the 80% though, the key point here is you tend to get a little bit more strong.

A

Yeah.

B

Right. So that's the added benefit of doing higher loads.

A

Yeah, yeah. So presumably when you're lifting 30% of your max, it's not going to stimulate much strength because you're not challenging overload. And do we have actual cellular data to suggest that that 30% is sufficient to induce mechanical tension?

B

Casey Sexton published his dissertation in our lab showing, you know, we did one acute bout and these were in well trained individuals, free biopsy in the morning. They then did either 30% or 80% squat and leg extensor training. And then we took biopsies six hours post and. Excuse me, three and six hours post. We looked at the global MRNA expression signature in that biopsy. Exactly the same. We looked at the MTORC one signaling from those biopsies. Exactly the same we looked at the myostatin markers in terms of downregulation of the pathway. Exactly the same. So that tells you indirectly that the mechanisms associated with mechanical overload respond in a similar fashion when you do 30% fail training or 80% fail training. In addition to that, Stu Phillips has shown that the muscle protein synthetic response is relatively similar. And what is interesting, Andy, is that when you do the volume load calculations, whether it's 80 fail, 30 fail, it's actually the same volume load when you do the reps multiplied by the weight. There was not a statistical difference there.

A

So do we have then information, understanding of what the tension is directly? Because it's not the androgen receptors, it's not that side. There's something happening at the membrane itself that is physical. This is not an electrical.

B

I think it's a mechanical perturbation.

A

Tell me more about that. And how is that perturbation the same if I'm lifting light versus heavy and taking to fatigue? Because there's. What you're saying here is there's a fatigue component. So something to this, if we want to call it that, what is that? Actual perturbation. As best we know, yeah.

B

So the perturbation, again, it gets into the integrins and some Marty Bopart stuff and others. We think that protein that spans the cell membrane is tugged upon with the matrix of muscle cells. The extracellular matrix is transducing the signal to the interior portion of those integrins, which are these complexes. And then you can have sort of this signaling event leading eventually to MTOR and muscle protein synthesis. Your question's a good one, which is to say, okay, we're doing like time under tension. For instance, it takes a lot longer to do 30 fail training. If we're doing 40, 50 reps per set, why then are we not getting an enhanced response? I think that whether it's 80 fail training or 30 fail training, on the signaling side of things, you have met some sort of minimal threshold at the cellular level, and then it's almost like the all or none. Right. We've turned it on and it's going to do its thing now.

A

So if that is the case, if we'll just call this a physical stretching of the tissue causes some change in the membrane, which then kicks off an entire signaling gene and ribosomal cascade that

B

eventually results in mps. Yeah. Yep.

A

Why couldn't I simply stretch?

B

You can, but the stretch protocols are going to be brutal.

A

Tell me more.

B

You've seen the quail studies.

A

Sure.

B

So my postdoc Mentor Frank Booth. Jim Carson. Now it's stretch under load. There's something again that is magical about stretch much under load that leads to extremely massive hypertrophy. Joey Antonio, one of our common friends, he did this with Bill Gonia. I've never seen this, but that the quail wing model where they put weight on the wing and it stretches the ALD muscle in the back and they will see.

A

Can you just like I want you to draw that point out. Like, what are you specifically saying here is happening?

B

We are taking a muscle and stretching it basically with a weight.

A

Tying a weight on a wing.

B

Yeah. Let me see if I can do this in human terms.

A

To do it in the animal terms is totally fine.

B

Let's get on an incline bench and let's put £120 in each hand and look up at the ceiling in pain for seven days.

A

So you can do this work and you will hypertrophy.

B

I guarantee you 100%. You don't drop the weight and if your muscles don't rupture.

A

That's right. Or tendons or anything along that pathway.

B

There you go.

A

If one could do this, let's just, you know, say we're sit. We're stretching, we're doing a hurdler stretch. We're stretching our hamstrings. If one could hold that with that overload again for many days, if not weeks on time, I think people are going to be very surprised to hear that that will not only result in some muscle growth, but a very large amount.

B

100%. And this is getting into some, some key topics that are at the forefront of physiology that my good friend Troy Hornberger is working on at Wisconsin, which gets into. Not only do we see some radial hypertrophy, but now we're seeing the addition of sarcomeres in series and longitudinal hypertrophy, which is again going to be a very hot topic. And not only that, but okay, how are the sarcomeres increasing in series? Meaning how are we lengthening the myofibril in the cell? How are we making the spaghetti noodle longer? Longer. And Troy is doing exceptional work in that area. So he has a pre print published more or less indicating that the anabolic signaling response to making the spaghetti noodle bigger in diameter. Right. Is canonical MTOR signaling, but longer is not MTOR signaling. It's some other signaling cascade. Right. So more to come there. Troy also has some crazy awesome images showing how we have the addition of sarcomeres with longitudinal hypertrophy, as well as how we have the addition of myofibrils with radial hypertrophy. So if you geek out about our conversation, Andy and I's conversation, follow Troy Hornberger's work. He is doing it. He is driving the field in this area, if that makes sense. So Brad. Brad Schoenfeld. Right. So they did intersect stretching and showing it was like a somewhat pretty decent effect when you did intercept stretching versus not on hypertrophy outcomes using the ultrasound.

A

This is human. So this is you lift some weights and when you're resting, you sit down and stretch the muscle.

B

Yes, now and then. Danny Plotkin, one of my students, and Dakota T. Did they. They've told me, and I need to do a better job of following up on this. But for instance, like, imagine an immobilization boot, but that puts you into dorsiflexion, and that apparently can cause some hypertrophy as well. So, yeah, stretching is a component. And again, I think it operates through the tension, the tugging extracellular matrix all the way to anabolic signaling. That can explain some of this stuff.

A

All right, you got me fired up. There's three ways I want to go with this. I'm going to probably forget them. But the first one that I cannot pass up this opportunity to get into. I don't know if you know this about me, but I am a day one die hard hyperplasia guy.

B

Oh, yes. Here we go, dude.

A

Okay, I'll frame it a little bit. You've been talking a lot and you're using this phrases like radial increase.

B

Yeah.

A

This is the spaghetti noodle getting thicker.

B

Yes.

A

Right.

B

To be clear. Yeah.

A

And you've used CSA a lot.

B

Yep.

A

Cross sectional area. Same thing.

B

Same thing. Spaghetti noodle is getting thicker.

A

If it's a circle, the circle is larger.

B

Yes. Right.

A

And that is functionally how a. You know, again, your, Your, your shoulder muscle is bigger is because those got thicker.

B

Radial hypertrophy is the bodybuilding hypertrophy that we classically think of.

A

Amazing. Yeah. Where we have some controversy. I'll say. And when you brought up Joey, you made me think of. This is the idea of hyperplasia, and that is the fact that you would not necessarily make the spaghetti wider, though that could happen as well. But that you would add spaghetti noodles. This is. You would add additional new muscle fibers. For the last 50 years, we've been told that that does not exist in humans in response to exercise. We have certainly seen it in humans in other models. Aging. Or I guess the opposite with aging.

B

Yeah. The loss of mild fibers.

A

Yeah. We know what happens when you're A young baby, an infant and stuff like that. The question is, in an adult human, in response to exercise, we've also seen excellent evidence, well, good evidence, I should say, of it happening with exogenous testosterone or some other. Some evidence. Excellent. Was too strong.

B

Well, no, that's going to be the paper that I end up referencing. So keep going. Ask the question and then we're going to go there. Yeah.

A

So now the thing I've been burning on is I'm waiting for us to be able to officially identifying. And Kevin and I have always. A couple of my other muscle physiology friends, Kevin and Jimmy, we've always talked about. Oh, yeah, you know Kevin.

B

I know Kevin. Yep.

A

Like, I'm just like, he's always like sending me stuff. I'm like, look, more evidence. I'm like, come on, man. Like, give me the paper that, like, does it so break my heart or I'm not gonna. Fill me with joy. Where do we really stand? If you had to guess, does hyperplasia happen in humans? In a normal exercise response, yes. Oh, my God.

