Welcome to the Empirical Cycling Podcast. I'm your host, Coley Moore. We are not joined, unfortunately, today by Kyle, but we have a new co-host briefly for a stand-in. We're going to see how this goes. So thank you, everybody, for listening to the podcast. Especially if you're new here, please consider subscribing to the podcast, especially if you like what you're hearing. But if you want to support the podcast, you can always let people know that you like it with a nice podcast rating. And for you, wherever you listen to podcasts, and especially sharing the podcast goes a long way. Thank you all for all of that. We appreciate seeing the record. for the podcast on forums and just while we're riding around and at events. So thanks everybody for all of that. And if you want to support the show with a couple bucks, please consider a donation at empiricalcycling.com slash donate because we are ad free. And I was actually considering, I was talking with Kyle the other day. I was thinking that we should do an episode about all the advertisers I have turned down on the podcast and why. So that's potential in the future. Anyway. But if you really want to support the podcast, please consider becoming an empirical cycling client. We are always taking on athletes for coaching and we do consultations as well. We can look at your season. We can plan your next season. We can look at your files. We can just talk biochemistry or whatever you want. So our time is your time. So yeah, empiricalcyclingatgmail.com if you'd like to reach out for that. And of course, we have negotiable rates for professionals and students because we know that you all don't really make that much money pretty much until you get to being Tadej Pogacar. So if you would like to ask some questions on the Instagram, you can do so at empiricalcycling on Instagram, of course. And that's where I have weekend AMAs up in Instagram stories. And at the end of this podcast today, that's where I ask for listener questions on our podcast. So if you'd like to ask a question for future podcasts, please go give me a follow there. And so let's get down to business. So Kyle is basically working 12-hour days out in the desert for NASA. And it's over a holiday weekend, no less. So rest in peace, Kyle. We wish you well. We'll be glad when you are revived when you get back, which will be in a couple weeks. Um, I also have a problem with podcasts sometimes where I do all the research and everything's fresh in my head and I want to get it recorded and done and out. And if I wait a little while, I forget everything. And then I have to go back and redo all the reading and read, read, read all the scripts. And then I usually, then it's basically never done and it never comes out. So I've had issues like that in the past. So who we have today is Marinus Peterson, who has been on the podcast before. He has studied exercise physiology at the University of Loughborough. And he is a coach himself. He is a very fast cyclist also, a former Welsh national champion. And he is very fast. And he is also a client of one of my personal clients. So we have a nice little circle going on. And so Marinus is awesome. He's one of the few people who's got the background and the wherewithal to keep up with this podcast. Kyle, of course, being the number one. We were going to try out Rory today because everybody liked him last time, and I knew he would be able to handle this. Rory is also unfortunately indisposed for an indefinite amount of time. Um, and so I was going to do the solo and, um, and I may still yet, but we've got Marinus here and we're going to see how this goes. So, um, so Marinus, thanks for joining us on short notice. And also, um, I guess it's time to get down to business. So today we are talking about AMPK. So generally speaking as background information before we really dig into this, cause you've seen the script, you know, what's coming, um, or, well, the script, the outline, the notes, um, what. Have you generally heard of, what do you usually think of, or what do you think people think of AMPK? Because a lot of the time I've been on forums and somebody will say, I've heard some really silly stuff. So we're going to get into that at the end of the episode where we talk about how not to big brain the AMPK stuff. So Marinus, what do you think is out there right now for AMPK and aerobic adaptation? From what I've seen so far, it just looks like more AMPK is better. If a study finds or a new type of training finds that it gives you more AMPK, that seems to be like, oh, therefore it's great. And I just sometimes think people aren't joining the dots or going beyond that. And yeah, so it's like people are looking for AMPK signaling before they're looking for performance. without even knowing what it is or thinking about what is the role of it in metabolism and in consequent changes in performance. Right, right. Because people think that, oh, AMPK is directly correlated to exercise intensity in a lot of ways. And so if you want AMPK activation, you've got to go really hard. And if you want more AMPK activation, you've got to go really hard. all the time and what happens when you go really hard all the time uh not not very pleasant things in my experience uh yeah yeah this it leads right to the o word which is not orgasm in this case it is overtraining the not fun one not not fun o word um yeah so so um and i actually remember uh having a discussion on a forum uh, quite a few months ago at this point, uh, that prompted me to start thinking about this side of things and doing a podcast on this, um, is that, um, it was, you know, kind of just what I was saying before was like, if you want more