B

Now keep going. I am going to. And, and by the way, Kevin Murak would know more about this because he worked with the synergist ablation model. There is a. There is a backstory, but instead of like, there could be public banter, there could be Instagram stuff on this or X or whatever. But there is actually a pretty considerable debate with our small group of friends. Yeah, yeah. So Troy Hornberger and Stu Phillips, they're no go's.

A

No, I know.

B

No, no hyperplasia. But then Kevin sue, when Troy says

A

no, I get scared. No offense, Stu, but when Stu says no, I'm like, I don't. Whatever, I don't care.

B

Stu would admit I'm saying no. Because Troy said no.

A

Yeah, 100%. When Troy says no, I'm like someone who's like, Kevin, tell Troy's wrong.

B

I think the famous interchange here that really got a lot of us thinking about this was Kevin had put out a paper, a review article, sort of summarizing like, what happens with synergist ablation. And oh, by the way, like, we see a number, the number of muscle cells in this massively hypertrophied rodent plantaris. When you remove a portion of the gastroc, the plantaris takes over in terms of ambulation and there is like almost a doubling of the mass of the plantaris. Not only do we see an increase in the thickness of the spaghetti noodles, the cells, but we see more spaghetti noodles. Thereby fiber splitting is responsible for Some of this massive hypertrophy. Well, Troy put a pretty big, soggy, wet blanket on that because he and Kent Jorgensen, awesome student of Troy's, put out this rebuttal. And they had this mathematical model saying, look, you're looking at a muscle that has a penation angle. You have to think more in terms of three dimension, right? When you have massive hypertrophy, that is going to force changes in penation angle. And when you do that and you look at the number of muscle fibers in cross section, you're going to change the number just by mathematics. Changes in angle, the nation angle. He mapped it all out. He did some sohcahtoa, you know, and sure enough, it seemed to check out, at least according to a lot of independent reports. Some saying, okay, when you do synergist ablation, this is the percent change in venation angle. Then when you look at Kevin's work, this is the number of fibers that he observed with syndrome sublation. And so if you sort of do all of this mathematical stuff together, it would explain almost all of the increase in mild fiber number. However, however, however, here's the deal, man. Time and time again, if you take a biopsy from somebody that's well trained, 10 years lifting weights, then you take somebody off the street that doesn't lift weights, okay? The person that lift weights has, we'll call it 30% larger muscle, VL muscle. And the fiber size differences between those two individuals does not explain why that muscle is larger. Therefore, there seems to be more muscle fibers in the trained person time and time again. In addition to that, the paper from, I think it's from Norway. Again, I apologize. Lost the citation in my head. But you see some interesting things with large muscle fibers. You see fissures, you see centrally located nuclei. We had talked about, hey, look, man, this spaghetti noodle sharpie marker, all those little dots, those are myonuclei on the periphery. This group, I think it was in like the mid 2000s, had histological evidence showing that as myofiber size increased and these power lifters who were on steroids limitation, those large fibers started having the invagination of the cell membrane, looking like the myofiber was splitting into two daughter cells. And to me, it looked convincing enough. Then you look at Joey's work with the LD model quell, and he shows he's plucked out myofibers that are branching, that seem to be splitting. We cannot dismiss this and say it doesn't occur. This is all evidence.

A

Right?

B

Right. And so we have to be fair, on both sides of the coin, I've said, look, I think a lot of stuff doesn't matter appreciably, but it may play a small portion of the variance. And on the other side of the coin, if we have evidence across independent laboratories, different epochs, right? Going in the 70s and Kevin's work with John McCarthy and Charlotte Peterson and the Norway study in the early 2000s, like, we need to look at this and we need to consider it when we do, you know, future work. Right. More. More innovative methods, histologically, et cetera. But I don't want to dismiss it yet.

A

I just think that. I think that there's something there. I don't think it's a lot. It's not explaining half of muscle growth or anything close. But I think it exists. So I feel very validated that you're supporting me in this.

B

I do, and I support you firmly. And here's the deal, right? When you look at that Norwegian paper, I think it was controls and it was also these bodybuilders, the number of. We'll say the number of splitting fibers per 100 fibers in these individuals, right? It was perhaps 1% in the controls and like 2 or 3%. And so people would say, oh, that's a rounding error, or, sorry, that's a, that's a technique error, or that's. That could be, you know, variance, da, da, da, da, da, da. No, but if you say, hey, look, this is a snapshot and this is a dynamic process, we're just getting a snapshot biopsy picture. But if we consider this dynamic, 2% over years, right? If the number of fibers that are splitting at any given time, or 2%, well over years, compounding interest is a powerful thing.

A

Thank you for letting me run that. Yes, I appreciate it. Makes me feel better spiritually. I want to come back to the stretching thing, okay. Because this is very counterintuitive and interesting and it has some implications that I know you guys are currently working on in your lab.

B

Yes.

A

So we want to get into this. We've established the fact that if you literally physically stretch tissue, muscle, skeletal muscle specifically, that you will see muscle growth. This, until Brad's paper, didn't really think this had any human practical implications because you can't.

B

Again, who's going to sit there looking at the ceiling with 120, you know,

A

even if you stretch for an hour a day, this is not going to do it.

B

Right.

A

You need weeks. And like traditional models with this, by the way, when we do this in cell Culture, it would be things like you tie tissue, a muscle fiber to something, hang a weight on it and come back in a month. And, you know, like, these are the types of things that we're talking about. But that said, what does this tell us about things like range of motion? With our exercise selection, is it fair to make the stretch then to say, hey, maybe larger ranges of motion in our exercise technique, or selecting exercises that allow us to go through larger range of motion, should that then result in more growth than partial range of motion?

B

Yeah. Okay, so Brad has done a good bit. I'm familiar with some of the stuff indicating that partial squats, for instance, seem to be just as effective as deeper squats, according to the meta. And I also know that he's done lengthened partial work, which is to say that imagine yourself going to the gym and oh, by the way, this is a study we're doing. So Daniel Plotkin. All of the glory to Daniel. He wanted to pursue this pretty much from day one when he came from Brad's lab after his masters, into my Lab for his PhD. He has taught me a ton on lengthened partials. Apparently there's a lot of good evidence at the ultrasound level that lengthened partials, which is to say you go to the gym, you get in the leg press, the hip sled, all that weight you know, loaded on, you sort of unrack it, and then you start working in this range of motion, knees to chin. And that's the lengthened partial for the quadriceps.

A

This is the opposite of how most people think about it. In the traditional way, people would do a shorter range of motion. It'd be the other end. So maybe with the leg press, you let it come down halfway.

B

Yeah.

A

So, and then go back.

B

Yeah.

A

What you're saying is the opposite. You let it come all the way down. So your knees are on your chin and you only extend halfway.

B

Yes.

A

Instead of full lockout, your knees not even stopping lockout, you're not even going, we'll call it roughly halfway. So you go up a little bit and then come back down.

B

Correct.

A

Which means you're spending most of the time in a really deep stretch.

B

Deep stretch. And this sort of integrates the notion of, okay, if we can't sit in the gym, look at the ceiling. Hold 120 pound dumbbells for seven days straight. What if we adapt the training over 10 weeks? Right. Where all of our movements are lengthened partials. And again, this is Danny Plotkin. I said initially and then I thought about it and he showed me some literature that he had dug up on the topic, and I thought, oh, this is cool. This is actually kind of interesting because, you know, the time under tension. Yes. With one bout isn't that much, but then you take this out to 8 weeks, 16 weeks a year. Train like that all the time. Can you see enhanced hypertrophy? So his dissertation right now we're currently analyzing. And what we did was we had within subject design, which is a great way to run studies for you young folks out there that are in, you know, doing dissertation projects or whatever. One leg of the participants did length and partial leg press, and then leg extensor. The other leg did full range of motion before and after the intervention, we did MRI scans, and we did it actually from knee all the way up to the hip. And so we're going to get across the entire quadricep regional hypertrophy differences, which I think is critical. We also did mid thigh muscle biopsies. Obviously, would have been cool to do, you know, five biopsies at, you know, different sites. Couldn't do that. But we're analyzing the main players. Satellite cells, ribosomes, fiber, csa, myonuclear number. Okay. And then we're gonna look at mri. Too early to tell as of yet. Except I will say this at least numerically, not statistically, but ribosome content increased in the lengthened partial leg, which I think is promising. Can't quote you on P value, effect size, stuff like that. Got to go look at the satellite cell stuff. And we're still doing the myo vision, fiber analysis, monuclear numbers, stuff like that. But, yeah, I guess. Stay tuned. I think it's a. I think it's an interesting way to train if you do want to maximize hypertrophy. Because aside from what we're doing. So Danny is going to be publishing the most sort of mechanistic study on the topic. But other laboratories, including some Japanese papers that he had made me aware of, and then I think Brad Schoenfeld just published something in 25, showed whether it's triceps or biceps, that lengthened partials seem to confer some added benefit to hypertrophy.

A

Yeah.

B

Which then you say, okay, well, if I'm a. If I want a hypertrophy, man, when I was coming up, I was like, I want to look like Ronnie Coleman. Right. And if I wasn't growing, well, then up the volume and maybe integrate some lengthened partial training into your program and see what happens.

A

You mentioned the fact that you can wear a boot and you put it in flexion. So dorsiflexion, plantar flexion is a confusing term, but this makes your toe point to your face. Right. Imagine if any of you have ever had plantar fasciitis and they put you in like a little boot and then it constantly stretches you.

B

Stretches, yeah.

A

So we've used that in that model. And I won't go into if that's a good idea or not for that injury, but those things have been around for a long time. But what you're talking about, though, is using that boot, actually, and then seeing

B

hypertrophy of the plantar flexors. So think about gastrocnemus and things like that.

A

Your calf muscles, right?

B

Yeah. Yeah.

A

So then here's my question. If it works, can I wear that boot for, I assume, several weeks before that effect takes place? Like it's not going to happen in a couple of days?

B

Sure.

A

Is this something we should be thinking about for unloading individuals? So when someone gets a major surgery or an injury and a tissue, you can't lift weights? Of course, space flight is the one that we will always use.

B

Yes.

A

Or this model. And you and I could probably share stories about some of the funny suits that have been tried to put on astronauts in space to alleviate this. But we'll stick to the planet.

B

Yeah.

A

Is this a reasonable thing for someone to think about if they're in one of those situations, either short term or kind of long term from an injury or other unloading situation? Is that a reasonable thought process?

B

I think it is. We're getting outside my comfort zone because this is like pt, but we did a disused study, by the way, which we can sort of.

A

No. Yeah, tell me.

B

I can like strategically left turn on this.

A

Of course.

B

What I do know is that the angle of fixing a brace or a cast is at play. And it's because of that reason, if they're trying to preserve joint function after surgery, they don't want to put you in this contrived angle. And if they do, you know that that may influence outcomes afterwards. So I think. I think function is. Is the main concern rather than hypertrophy. Although hypertrophy plays into function.

A

I mean, let's just go into the. The broader question on this topic, which is just simply disuse models.

B

Yes. So you're going to geek out on this.

A

Yeah. Cool.

B

Max. Michelle. He's postdocing with Marcus, just finished his dissertation. And his dissertation was this. Andy. We had people with resistance training history, men and women. It was 11 of them. Come to the lab. We had controls that had no training history. Coming to the lab, we put a knee brace on them for two weeks and then after that two week knee brace took it off and recovery resistance trained them for eight weeks. Now, strategically, biopsies, walking in the door right after the knee brace and then right after the eight weeks of training. And what Max wanted to answer was this. Does training history play a significant role in the retraining response? Well, does it, does it mitigate the atrophy? Right. And then does it give you a conferred advantage when you're growing the muscle after the atrophy? This was in young healthies. It was non complicated disuse, meaning there wasn't like trauma to the tissue. Putting a brace on them, brace on them. Limitations. Fascinating results that bucked all kinds of sort of preconceived notions. The rate of atrophy, the rate of VL atrophy was the same whether you had prior training or not. But the key point there is your, your tissue bank was larger. So even though folks lost the same relative amount of muscle mass being either trained or untrained. Right. The absolute levels are still higher and those that had training experience.

A

So we'll pause you right there. This implication would suggest if one were to go into a surgery or something like that, whether you started trained or started untrained, how much muscle you lose as a result of this. In your case, two weeks of being in a brace.

B

Yep.

A

It didn't matter your previous training status.

B

Yep.

A

But if you start off with a lot more muscle and you lose, we'll call it 10%, then you're going to end up with still a lot of muscle. If you don't have much muscle coming in and you lose 10%, you don't have much total muscle left.

B

That is correct.

A

Okay.

B

Which I think strategically works. Back to your original question. Rather than thinking about like bracing angles, let's just think about, okay, let's condition ourselves. So in the event that we have an injury, we're going to be sort of primed to deal with it.

A

I'll tell you a little secret. Behind the scenes, when we have had athletes, and I had one very high profile one this year go through an incredibly traumatic injury and he damn near blew up the Internet because people were gonna assume he was gonna be out for like 10 to 11 months. And he almost made it back to play to the end of the season. I'll stop the story there. But what we always do prior to any surgery is have them train as hard as humanly Possible in every other area, affected area that we can, and even in that area, if we can as much for this exact reason and plenty others. But that is a really, really, really good way to come back from surgery much faster is getting as much muscle as you possibly can prior to going into it for not the reasons people think, but for this included. So, yeah, it works.

B

It does. And I think while you were in the brace, Matt Stock at UCF, he had done some work with one of his PhD students where they did action imagery, imagining the affected limb contracting, things like that. That can add a little bit of at least function. In addition to that, Darren Kandao creatine during a bracing. Arnie Ferrando high dose essential amino acids. So let's put all these in the bucket. Of course, say this is how we optimize. We do all that stuff. Yeah, exactly.

A

Because that's the way to go.

B

Yeah, exactly. So, Max, awesome study. He is now going to try to make sort of a career out of disuse atrophy. Yeah, he did some really cool stuff showing that certain proteins, these are like nuclear proteins, they seem to be main players in terms of mechanisms that are involved with disuse atrophy. But long story short, to the point of like priming the body, resistance training. Right. Is, is the answer in terms of maintaining the muscle bank because yes, you will lose muscle, but you will, you will certainly have more muscle after the brace compared to someone who didn't train. Now, the retraining, the recovery resistance training, this is where it gets a little bit dicey. Relative meaning body mass adjusted muscle mass increases with eight weeks of recovery. Resistance training was actually more in those that didn't have any prior training experience,

A

more in those that did not.

B

Yes. So newbie gains, newbie gains outpaced the recovery gains with people that had prior training experience, which I think is good news. Yeah, ish. Which is to say that, look, if you are like training for years and years and years, this works towards sort of that ceiling effect of adaptation. You are going to have newbie gains which are almost like this exponential phase of hypertrophy and strength. And then we hit this putative ceiling. If we then go disuse, we go here and then if we retrain, we get close to ceiling again.

A

Yeah, Right.

B

If you're somebody that's a newbie and you have a bracing event and you have muscle atrophy, the good heart warming story is when you're done resistance train and you're still going to have gains and you're going to set yourself up for a better outcome in the long run. Right.

A

What's interesting about this, and if I was a reviewer on that paper, this is what I would ask you. Your two week bracing model is a very short term. Yes, but it's full bracing. How much does that differ from a more traditional D training, which is. I stopped exercising for six weeks.

B

Adam Sharples.