than you've got to write hard all the time, you've got to always empty the tank and stuff like that. But what we're going to see is some pretty concrete evidence that that is not a good strategy for this. Um, so, uh, so actually before, uh, I started. doing the research on this and, uh, you know, kind of like, you know, dotting the I's and crossing the T's on my own AMPK knowledge. Um, I wanted to title this episode, uh, something about how like, you know, the importance of AMPK is over-exaggerated or something like that. Um, and I actually don't think it is in a lot of ways. Cause I think in, at least in the scientific literature. people who do the research on the actual mechanisms of aerobic adaptation know exactly how important or unimportant AMPK is and the circumstances in which it is and is not activated and all the other signals that are also important, like the last episode on calcium. And so that was really just some simple takeaways. Just ride your goddamn bike. It's not so hard to get some calcium adaptations. But when we start talking about AMPK, there's duration, there's intensity, there's glycogen stuff, there's training load. There's a bunch of different aspects of this. So this episode is going to be notably more complex. So hopefully it will actually give the listeners some more tangible information to go and enact in their training rather than the basic stuff that we already know. Yeah. And so as we get closer to the end of our notes here, what we're going to start doing is we're going to start focusing more on our coaching experience and our training experience on this kinds of stuff and how the kind of stuff that we're going to look at in these studies is going to influence what we should and should not do on the bike. And spoiler alert, it really just enforces the basics in a lot of ways. So, and then we're also going to talk about the ways not to big brain this thing to death. So anyway, what is AMPK? Why does it matter? I know a lot of people, you know, I know there's like eight people I probably argue with at events and on forums and emails and stuff like that, where we argue about the minutia of this stuff. But for most people who are probably going, what the fuck is AMPK? So AMPK is a protein called AMP activated. protein kinase. And a kinase is just something that adds phosphate to things, other proteins. And it's pretty simple. And that is actually a common way to modulate the activity or rate of catalytic activity of other proteins and enzymes or whatever it is. And so it can also reduce or stop other proteins from doing stuff, or it can turn them on. So just being phosphorylated doesn't necessarily mean on or off. It just means it changes something. So AMPK is a protein that acts as a cellular energy sensor. And we've probably discussed it a little bit before on the podcast when talking about things like glycolysis and adaptation. I'm pretty sure we did in Wattstock 40. That'll come up again in a little bit. But the big question is, how does AMPK sense energy? So when things in the cells are pretty chill, when you're like laying on the couch. And your muscles are inactive. You've got a lot of AMP in your muscles. So your quads are very, very happy. Lots of AMP. Everybody's chill. And ATP binds to AMPK and says, shh, everything's okay now. Shh, they're there. It's all right. But when we get on the bike and we start riding, When activity levels start to go up, ATP starts to get used and becomes ADP and AMP. Those phosphates start to go away from ATP. Increasing levels of AMP bind to AMPK and block the ATP signal. And this means AMPK starts to go, whoa, our cell is running out of energy and I need to do something about it. So does this all make sense so far, Marinus? You're sitting on the couch. Everything's chill. Everything's great. And to get this AMPK signaling, you do actually have to put in some amount of effort, I'm gathering here. Yes. And at this point, when AMPK is being activated, you've probably done some kind of significant work and you've noticed that you'll know about. So, yeah, changes, cellular changes in that ATP and AMP balance is kind of... one of one of the markers for fatigue yeah it's actually one of one of the big markers uh and uh basically what this is is like energy stress of the cell because like when things are chill you've got like and we've talked about this on the podcast so many times at this point but we'll review really quick anyway so when atp and like atp gets its ability to do work by how far it is kept away from equilibrium with becoming adp by getting that one phosphate removed that is the big major driver of potential to do work, chemical work for ATP. And so a good cellular energy state means a lot of ATP, basically no ADP, ADP levels in the cell at all points until very, very extreme situations are kept basically almost at zero. They're like micromolar levels. And AMP is usually what ADP becomes to, well, anyway, we don't have to get into it. into that level of detail. I think you'll often read in studies that people in the past have thought that lactate was the cause of fatigue when actually it's this cellular energy balance and lactate is actually kind of... a red herring if you like in the region whereas whereas this this yeah uh cellular um energy balance is actually energy state is actually what's yeah i would i would almost say the lactate is like smoke but it's not even smoke because the smoke is a direct consequence of the fire and you know in a way we could consider that but also in a way it's completely unrelated because um because of well if you're a regular podcast listener and you remember all of the recent stuff we've done on electron