A

Right. So I wonder if this is just a classic. You just didn't do long enough. And so they, they maybe got like a little bit of the training group. Right. Of course. Got. They didn't really. They kind of just recovered a little bit. And then

B

you get what I'm sort of. I do. Yeah. And I think like Ricky Yoga Sawara, they did that. Him and Jeremy Lineick, he did like that six month bench press training. Could. Could you do three weeks on, one week off?

A

Yeah.

B

Or maybe even two weeks off versus continuous. It's like. Yeah, you can take like one to two weeks off over six months. It really doesn't. Yeah, often. Exactly. Yeah. Good question.

A

This entire detrain, retrain model stuff and muscle memory, if you are talking to a neuroscientist, muscle memory is a motor control thing.

B

Yeah.

A

Right. I remember how to ride my bike, so on and so forth. When you talk to muscle physiologists, that's not muscle memory from our perspective. So maybe just start us right there. How do we think about us and our small group of dorky friends, how do we think about muscle memory? What is it? And. And what do we know about that in. In all levels, actually, because this is a very interesting topic.

B

It is, it is. So, yeah, to your point, when we think about muscle memory, we think about the spaghetti noodles. We don't think about the alpha motor neuron that innervates it for anything upstream.

A

Yeah.

B

Right. And. But there is evidence of muscle memory at that level. Of course, when you look at spaghetti noodles, which is to say, hey look, we resistance train, we take these spaghetti noodles and we make them larger. We put more dots with the sharpie marker. Those would be monuclei. If you then stop training for six months a year, those spaghetti noodles will sort of retract and go back to their original size repeatedly. Right. You won't see the loss of sharpie marks. Those myonuclei that were glommed on typically like to hang around. Now, I know Kevin and Corey Dungan, they have like this power model. There's a little bit of rodent evidence suggests maybe that's not the case. But by and large, most people would Agree on this. Okay. So myonuclear permanence is one of those theories.

A

This is the analogy I gave everyone earlier was the store manager. So you opened up a bunch of new shops. You hired to make sure you have one manager per shop. And now you like kind of start closing down stores. But you keep the managers.

B

Yeah. You don't take them in the back

A

and you know, so the store is not there. And this theoretically then should allow you to reopen that store.

B

Yeah.

A

Because you already have a manager ready to go 100.

B

Good analogy. Great analogy. Yeah.

A

Okay, so keep going with.

B

So there's that aspect of it is that we have monuclear permanence. We keep those, retain those, so that when we retrain they are reinvigored. Right. So this manager that's hanging out in store A because store B was closed. Well, now we're opening store C. He's going to store C and he's. All the knowledge he had retained from running store B is, is kicking back up and you know, business as usual. That's kind of what we think about

A

in terms of do we have a sense of how long that permanence stays for? Is that 6 years, 12 years, 60 years.

B

So if anybody has this, it'd be Lexverdick. I think they did. Sort of population wise, looking at across the age spectrum. I'd have to go look in the literature, to be quite honest with you.

A

It's certainly dependent upon how long stimulus. Exactly.

B

There's a lot of caveat with that being stated though. I would be surprised if you don't retain those. If you train consistently, be it on and off. If you don't retain those until sort of, we'll call it age 50 and beyond. Boy, I'm shooting from the hip.

A

Yeah, yeah, sure, sure.

B

And then at that point now there's debate with age related muscle atrophy. What are the. Whether you know, the drivers of. Of why the muscle tissue can't grow in response to training or taking a lot of protein in. This would be the classical term of anabolic resistance. Still an active sort of area of research right now. But with that being stated, I think if you're young, you're healthy, the good example would be trained from the age of 8 until high, you know, senior year of high school, intense travel ball did the conditioning, sort of partied around in college. But then you know, junior year re engages like those myonuclei gains are not going away in my opinion. Yeah, we have zero data to support that.

A

But well, you're not stretching that far though from what I think most people that do this research would say. Yeah, I don't think you'd get a lot of pushback. Yeah, that's fair on that. It certainly is a situation where that retention is not going to go away in two weeks.

B

Yeah.

A

So if we look at your model, even with a full disuse, I would struggle to think that you're going to have back to baseline accretion. Like they're just not going to have that.

B

And we measured that in our study and we did not see a retraction in the number of mononuclei per fiber in the trained group. So that speaks to your point.

A

So that is two weeks, but it's

B

full, it's almost full. Yes, full lockdown.

A

So if you take this into a quadricep muscle or group of muscles rather that are maybe you're not lifting weights, but you're still walking and standing and squatting and moving around, there's enough stimulus there to probably keep those around for many months to years. I would think after a number of decades you've probably seen some return to baseline. But where that line is, I don't know. Maybe again Kevin might have a better opinion on this. But okay, so we know that point is you can take some, some amount of time off and then when you get back to training, what happens?

B

So Adam Sharples again, go read his papers because his initial work here would indicate that, look, if you train for a period of seven weeks, resistance train, you see hypertrophy, you then take a seven week period off and then you retrain for seven weeks. You, you not only will get to that initial hypertrophy during the first block pretty rapidly, but you actually exceed that level. Right. So the conferred advantage aspect there is that be it monuclear number increases in retention, be it three dimensional changes in the chromatin within the nuclei, which leads to this sort of modeling of genetic material so that when you retrain you can express those exercise responsive genes very efficiently. That's what we're talking about. It also hinges on the mononuclei, the number and then the dynamics in terms of how your genes are expressed is what we talk about when we talk about muscle memory.

A

So we have an ability to gain some muscle initially.

B

Yeah.

A

Lose it.

B

Yes.

A

But we conserve that ability to gain muscle so that the second time we go after it, it's actually easier.

B

Yes.

A

In fact there might even be an advantage where you can go past. Yes. Where you were is there. And there genuinely might not be but is there anything that Adam or anyone else in this field would say we can then take that to enhance our training programming strategies. What could we conclude at this point from that information?

B

There is a one off paper. It was in older participants and what they did was they trained them for, we'll call it a typical 12 week. It could have been actually longer. It may have been like a six month training period. It was either 80%, you know, one arm training generally speaking, or it was something to the tune of like 55%. One arm training, six months of that. Okay. Clearly both groups are gaining strength. I think the 80% is probably getting a little bit stronger, et cetera. Then they had this like one year hiatus and then they tested at the end. Guess who was stronger about baseline after the one year hiatus it was the high load group.

A

Yeah, right.

B

Which is remarkable. Now the hypertrophy, they actually didn't do any imaging. I think it was like all circumference, tape measure stuff. So they didn't have sophisticated methods. But I looked at that paper thinking wow, that's crazy. Which speaks to the, the sort of, the neuromuscular neural aspects of that can be at play as well with you know, there's some sort of retention of motor drive, central motor drive to the muscle or whatever. And that seems to be manifested better with higher load training, if that makes sense.

A

Yeah, no, it totally does.

B

Yeah.

A

What about for aging muscle? Yeah, Anything we can learn from this understanding of D train retrain for folks? Does the story change? Do we have any information that hey, maybe that is true in your college age but not true of our 50 plus year olds? Do we have any data on that?

B

So to the best of my knowledge there have been more sort of sub chronic studies looking at the effects of proteostasis and muscle protein synthesis decrements therein. With younger and older pops we put Matt and I, with a colleague that Matt had in Orlando, we actually put in an NIH proposal. We thought we're to going get funded.

A

Didn't boohoo story of everyone, you know.

B

But we wanted to do the study that we did. But we wanted to do a younger and older pop with the notion that the retrain and the older pop would probably be impaired because generally speaking the adaptability response in somebody average age of being 55 in our hands is not as good. When you start talking above the age of 80 like some of the Scott Trappy stuff, you work with Scott, there seems to be strength adaptation, but debatable as to whether or not you have Hypertrophy with resistance training. Look at single fiber level stuff, right?

A

There's some insights I can share with you offline about that. So.

B

Okay, all right, all good. But there is a general anabolic resistance. People ask what is the magical age? So recent Stanford paper, I think, Michael Snyder's group, and they looked across the gut microbiome, the pnbcs in the blood, the blood markers, and they showed that when you look at all this, these multi omics, so how genes are expressed in tissue, how the gut microbiome is altered, what happens to these proteins in the blood that are linked to this SASP phenotype, et cetera, et cetera. Just the whole body. We're getting this molecular snapshot. We have two critical ages at which things start to sort of turn on us. One is the age of bingo, 44, which is me. The other is like at the age of 60. I think the age of 60 is really that inflection point at which, okay, now we're going to have a diminished response to training, be it endurance, resistance, whatever, because that is a primary effect of aging, especially at the muscle. I think we just have something that triggers, be it three dimensional changes in chromatin, be it ribosome function, be it the sensing of nutrients and the proteins that were responsible for that. But some switch all of a sudden goes awry, right? And that's a scary thought. But long story short, the good news is if you do train, even at that age, you still will see adaptation, you will get stronger and you will hypertrophy in our hands compared to college age cohort. The gain in muscle mass is about 50% which you would see as an older individual.

A

You've published some stuff on this and I actually just read a paper probably two weeks ago that came out postmenopausal women. And why I think this is of interest to what you just said is I don't know why, but there's a narrative that because of the known hormonal changes that happen post menopause, that then therefore is a reduced, blunted or completely ablated ability to grow muscle. When in fact, I don't know where you stand on this, but my indication, my reading of the literature is that is as dead wrong as one could be on that topic. So first of all, do you agree, disagree on the simple question of women have the ability to grow muscle post menopause?

B

Yes.

A

At the same rate as they were pre menopause. Okay, tell me more.

B

Yeah, and that's because with the current analysis we're doing, we're taking a molecular approach, albeit it was a 12 week study, but we've trained a lot of older and younger individuals and the, the summary is we just don't. With our two day per week training program, which typically tries to target around 12 to 16 sets per exerc.

A

It's a very reasonable program for a normal human being.

B

Pop. Yeah, right. This is something that you would program as a Gold's Gym personal trainer, you name it. Right. Quality. Yeah. Yeah. So long story short, we just don't see the same magnitude of hypertrophy when we look at our more nuanced methods of ultrasound or changes in dexalane mass, et cetera.

A

Okay.

B

In our hands.

A

Yeah. Tell me more. So what you're saying I'm an assumption is when you get a better view of the muscle, then you actually start to see nuance.

B

There's nuance there, but that's for men and women alike.

A

Okay.

B

So again, whether you're a post menopausal or you're a male, that's starting to really feel the andropause of effects and test is going down. Your, your gains are about 50%. That which would be seen in the college age cohort.

A

Assuming the same training volume and the same relative. Yeah, relative corrected for as many things as reasonable. Yeah, one can be correct.

B

Yes.

A

But that happens independent of hormonal changes.

B

Yes.

A

In the sense that we don't think

B

that it's the testosterone and we don't think that it's the estrogen that's the primary driver there. We think that again.

A

And it's not the receptors either.

B

I don't think so.

A

It could be the ribosomal stuff, it

B

could be the ribosomal stuff, it could be things that we're currently unaware of. And to give you a spoiler alert on this topic, okay, here's where I'm going. Our study, we have an older cohort, we have a younger cohort. This is not published yet. So Dustin Lewis is doing this analysis right now. But what we're seeing is with 12 weeks of training, be it the imaging of the VL with an ultrasound, be it DEXA, lean body mass changes, we have a 50% reduction in hypertrophy. There's still hypertrophy, but a 50% reduction in the older group. Okay.

A

It's attenuated.

B

Yeah, attenuated hypertrophy. We took pre and post biopsies in all these individuals and we ran global proteomics, which in my opinion is what you ought to do, especially with chronic training paradigms. When you get into Omics, this is a whole different episode. You can do genomics, you can do microwave, you can do deep sequencing, microarrays, et cetera. You do transcriptomics, which is all of the MRNA's in a tissue. You can do proteomics, which is all the proteins in a tissue.

A

Ultimately, genomics is all the genes.

B

Yeah, yeah, yeah.

A

Metabolomics and all of the omics.

B

Exactly. A lot of people have done transcriptomics because they've been intrigued with the notion that when we have mechanical tension with resistance training, we see a huge sledgehammer effect on the gene changes at the MRNA level. And so that's just naturally where the field has gravitated. Hardly anyone was doing proteomic work. And so I really wanted to sort of pound that drum hard because I said, well, this is a knowledge gap opportunity. And, oh, by the way, we have a really nice collaborator on campus that does this work and she's excited that we give her human muscle. What we are seeing, Andy, is this the. The young cohort, on average. Apologies if I misquote this when you see the publication, but the muscle proteome is changing robustly in the young cohort, which coincides with the enhanced hypertrophy.

A

This is more turnover, right? This is. Yep.

B

Turnover proteins, expression of. Of new MRNA's, where you have the. The production of new proteins at a higher level that weren't there prior to training. Okay. That coincidence.

A

You're getting more people in the restaurant and getting them out. Yeah, Faster. Right. Like there's a much bigger turnover of positive, negative. The whole thing. The ship is just moving really quickly.

B

Yes. And, oh, by the way, when you run that, that. That protein list of what changed in the young people, a lot of those proteins are related to proteostasis, which. That works to that. That mechanism that you just spoke of, there is a lack of proteom plasticity in older people, which coincided with the diminished hypertrophy. So that is going to be probably, if not the title of the paper, we need to pay attention to this. We're not seeing enzymatic changes with resistance training. We're not seeing much by way of proteins that are ribosomal proteins, for instance, with resistance training. Stuff that we're seeing in the younger people, we're not seeing in the older people. Why is that? Don't know. Except to say perhaps that there's altered proteostatic mechanisms which let some proteins hang around. They could be damaged in an older person. They're not getting cleared through proteolytic mechanisms. You have ribosome Deficiencies which don't produce the new proteins needed for growth, et cetera. All this could be happening with aging, but not in the younger college age.

A

In this instance, you're Defining older as 55 plus 55 was the average age.

B

Okay. But it was between the ages of. We'll call it like 50 to 70, you know, lower 70s.

A

Well, this is really interesting. I don't know if folks listening will get the full appreciation of what you just said, but that, that's really interesting because traditionally, when we've looked at the molecular aspect of muscle growth in humans, skeletal muscle, we've hedged towards muscle protein synthesis.

B

Yes.

A

This is this direct marker right now. How much protein are you building? It's again, skipping some steps there. What you're looking at, though, is miles above that, which is all the proteins in the entire thing. How are they working? And I say that as a distinction because some people have done this. But I don't know, 90 plus percent of the papers that have ever been done on protein synthesis don't account for protein breakdown. It's really hard to measure. It's a giant pain. And so we kind of just say, well, how much was synthesized. And the assumption is then if you built more, you have more. Of course, the down part of that assumption is you're not accounting for how many you broke down, which you have to turn over. Right. So you have turnover, meaning you kind of have to like some damage stuff, get that cleared out. I'll use the restaurant analogy. I don't know how long this is going to last or how well it's going to work, but you have enough people coming in your restaurants. Some tables will break and you want a nice restaurant in case you got to clean out the garbage. If all you're ever looking at is how many new things you're buying, but you're not accounting for how many things you're taking out. You don't actually know the net. Right. This net protein balance is how we described it. What you're talking about is all of that combined with everything else in the equation, and you're simply saying we have just way more activity. We have the entire protein side of the equation is moving. So this encompasses so many layers besides just protein growth.

B

Yes.

A

Protein addition.

B

Yes.

A

Which is very compelling.

B

Can I take your analogy? I think it was a great one. I'm just going to, like, add on to it.

A

Okay.

B

This is what we do in science. Like, oh, Andy had a great paper.

A

I'm going to make analogies, and we make acronyms. We're very good at acronyms, very good at acronyms.