transport chain and energy balance, Wattstock 40 especially, this is something that you should be familiar with. Whereas I guess an analogy you could draw there is like the energy state of the cell is how hot is the fire and lactate is like the smoke. So if you chuck a load of wood on the fire, it's not going to, or no load of grass, you might be able to make loads of smoke, but it doesn't mean- Yeah, wet grass, that would be a good one. Yeah. Like the energy doesn't mean the energy state is, you know, optimized or, you know, is, is, is whatever you're trying to achieve. So yeah. Cause they're not, they're not directly proportional. Yeah. And what we're going to see in a little bit is actually that, um, that in some ways at some intensities, even if we are making more lactate, we are actually not getting more MPK signaling, but we're getting ahead of ourselves. Cause I I'm really excited to get to this stuff. Uh, you all know me at this point. Um, okay. So, so why? why does it make sense for the cell to monitor energy state? Because it doesn't want to be in the low energy state. Right, because if you lose the energy state, the cell dies. You die, yeah. Yeah, and so we don't want to do one sprint and have all of our leg muscles wither and have to be rebuilt. That would be horrible. Apoptosis is the name for... Apoptosis. Actually, there's debate as to whether the second P gets pronounced, because technically it's apo is the prefix, and then P-T-O-S-I-S is the Greek word. So it could be apoptosis. Apoptosis is how the middle school folks say it. So to prevent apoptosis, one cell must activate AMPK. Yeah. And this is what we're talking about here is like in the muscle, like there's a lot of stuff with AMPK and other things involved elsewhere in the body. But right now, because this is a cycling training podcast, this is where we want to focus. So AMPK reacts to the cell's energy state and the cell's dropping energy state. And when the energy state is dropping, you're losing ATP, but you're mostly gaining AMP. especially at moderate intensities, very, very high intensities in extreme situations, we get ADP too. So what happens is the cell's energy state dropping means it has to be maintained. And AMPK is one of the main cellular switches, quote unquote switches, that starts to change the cell's focus from rest and digest. We're going to store energy. We're going to build intramuscular glycerides. We're going to build glycogen. And it starts to switch it to, we need to start consuming these things to maintain the cell's longevity under workload. So when you're moving, that's going to have quite different implications from rest. And a lot of studies, I think in one of the... studies on fat burning and transport, one of the things that we looked at is how one of the targets of AMPK is actually acetyl-CoA carboxylase, which is one of the things that is one of the first steps into an energy storage pathway. And as AMPK gets activated, ACC, or acetyl-CoA carboxylase, actually gets phosphorylated and it reduces its activity as AMPK's activity starts to go up. And so that is one of the ways that a lot of studies actually look for AMPK activation is by looking at some of the targets of AMPK and seeing how phosphorylated do these get as in how reduced are their activities because it's showing the cells switching the state from rest and digest to fight or flight in a manner of speaking. So that's the big role of AMPK. It's an energy sensor that shifts. things in the cell to maintain the energy state so the cell doesn't die. But here's why we care for adaptation. Oh, excuse me. Evolution saw fit to also make AMPK simultaneously take this function of sensing the cell's energy state, but it also, AMPK also helps the cell respond. to this energetic stress by making aerobic adaptations to help reduce future energetic stress in the cell. And this is why it's your magic bullet for all the cycling gains you could ever dream of. Well, this is why some people think it's the magic bullet because it's like AMPK was one of the earliest things known about like exercise, like AMPK, yada, yada, question marks, adaptation. Um, you know, like one of the earliest things known was like repeated exercise bouts yields mitochondrial biogenesis. And AMPK was one of the first and most well studied things starting in the early aughts. Um, but at the same time, calcium was studied as well. Calcium signaling for just like regular muscle contractions. So those were kind of co-studied together at the time. But, um, but anyway, so they both have kind of like in the last episode, we talked about how one of the eventual. uh, targets, uh, through calcium, uh, you know, activates, uh, uh, cam K two and all that stuff. And it eventually gets to our old friend, PGC one alpha. Um, and so AMPK turns out to do the exact same thing. It has the exact same target. And that's one of the reasons, one of the many reasons that, uh, a lot of studies in like moderately, you know, kind of untrained individuals will show the exact same adaptations between sprint interval training and like moderate. you know, intensity exercise. Although I think as we'll get into the studies more, you'll, when we look at the actual, uh, participants in these studies might not be the most representative population for our audience. Yeah. Uh, well, one of the cool things that we're going to see is that training load has a big effect and like how well-trained you are. So, um, so what I want to do first though, is I want to look at a study. help the listeners kind of get more context on AMPK is that we're talking about peripheral adaptation, so specific to your cycling muscles. If you have a look at