B

So if you had a restaurant and you said I want to grow the restaurant. Right. I want to become a competitor with these high end restaurants. Right. So what's the goal there? Getting clients in and you got to get them out. If they just came loitered, you're not making money, you're not growing. All right, so the turnover of clientele would be sort of what we're talking about when you talk about synthesis and when you talk about breakdown. All right. What we are doing with proteomics is saying what, like who are all the clients in there? What are they buying? High ticket items. Right. Low ticket items. Right. How do they function? How can we refine the blueprint of our restaurant to better serve a class?

A

How did they find us?

B

That's proteolytics, looking at all these different proteins. Right. And then you take advanced bioinformatics and say, oh wow, this bucket of proteins, these bucket of clients here, they, they, they themselves work for a company. This is important for our business to grow, we need to serve them better. That's what we're doing with bioinformatics. In these protein lists, saying in the, in the young participants we're seeing a lot of proteins related to turning over clients. Like they are totally populating the list of what adapted to training. Whereas you did not see that in the older population. Right. Along with that there's like other just list of things that we can predict are going on because of these protein changes in the younger individuals. And we just saw the lack of proteome alterations and therefore no predicted pathways that, that are changing in the older population. Right.

A

So that's really compelling stuff. It does highlight something that we talked about. Geez. A couple of hours ago.

B

Yeah.

A

At this point, which is the magic here is still in the muscle.

B

Yes.

A

It's not at this point, and I will acknowledge we are muscle physiologists so we're going to be quite biased on this approach.

B

That's fair.

A

Fair distinction. Yeah. But it's not necessarily all driven by something outside hormones endocrine system. Not to say that there's zero, but it looks like if there is a reduction in ability to grow muscle post menopause or post age andropause for the male side of the equation, it's probably something happening inside the muscle or a collection of, collection of things that are, that are mainly driving it. Is that a fair.

B

I think that's a fair assessment. Yes. This.

A

So if we're going to Solve this problem. If we're going to improve it, we need to continue to do work in there to figure out what's going on.

B

Agreed.

A

One more big topic. For as long as I know exercise physiology programs have been around, we've all been indoctrinated to our classic interference.

B

Ah, yes, right. Yes.

A

Bob Hickman stuff. And you probably share the paper in all your classes.

B

And yes, the classical week by week changes with the concurrent versus the strength only endurance.

A

So the interference effect is effectively the idea that endurance exercise, aerobic exercise, potentially interferes with the ability to grow muscle.

B

Yeah.

A

However, strength training, muscle hypertrophy does not interfere with the ability to enhance aerobic capacity. So that paper, I think that first paper was 1980.

B

It was. Yeah, yeah, yeah.

A

And then it went about, I don't know, maybe helped me here 20 years or so before we started to get the molecular mechanisms.

B

Yes.

A

And this launched what I still see all the time of this idea that ampk. Right. Is somehow turned off when MTOR is turned on, which is the prevailing way. You've mentioned it as mtorque. That's the more appropriate way. But in the popular sphere, you might hear this as mtor.

B

Mtor, sure.

A

Right. Yeah. But the basic idea is the same as it was in 1980. If you do strength training, you activate. In fact, we mentioned the primary wave phosphorylation is like one of the big things. But you turn on mtor.

B

Yeah.

A

MTOR then turns on muscle growth. Okay, I'm cutting two hours of conversation.

B

That's fair.

A

Down. If you do endurance exercise, it activates something else called AMPK, which then turns on and activates mitochondrial phylogenesis 100%. I got more citrate synthase. I can utilize aerobic. Whether I'm using fat or carbohydrate as a fuel doesn't matter at this point.

B

Correct.

A

I've got more mitochondria. I'm almost done, and then I'm gonna let you take over.

B

No, this all sounds great. This is good.

A

Here's the issue. We've also been taught for 30 plus years that because of that, two things are important distinctions. One, if you then do aerobic exercise, this will block or blunt or eliminate your ability to grow muscle. So that's a set of questions I'm going to ask you. The other set of the equation is if that is then therefore true, the only way for me to build mitochondria, which is one of the most popular things in the whole health wellness field right now.

B

Oh, yeah, Mitochondria yes, yes, yes.

A

All of it.

B

Right Y.

A

And if you ask the wrong person on, on Instagram or on X, the whole world, I guess, comes down to mitochondria. Every health ailment ever is mitochondria's function. Great. If that is the case, then the only way to get that from an exercise via pathway is aerobic exercise, endurance exercise.

B

Yeah.

A

So I want to ask the interference question and then I want to ask you about where do we really stand? You know, what has your lab done? Where do you see the data on the ability to increase the amount of mitochondria? We have the effectiveness of them, the size of them, whatever variable is relevant. There's what do we need to know and what do we know about the exercise stuff? And we'll save supplements, pharmacology and all that and drugs for another discussion. So big topic.

B

Yeah.

A

But start me there with the interference effect.

B

I think the interference effect holds true. You can also expand the reticulum of the mitochondria and muscle cells with resistance exercise, especially in the older population. Especially and the older population that's deconditioned. We see mitochondrial biogenesis all of the time, be it an acute bout. And we're looking for markers like PGC1 Alpha is a famous one, TFAM. These all drive mitochondrial biogenesis precursor up the chain. Right. We published one of the, and this is an accidental paper. This is done with Robbie Seaburn and Adam Sharples. We had a bunch of epigenetic pyro sequencing data from a six week training study and older participants. And we said, hey guys, y' all know how to deal with this data? We don'. Can we collaborate? They said, sure. Robbie comes back and says, well, we didn't see across the entire genome much in terms of methylation changes based on the depth of sequencing. But what we saw consistently in all these older individuals was the demethylation at the region of the mitochondrial genome which is responsible for biogenesis.

A

This is epigenetics.

B

This is epigenetics. So if you demethylate that region of mitochondrial DNA, which by the way is mutually exclusively in terms of location in the cell, this mitochondrial DNA is in the mitochondria. If you replicate that, that is a sign that you're making more mitochondria. If you demethylate the region that we looked at, that indicates that you're going to make more mitochondrial DNA. This was with resistance training, 12 sessions, older deconditioned people.

A

So all you longevity people, hopefully you just paid attention to what Mike Just

B

said resistance trained for mitochondrial health, especially if you're an older individual. I will stand by that statement. Yes. Amazing, amazing. Do you need, you know, so, so people have talked about the hormetic effect if you take antioxidants. That's a mess. I, I think exercise, exercise first and then we can start talking about other things in terms of antioxidants. You know, megadose, vitamin C and E and this and the other. There does seem to be an interference effect there that was reported.

A

C and E together.

B

Yeah, C and E together. And Schwartz I think did something at South Alabama with green tea catechins, which is an antioxidant, showing that with endurance training that interfered with mitochondrial biogenesis. So my answer is just bolster the endogenous muscle cell redox systems with exercise while also stimulating mitochondrial biogenesis with exercise. Supplementation has its place. And we can talk about this later. We talked about this in the car ride. I believe in supplements, it's improved health outcomes at the society level. When we fortified certain foods that are on our store shelves. Right. I mean that is not a bad thing. It's not a four letter word. There are certain supplements that have a time and place. But long story short, I haven't been a big proponent of antioxidants. Right.

A

As a prophylactic supplement.

B

Yeah. Now, you know, I've seen stuff with ultra endurance athletes, for instance, looking at expired methane, like whatever methane exhalation. Looking at what's the. There's some sort of lipid peroxidation marker in the blood that is sort of reduced peri. Exercise with like megadosing. That's all fine and good. So you're seeing biomarkers change much. But some people would argue on the other side of that coin, you need the re. You need the oxidative stress to then promote the adaptation and muscle.

A

That's your signal.

B

If you blunt it. Yeah, if you blunt the signal, it won't happen. So anyways, okay, let me go back to the full stop period on interference effect. So we did a study, Palomasquita, in collaboration with Andreas Cavazis. He had a very interesting, intriguing question. He said, look, if we took two groups of people, it's always two groups of people walk into the lab. This sounds like a bad bar joke, right? So one group of individuals, all they did for 14 weeks was endurance train. They did sit training, which is like the Marty Jabala master protocol.

A

That's really short, high intensity stuff, right? Yeah, probably, I don't know, was 30 on a minute offer Exactly.

B

So it was like a minute on and two minutes or a minute on, two minutes off. And they. They started with, you know, four sets. They worked all the way up to like eight or ten sets. Yeah.

A

So the max interval intervals.

B

Yeah, max intervals. Three days per week. They did this for 14 weeks. Saw a clear increase in mitochondrial biogenesis. With biopsy, they saw a clear increase in VO2 max. Great. The second group. All right. Was why don't we exclusively resistance train them first? In order to promote hypertrophy of the muscle cells in order to increase the number of ribosomes. In order to increase the number of myonuclei per muscle cell.

A

This is six weeks of seven. Seven weeks of the seven weeks. Yeah.

B

So we're going to prime the muscle cell with resistance training in order to make more machinery so that then when they endurance train during that second block, they have more mononuclei, more ribosomes, they can make more mitochondrial proteins, thereby enhancing the biogenesis response. We saw the opposite happen. Hampered response. And what is the hypothesis now? Well, the short answer is I'm not really sure. The long answer is, I think what's happening when you resistance train or you endurance train? It's more complic than mtor and ampk what happens inside of the myonuclei? Right. The store managers, you're sort of. With one training stimulus, you're rearranging their thought process. The architecture of the DNA to express genes needed for the adaptive response to resistance training.

A

Yep, yep.

B

You then go to exclusively endurance training. And yes, eventually, if it were longer than seven weeks, that response, that diminished response would have dissipated. However, there is a lag time. We have primed the muscle to adapt to resistance training. Right. So interesting stuff there. Aside from that, the. The meta analyses. I always like Jake Wilson's. I thought he did a really good job. This is like a 2012 GSCR paper where they tried to take into account. Okay, look, if you can currently train, if. If you want to just be the Matt Frazier of, you know, like, I just want to walk around, be strong, be. Be well endured in terms of doing, you know, shorter endurance events or whatever, what are the variables that matter in terms of, okay, how much aerobic training with my resistance training is going to. Is going to hamper things. What type of endurance training should I do? And it looked like, according to that meta, that if you were to want to do endurance training while also trying to best maximize strength and growth, you need to do sit training on a bike.

A

Yeah. Two days a week, you hit three Things right there. The exercise choice, that was not an accident.

B

Yep.

A

I'd love for you to share why that bike matters. You hit frequency. Yep. Again, not an accident there. And then you also had intensity. So if you wouldn't mind, why are those variables important to choose if that's the outcome you're looking for?

B

So less is more in terms of the interference effect. I think that's simple. Right. If you go out and you just crush, whether it's running or biking, whatever, seven days a week, and then you go lift three days a week, you probably will have a good physique and good health, albeit overuse injury. But if the goal is to maximize hypertrophy, good luck.

A

Yeah. You just don't have enough specific signal, let alone metabolic and energetic capacity to grow.

B

Correct.

A

You're over two.

B

You're over two. Yep. Yep.

A

Makes a ton of sense. I think if you're running 100 miles a week, I mean, you could fill in the blank here. Not gonna matter what you do from the. That makes sense. So from a. Just a straight up numbers. Okay, I believe you Bible story. Dr. Roberts. What's the next one?

B

Okay, the next one is intensity.

A

Yeah.

B

I think this is a little bit more difficult to disentangle, but I think this is. And this is a little bit more evidence led than evidence based on. But what I do believe is Marty Jabala did this study. I'm gonna misquote the heck out of it, but the gist is this. They were interested as to whether or not long slow distance training versus sit sprint intervals affected the ability to activate higher threshold motor units.

A

Yep.

B

And the answer is sit is better.

A

You're drawing a clear distinction. You keep using sit as well, not hit. Yeah, this is it. Because it's sprint.

B

Yeah.

A

This is the key factor in that question.

B

Yeah. And I. And I want to say when we talk about sit, I mean, I like people, you know, it's a spectrum for crap. I mean, you can do hit, which is two minute intervals, two on, four off, whatever. A sit would be more of that 30 second Wingate type of stuff.

A

Real true velocity.

B

Oh, yeah. I don't like doing it. I like doing hit. And I like, like doing. I'm gonna jog hard. Jog hard. You know, all my belly fat bouncing and then I'm gonna jog soft. That's my training. Right. So. But yeah, the idea there is that when you do sit training, you can actually see a bump in power as well. And I think that speaks to some of the neural adaptations.

A

Practicing going fast.

B

Yeah. Moving fast, sprinting fast. You're activating more higher threshold motor units. And those higher threshold motor units, like, they innervate a ton of type 2 muscle fibers, which basically means this. I, I think that's more favorable towards then translating to resistance training and sort of triangulating that to like maximize growth rather than doing long, slow training for 30 minutes, an hour, whatever. You're. You're not activating high threat threshold motor units and then you're trying to adapt them with resistance training. Just seems out of whack, if that makes sense.

A

Why does the bike matter?

B

This is the hard one. This is just shooting from the hip, Andy. Ground and pound time under tension with grounding and pounding just doesn't seem to work well with then trying to grow muscle.

A

Yeah. If you look at Jimmy and Kevin's review paper on this topic, they walk through it pretty carefully. It holds up. Yeah, it holds up. Why I would have to jump from the hip as much as you did. But it. I would say the same thing you did. Right. If you look at something like rowing and cycling versus running, I don't think it's a stretch for us to say, yeah, lots of that. Same amount of time is what we're saying. Same amount of energy output, same amount of miles or however you're calculating it, if it's done on a bike or a rower or but more specifically a bike rather, there's no eccentric component.

B

Correct.

A

There's not as nearly as much load on the body. Physical load, gravity load. That probably takes some recovery resources away. It probably adds to maybe additional damage or injury or something like that. Because when you actually look at the papers, the papers themselves show that. And so why we're speculating, but the actual outcome is the part that we have. Have pretty clear evidence on which matters. So if you're gonna do it, keep the volume reasonably low, make the intensity high. Because if the volume is low and the intensity is low, then it's probably not enough to stimulate the mitochondria to do anything.

B

That's fair. Yeah.

A

And then do it on an exercise choice that doesn't zap all your recovery capacity, which a bike is probably a

B

good route for it A hundred percent.

A

Makes a lot of sense. Makes intuitive sense. So an interference effect does exist.

B

Yes, it's there.

A

It's probably a little bit more complicated than simply MTOR and mpk.

B

Yeah, I agree.

A

Last thing I want to press you on is this relationship between ribosomes and mitochondria.

B

Sure.

A

If we were to just. I'm sorry, I Will insult. If I insult any mitochondria or ribosomes in the room, I apologize.

B

And they are distinct camps.

A

Yeah. This is not holy.

B

War is about to be waged right here.

A

Sure. Roughly. We will say, as we've been talking about pretty consistently, the ribosomes play a large part in. In muscle growth.

B

Yes.

A

The mitochondria play a large part in energy.

B

Yeah.

A

So we will often then kind of bucket. These ribosomes are a strength training stuff. Muscle growth mitochondria, or energy and endurance and things like that.

B

Can I add a wrinkle to that? Please do. Okay. I have a student, his name is Nick Contos. And I want to shout him out because he has found a way. So he is interested in cardiomyocytes and he wants to elicit hypertrophy to mimic like ventricular hypertrophy, heart failure with phenylephrine. You can do this in a petri dish. He found a way to get mitochondria endocardiomyocytes to see if that mitigated any of the bad response to hypertrophy. What we want to do, and I've told Nick this clearly is what happens if we take muscle cells in a petri dish. We transplant mitochondria into those muscle cells. We have another bucket of cells that we do like a vehicle, so no transplant. And then we give them both an anabolic stimulus. Does that added mitochondria lead to enhanced hypertrophy? Because that is an unsolved question.