all of these studies, they're typically taking muscle biopsy samples from the vastus lateralis. That's the quad on the outside of your leg. That's the quad on the outside of your leg. My hypothesis would be that if you took muscle biopsies from the, what's the big bicep muscle called? The biceps femoris? Yeah, biceps femoris. Biceps femoris? No, that's the one on the leg. We don't know anything about arm muscles. Yeah, whatever. Your bicep. Your bicep, yeah. If you took a sample out of that after two hours of, three hours of steady state cycling, I don't think you'd see any particular potent effect changes. Whereas if you did the same with swimmers, you'd see the exact reverse that in their delts, that they might see AMPK activation. Yeah, your lats especially, yeah. Yeah, yeah. Whereas they wouldn't see much in the vastus lateralis. Right. So it's specific to the worked muscle group. And this is actually something that, I mean, I know you listen to the podcast and we've talked about this on the podcast multiple times, but you're right. It's always good to refresh on this kind of stuff for people who are just listening in for the first time or may not swim in this stuff constantly like people like you and I do. Sad people like us. Sad nerds like us. This is where Kyle would always call me a nerd. Whilst he's spending two weeks in a field watching stars. Yeah, working on weather balloons or whatever kind of... No, they're actually balloons. Show me a picture. Remember the lead balloon episode of Mythbusters? It kind of looks like that. Oh, wow. Anyway, so let's first take a look at a paper where we can watch AMPK activation lead to mitochondrial biogenesis. So like one of our main and one of the earliest observed training adaptations to endurance exercise is noticed by John Hollisley, I think. And so now we're going to be able to see the energetic stress lead directly to the action of adaptation. So our first paper today, we're going to do two. So the first one is called chronic activation of AMP kinase results in NRF1 activation and mitochondrial biogenesis, which is... And for dramatic effect, we should always read these last. I don't know why I start with this. So we've got a link to the paper in the show notes, and I believe it's open text, actually. So if you want to check this out, please feel free to read along. But this paper is from 2001. This paper is not vegan friendly. It's not. They sacrificed some rats, but this is pretty typical. And actually, you could tell what era. a paper was from based on the, well, based on, well, based on the verb that they use, um, around, um, the animals, uh, that they use. So, um, yeah, so sorry, sorry, folks, we are gonna, um, we are gonna lose some mice in the name of science for this. Um, not to pass judgment one way or the other, but it, it happened. So it would have been pretty brutal to put humans through this, uh, protocol. Yeah, that's not going to pass an ethics review, is it? Depleting your muscle creatine and ATP concentration by 40% to 50%. Oh, shh, shh, shh. You're spoiling it. Oh, my God, dude. Okay, so yeah, 2001. So this is really early in the study of AMPK activation and its effects in cellular exercise or cellular effects in exercise. The abstract's first sentence actually gives really good context for what 2001 was like for the study of AMPK and aerobic adaptation. Quote, the underlying mechanism by which skeletal muscle adapts to exercise training or chronic energy deprivation is largely unknown. Unquote. So they also discuss as a probable cause, if you will, for its involvement, how at the time, AMPK activation by AMP-like chemicals, led to then known adaptations caused by exercise like GLUT4 expression, which is the one that transports glucose into the muscle. And it also... Oh, sorry, go ahead. When you're trying to load carbohydrate, GLUT4 is that key thing that you'll get from your pre-race ride to help with the glycogen synthesis. Yeah, because it moves from the rough endoplasmic reticulum to your actual muscle. cell surface. Um, and so that, that is part of, but the many things that happen when you do openers, for instance. Um, so it also, um, uh, I lost my place on the page. Um, oh yeah. And also, um, they also knew that AMP like chemicals led to increased mitochondrial enzymes. like activity of stray synthase or cytochrome C were some very common things, easy to measure for the standards of the day. Super easy now. But anyway, so the experiment that we're going to look at is meant to elucidate more on what was known at the time that repeated bouts of endurance exercise may lead to relevant adaptations via AMPK, but they're looking for specific mechanisms because they know other things. which we'll get into, like we're already more directly linked to expression of these enzymes and better endurance performance. So we're really trying to find like, quote unquote, missing links, if you will, the same way as like people are looking at like, you know, Australopithecus kind of skeletons as like missing links between humans and apes. So what they did here is researchers fed beta guanodino propionic acid, or we're just going to call it beta GPA to rats. with a control group not receiving it and so beta gpa is a creatine analog and what this does is it out competes the actual creatine in cells in spots where creatine would normally bind but it doesn't do any of the useful things for a cell that the creatine actually would by being a spatial and temporal energy buffer as discussed in wattstock 38 so it basically creates uh some really shitty situations in all of the rat cells uh but their researchers are only looking at muscles so in the muscles could we just uh revise coley because i i remember that particular what stock yeah um what is what it would be like to be one of these rats with no creatine oh you it would be lethargic like your vision would always be blurry um like you you'd have brain fog constantly Uh, I can imagine you'd be very, you could be very hungry. Uh, if I recall correctly from reading the study, I think the, um, I think the rats that, um, that had the, um, that had the beta GPA were actually a little underweight by like 50 grams or on average or something like that. Cause what's interesting is 500 grams. You think of, uh, with creatine as being something you only use for your really high intensity stuff, like, you know, your weightlifting, your sprints. But actually, it's required just to initiate any movement. So to get off the couch, you need some creatine to get moving at all. Yeah, because in that episode, what we saw is that creatine and creatine phosphate, they have an easier time actually dispersing in a cell. And so a lot of the time... like ATP that gets made in the mitochondria actually becomes creatine and then becomes ATP out again later out further in the cell. So like, there's actually like a conveyor belt between like, you know, between the mitochondria creatine phosphate and like actual ATP further out in the cell. Um, and so, yeah, so that's, that's the spatial energy buffer, but the, uh, the, but the temporal energy buffer is like when you stand up from the couch real quick, um, like one of the first things that happen is your creatine like depletes like a little bit. depending on, you know, if you're like standing up from the couch or you're jumping up as fast as possible. And so, so yeah, so like that kind of stuff would take a big hit. So you would not be happy as a, as a rat, like eating beta GPA, like in your diet. But the other rats, they had a fine time and they, they also unfortunately had to get biopsied as well. So, so the, yeah, so the rats that had the beta GPA, Their phosphocreatine stores were depleted by approximately 85%. Yeah. And their ATP concentrations in their cells got decreased by 40% to 50%. And this is a massive hit. And we're also talking about that. That's a chronic state. So that's like going around having always just done a six-hour ride. Or worse, a six-hour ride with FTP. That's you morning, day, and night. It would feel like you've done a six-hour ride, but in terms of the cellular conditions, it would be like having done a 1,500-watt-for-20-second sprint. like that's the kind of cellular conditions we're talking about like immediately i wish i wish i knew what that felt like i it's no fucking fun like if you watch any of the track cycling um like for the olympics uh or like world championships or anything like that if you watch the sprinters especially at the very very end of the night um they are breathing so hard between efforts they're just and it's it like So that's how much oxygen deficit you incur. So yeah, these rats were probably not very happy. But yeah, so this is how the researchers created a perpetual state of energy stress in these rat cells. So let's look at what happened when they looked at these rats on the other side. They looked at the quad muscles and the calf muscles of rats in a variety of ways. And we're going to talk about these in a sec. For the energetically stressed mice, for the beta GPA mice, they looked at a transcription factor. The mice have four quads. Yeah. They've got four legs. Oh, I guess they mean. That's one of those things like which way does the brontosaurus wear pants? Is it like on all fours or is it on the back half? This would be just in the back half. Just the buck. Yeah, because the forelimbs, their musculature is much more akin to what we would expect for humans and other quadrupeds. So we're not that different from rats. But yeah, it's the ones on the hind legs. The ones on the hind legs. Yeah, so what they did was they looked at a transcription factor called NRF1. And a transcription factor is just something that... Binds to or helps things bind to DNA to actually turn genes into useful stuff. It's like part of the whole process of like turning your DNA into proteins and whatever that helps you do whatever better. It's like the middleman. Yeah. It's kind of like a middleman. It's actually kind of like, it's kind of like something that puts in an order with the middleman. And so it's like, it's like, you know, you might want to mail a letter. Like I mail a letter to you and you're the person who's going to like make my new arrow bars or something like that. And so like, like this would be like the letter getting to you being like, Hey, we need this thing. Um, so what they found was the, um, and so at the time NRF one nuclear respiratory factor one, uh, it was known to regulate some big key genes in mitochondrial biogenesis and cell growth. Because actually the two are not quite so inseparable. And this is one of the reasons that in like cancer study, you see a lot of the same energetic pathways being activated for cancer as we do and self-proliferation as we do for like exercise and all that kind of stuff. So the energetically stressed mice had almost 10 times the amount of NRF1 as the control mice. You would hope they would be... compensated in some way for this is one of the ways to compensate yeah so it's one of the yeah so so like the cell cellular stress is like this is what actually so this is one of the reasons i love this paper because it was early on but they knew that cellular stress they weren't like oh we're gonna make the rats burn lactate or burn fat or whatever like they're like no no this is cellular stress um and so they made