A

There has been a paper on you mentioned earlier pre strength training prior to endurance training.

B

Yes.

A

There was a paper recently opposite of that.

B

Stu Phillips group.

A

Yes.

B

Yes.

A

And I believe they found that that did in fact occur. Did they not see they did enhance muscle growth after a period of four

B

to five weeks of endurance training.

A

I think it was low intensity cardiovascular cycling. Right.

B

Yes. However. What I will say this. Well, there's two howevers here, but yeah, yeah. One would be capillary because enhanced capillarization or the. The enhancement of the network of capillaries with endurance training also occurs when I even touching that in this conversation, which leads to enhanced perfusion, et cetera. And then with that, the other hallmark adaptation is the reticulum expansion of the mitochondria. So in the human model, it's tough to disentangle. Was it capillary, Was it mitochondria, Was it both? Was it something we didn't even look at? I hate like writing just in vitro only papers. But I told Nick this would be the perfect one because we're clamping all that. We're removing that from the equation. Let's give these guys more mitochondria in the petri dish versus not, and let's hit them with IGF1.

A

Yeah, yeah.

B

And if we see an enhancement in MPS, like muscle protein synthesis and an enhancement in cellular hypertrophy, then that's probably the best evidence we have that, hey, look, those older individuals, I told you earlier in our conversation, that are deconditioned and they see this, this robust increase in mitochondrial biogenesis with resistance exercise that could be part of the driving force course that, you know, enhances hypertrophy and. And those older individuals. So anyways, people say, look, man, when you synthesize muscle proteins, how much ATP is that? Yeah, yeah, right. There's some modeling in the 70s with bacteria saying it's like 3 or 4 ATP per peptide bond. And then you start thinking about, that's crazy.

A

That's a load.

B

A load. And then I told you, right? Like, how many contractile proteins do we have in muscle? I mean, it's 85% volumetrically filled with myofibrils. And then you look and you have all these sarcomeric proteins, M line, Z line, et cetera, et cetera.

A

A lot of ATP.

B

Yeah, bro.

A

The second caveat I'll add to that is I'm pretty sure a paper came out after that that repeated this study or it had a similar approach and did not.

B

Did not replicate. Correct.

A

So. Okay, I'm not making that second one up.

B

I think you are correct. I think. I think. And this is nothing against Stu, right? And this happens to you, and I will come out with something and say, oh, wow, we significant, but there are false positives like everything else in life.

A

And there's also. Neither one of us are obviously very familiar with that second paper. So that could have been an inferior design or a different design. A thousand things could have happened. But I would say I only brought it up to say I don't think it's a clear answer at this point.

B

Yes.

A

And whether or not that happens. So I think your. Your study still has legs to do, because we don't know the answer. Answer.

B

Yeah, that's really cool.

A

Is there a competition in this cell? Does it have to choose? Does it have to choose which one it's going to do? Support the ribosomes to grow, Support the mitochondria or those independent. What's the mutual exclusivity here between this? Because this is the ultimate question, right? This is if we know this answer. Then we know interference effect.

B

So we wrote this review article, Palomasquito, who did that, that, that 14 week, you know, endurance training or resistance followed by endurance. He wrote a very nice review article trying to find all of the papers that have done resistance or endurance training or even concurrent training. Looking at what happens with ribosome markers from biopsies and what happens with mitochondrial markers. And the short answer is anything you can imagine happens, happens. Some studies.

A

Yeah.

B

By and large, resistance training will increase more the ribosome biogenesis than the mitochondrial biogenesis stuff. However, acutely, PGC1alpha is activated in terms of MRNA expression, even phosphorylation of the protein with a bout of resistance exercise. Dude.

A

Yeah.

B

And then same could be said on the other end of the equation where if you do, you know this endurance exercise bout, albeit it's a little bit less, it's, it's, there's less of an effect there with the ribosome stuff. Like if you do one bout of, of treadmill running and Andy, I get your biopsy pre and post, you're not going to see ribosome biogenesis.

A

Yeah.

B

Markers move the needle. We've shown that endurance exercise doesn't seem to stimulate ribosome biogenesis. Certainly does though. Increase capillarization, increases mitochondrial biogenesis. But resistance exercise is more complex and that's probably volume load dependent, which is to say if you do a high volume training set, now you're sort of getting into this muscular endurance aspect that starts triggering some of those pathways more so than just doing like you know, sets of three.

A

Yeah.

B

Which probably doesn't touch those pathways. Right, right.

A

Well, I think it's fair you brought this up a while ago and this is a great time to come back to it and finish that thought up. The idea that I don't think it would actually make any sense to grow a significant amount of noodle size, radial increase, and not touch mitochondria at all.

B

Yes.

A

If you look historically, what you and I were taught growing up was the fact that resistance exercise does nothing for mitochondria and. Or it's actually negative.

B

Right.

A

Which I think was a really bad math problem.

B

Yeah.

A

Right. You're looking at density, but you've increased the size. Okay. So even if I actually added more mitochondria, my density would have gone down.

B

Yeah.

A

And this is how it was always described.

B

Right.

A

So if you look at those, those early papers, mitochondrial density is lower after strength training, therefore you're less fit, you're out of shape. More like, it's like, well Timeout. You still have more mitochondria. Yes.

B

On an absolute scale.

A

A hundred percent.

B

Yes.

A

And you are an absolute being.

B

Yeah.

A

So the total amount of oxygen you can handle and thus provide energy from there. So I'm not exactly sure what to say that literature it is, but in my brain that means we can now

B

end that myth that resistance training is bad for mitochondria.

A

Correct.

B

Oh, yes.

A

Gone.

B

Let's wipe that off the table.

A

And we can even say it's potentially

B

fairly beneficial for the deconditioned older population. For sure.

A

Not indicating at all. You take a highly endurance trained 25 year old, have them lift some weights and now they're gonna. Their VO2 max goes up.

B

Right. Like this is not gonna happen.

A

This is not what we're saying.

B

Right.

A

But for those people, I think it's a great start. Okay, man. Well, this has been just remarkable. You're, you know, my absolute go to source with muscle biology stuff. Anything I've ever put out, for the most part is, I would say 90 a quote of your work and your lab's working.

B

Oh, making me blush. That means a lot. It really does, buddy.

A

It's been great. So I learned a ton today and

B

hey, look, I. I just want to give you thanks. I appreciate all the support over the years. You have been so generous and every time we go to conferences like you give our work, like shout outs and my students are like, you know Andy. I'm like, yeah, I know Andy. They think I'm a rock star for knowing. There you go, man. So I appreciate you.

A

Yeah, man, appreciate you coming out here. I know it's a long trip and taking the time out from the fam. The lab and all that. And yeah, this has been great.

B

Thanks.

A

Thank you for joining for today's episode. My goal, as always, is to share exciting scientific insights that help you perform at your best. If the show resonates with you and you want to help ensure this information remains free and accessible to anyone in the world, there are a few ways that you can support. First, you can subscribe to the show on YouTube, Spotify and Apple. And on Apple and Spotify, you can leave us up to a five star review. Subscribing and leaving a review really does help us a lot. Also, please check out our sponsors. The show would not exist without them and their exceptional products and services. Finally, you can share today's episode with a friend who you think would enjoy it. If you have any content questions or suggestions, please put those in the comment section on YouTube. I really do try my best to read them all and to see what you have to say. I use my Instagram and X profiles also exclusively for scientific communication, so those are great places to follow along for more learning. My handle is Rndy Galpin on both platforms. We also have an email newsletter that distills all of our episodes in the Most Actionable Takeaways. We have newsletters on how to improve fitness in VO2 Max, how to build muscle and strength, and much more. To subscribe to the newsletter, just go to performpodcast.com and click newsletter. It's completely free and we do not share your email with anybody. Thank you for listening. And never forget, in the famous words of Bill Bowerman, if you have a body, you are an athlete.