cellular stress and they're seeing what happens so the uh the experimental mice did actually not have 10 times the mitochondria or mitochondrial enzymes or anything like that, as you might hope. They had about 120% of the cytochrome C as the control mice, which is involved in the electron transport chain. But pretty much across the board, when they actually looked at the rat muscles for the experimental group, they had approximately double the mitochondrial density as the control mice. So when you take a cross-section of these rat muscles, like the quads and the calves, like you're looking at tree rings, you look at, okay, how many contractiles, whatever, but you can see the mitochondria plane to stay. And they had approximately double. That's pretty impressive. Yeah, it's pretty impressive. So the last thing they looked at was they also found a doubling of something called ALA synthase. It doesn't matter. We're not going to get into it. Not that I know exactly what ALI synthase does in terms of this, but I do know that it's a rate-limiting enzyme for synthesizing heme groups. And heme groups in a mitochondrial kind of context are crucial for electron transport chain respiration and capacity. So when we get into a lot of papers, you'll see people talking about mitochondrial function. From my understanding, is that what we're kind of talking about here with mitochondrial function, respiration and capacity? Right. So we actually looked at in one stock 41, I think we looked at a paper that looked at mitochondrial function and typically you isolate mitochondria and you put it in a tiny little machine and you measure picograms of oxygen and you basically look at like, what is the maximal respiration rate per gram or like, you know, whatever tiny. portion of a gram of mitochondria and so you end up with like basically like the vo2 max of the mitochondria themselves yeah because from my understanding like doing more higher training volume gives you more of mitochondria whereas the high intensity training is really important for making those mitochondria Like you said, having higher VO2 max themselves. So you've got better mitochondrial function. Whereas what's quite interesting here is you can see that these rats have gotten more of both. So it's like they've done volume and intensity. Yeah. And in the context of rats, this is... You know, it is kind of like doing both. And that's why it's like the, like I mentioned before, like when we see a lot of papers, you know, showing in like, you know, early trained people that they have the same benefits from sprint training as they do from like moderate intensity endurance exercise. And this is kind of the same. And this is one of those things that creates one of those like crossovers between like, yeah, like, you know, you can get a lot of good aerobic benefits from doing high intensity. But, you know, when you mentioned like capacity. like versus volume. You know, you've also read a lot of the same David Bishop papers that I have, because he's one of the guys who talks about that the most, where like, you know, mitochondrial function in terms of the mitochondrial VO2 max, as it were, is higher if you do higher intensity stuff. But it seems like that's... not uh it's not a limiter when we actually do regular exercise but mitochondria needs the headroom uh it needs that extra capacity when we do the higher intensity exercise because the mitochondria like the cells don't want these things to be ever maxed out because like now you're really fucked if they if your mitochondria actually do get maxed out during exercise yeah that's pretty bad news yeah so um anyway so yeah so like would the other takeaway be that What these mice effectively have been doing is high-intensity exercise at all times with no break, which is not... And that's why they've seen both. Kind of, yes, but kind of no. But a real-world human couldn't actually do that. Yeah, no. I mean, that's why this is an experimental group, because these conditions... are like, you know, there's, there's no contractions here. There's no, um, you know, they didn't look at glycogen. So we don't know anything about that. Like they didn't look at, uh, at, at any of the other things that we would normally see, excuse me, with exercise. And so we can assume that there were a bunch of other things activated here, but we don't actually know because they were not measured. Like, uh, like our next podcast for Wattstock is going to look at like, you know, P38 and map K probably. And, and that was probably active. uh very well here too who knows i don't like it's it's not in the paper it's not included because they didn't you know it's 2001 what are they going to do um but like you said this this paper was to try and you know like you said fill in the gaps and go go a bit further because at this yeah at this point it was more just like well you do so you write you know you ride your bike you ride hard something happens and you get more mitochondria and happy days question question question profit yeah exactly um so it might not have provided all the answers but at least it was starting to fill in the gaps yeah yeah so this this paper really showed like energetic stress ampk activation like nrf1 um mitochondrial growth being put together in the muscle itself like in live animal muscle And, you know, that was a big deal at the time. And there was another study that did some very similar stuff. And I actually had to debate whether to use this one or that one, because I thought both were really good. But, you know, like, but again, like, let's not get to drill down in this. And let's step back for a second, because there are other things that like can cause these adaptations. I don't want to, you know, get too many. I don't want to like make it seem like NPK is like the one thing that causes adaptation. I think we've done a pretty good job of that so far, though. So, um, so yeah, so the study is, is actually lacking a performance aspect, which is normally something that like in people we would definitely want to see. Cause also we can't biopsy people like this and that would be really inhumane to actually do that. Um, and mice, mice and rats can't ride bikes. So it's quite hard to, although I would, that would be so adorable, wouldn't it? They could have two sets of cranks. Yeah. Yeah. Like a little mice on an assault bike. That'd be awesome. Um, yeah. So, yeah. So we don't see the mice run longer or anything like that, but I think one of the reasons I like this paper and that I give it a pass on this is because up to this point in exercise physiology research, one of the things that are most highly associated with improving endurance performance is mitochondrial volume and capacity. Like it's like, it's like, why, why add that if we see the thing like. If we see double mitochondrial density, it's like a no-brainer to these people at the time. Like, oh yeah, they're going to have better exercise endurance capacity. Like, why even test it? Because we're focused on the mechanism here. And so that's one of the reasons that actually with AMPK activation, there's not a ton of studies that directly... go, okay, more AMPK activation, more mitochondrial density, more performance, because so many studies already at that point had seen better mitochondrial density, better endurance performance, and better cellular energy state maintenance. So yeah, I give it a pass for that. But at this point, from my understanding, there's no knowledge as to the dose-response relationship. Not? So we don't know that more AMPK means, you know, more, you know, better maintenance of the cell's energy state. Yeah, exactly. Yeah. So, you know, so how much AMPK activation, how long, all that kind of stuff, how frequent, and then like how much more mitochondria do you make? Like these are, these are questions that are like, you know, we don't have exact dose response numbers, like you said. But in terms of real-world performance, because I coach people, you coach people, we know that when people do high-intensity exercise, this can be greatly improved. It's also from where we sit. We don't need to biopsy people and do horrible experiments like this. No, not at all. Yeah. So I think now what we should talk about is what everybody is probably wanting to know. All right. So how do I activate AMPK? How do I get benefits from this? How do I use this to better my training under what conditions and under what conditions shouldn't I think about this? So, um, yeah. So as usual, the knowledge that we're going to gain from the rest of this podcast is not only to let us train in better ways than we already know how, but to also allow us to. cross out all of the potential dumb ways that we could do this kind of stuff. Which is still very useful. It's still very useful. But also, this is one of the things that I also find very useful in consulting with people too. When I see certain patterns in intervals that people do, sometimes I'll say, this is great, keep doing this. Or I'll say, you should tweak this a little bit like this and maybe give yourself a little bit more rest. And I give them some... pointers on how to do this and you consult with people too like i'm sure you've done exactly the same thing yeah and and so there's there's stuff that you'd say like that people are you know it isn't optimal you know you could be doing better and there's also some stuff that is directly harmful they should avoid doing um yeah so we're gonna say hold on we're gonna i i don't want to scoop ourselves because i want to get to the directly harmful stuff at the end Cause, cause that's like, it's so much fun to, to get through that stuff. I don't want to scoop it because I don't want to, I also don't want to get the sprinter in front of the lead out train with this stuff. Like I want to do this in the right order. So, so we're going to get to the next big paper and I highly recommend people check this one out. It's a Rothschild meta analysis on what does and doesn't activate AMPK. And I was, you know, actually this came out last year in 2022. And if I had. attempted this episode like before this paper came out uh it would have been like it would have been an entire series long and we would have completely lost sight of the big picture because there are so many different ways to think about this and so i figure it's probably best for people to like not get lost in the weeds here including me especially me um and so so the paper goes through a bunch of studies i think they included like 89 or 90 or something like that or almost 100 And they looked at what does and doesn't activate AMPK. So we're going to go start with the positive stuff because the list of what doesn't is pretty long. So we're going to go with what does. We've got three big things that help activate AMPK. And number one is exercise intensity. And this is probably a no-brainer for a lot of people. Exercise intensity, because we were just talking about sprint interval training, right? So this is absolute intensity. and one of the coolest things that I saw, they referenced a paper in this review, and I went to read it. It was great. Just before we start on that, Coley, absolute intensity sounds like quite a simple term, and I'm sure a lot of the listeners will know about, but it is still worth clarifying that absolute intensity. So if me and Coley... both riding at 300 watts were at the same absolute intensity, despite it would be a different relative intensity for each of us. Yeah. Yeah. So 300 watts, for me, I could probably do right now for about three minutes. For you, you could probably do for about... I don't know, nine hours. So yeah, 300 Watts is like under your like first threshold. Like it's, it's pretty chill for you. It's, it's decidedly not chill for me. It's a happy place. It's a happy place. So like, so there was, there was a relative thing here, but like I'm talking absolute intensity relative to the same person. And so. That's what I mean by absolute intensity. It's not like, you know, your 500 watts is the same as my 500 watts, because you could probably do 500 watts for like five or six minutes at this point. And I could probably do 500 watts for like, like one and a half. So, so the study that, that they, that they mentioned that I was like fascinated by, I loved it. They had people ride at 72% of their VO2 max during hypoxia. So like basically an at altitude VO2 max. So 70% of this VO2 max for these people was 111 watts. And they didn't really see much AMPK activation. But then they wrote at the same 111 watts in normal oxygen conditions, no bump in AMPK activation. No change. So what they did... Hold on. Here's the third piece of this. What they did was then they had people go to the same relative 72% at the C-level VO2 max, their normoxia VO2 max, at 171 watts. Now they saw a big jump in AMPK activation. So this is linking back to what we said earlier about how AMPK is very much a signal for peripheral adaptations. Peripheral adaptations, we're talking about. in the muscle rather than your heart yeah yeah so typically cardiovascular system yeah so like the definition of peripheral adaptations is actually after the neuromuscular junction so like so when so when your nerve tells your muscle to contract at like where the that signal is on the muscle surface is being received from there into the muscle is considered the peripheral uh before that pre that is considered the central, which means I don't actually know where like capillaries fall in this range. But just in terms of like nerves and the brain and muscles, I know you're looking confused. I also do not entirely. I'm just trying to think about where capillaries would fall under that definition. Yeah, central or peripheral. I think they'd come under peripheral because you could, again, back to the swimmer versus cyclist example, I think you could have really good capillary densities in the muscle that you're that is trained okay hold on hold on this is nerd stuff we're gonna we're gonna skip over the nerd stuff we'll digress we are we are digressing as is our usual way um so yeah sorry people are listening we're gonna we're gonna keep it focused so anyway so what all this means is that no matter what's holding back your muscles from making power they're ready to handle a certain metabolic rate Like they're ready to handle a certain workload to maintain cellular energy state, to maintain their ATP. So that's one of the things that shows us that if you are not making the watts that you possibly can, that you're used to making, what happens is you are not creating... the cellular energetic strain on the muscles. Because if you normally train at sea level, then you go up to 10,000 feet or like 3,000 meters. Suddenly, your power output is diminished, but the absolute intensity is also reduced, and so is the AMPK signaling. And another training implication of this could perhaps be that when we're talking about doing FTP or sweet spot efforts, uh even endurance riding we just that there's no real good rationale to kind of big brain what cadence you're doing them at whereas because because you're going for peripheral adaptations we're looking for that total metabolic straight you know strain on the muscles which is um yeah the workload is the workload the workload is the workload 300 watts is 300 watts yeah um versus yeah which is different when When we're looking at VO2max and we're manipulating the cadence deliberately, that's for a totally different purpose. Yeah, that's for a very central adaptation. That's a very central adaptation. Whereas when we're talking about the peripheral adaptations here, yeah, 300 watts is 300 watts and it doesn't matter how you produce it. Yeah. And so actually the opposite can happen too. If you are used to being at altitude, like if you are from like, you know, 2000 meters. and then you go to sea level, suddenly your muscles have a huge amount of workload that they're not used to at this point, unless you are used to going back and forth from altitude to sea level. And so that is one of the other things that we can consider as a potential thing to think about when people are going to sea level to train from altitude or race or vice versa. But anyway, we don't want to go too far into this because we've got a lot more to get to. And especially with what general – so in normoxia, for most people, like at the regular oxygen conditions, like if you live at altitude, you live at sea level, it doesn't matter. Like what intensity seems to always activate AMPK? Big question. And – It depends. It depends, right? Oh, God. I'm so sorry, everybody. Time to drink. So this review, the Rothschild review does not actually say exactly, but they reference, I think they reference, I forget. They should have. But I know that there's a great study from Glenn McConnell, who hosts the Insert Exercise podcast, which is great, by the way. They showed that two hours at 65% of VO2 peak did not activate AMPK in well-trained individuals. And the reason that they did this study is because they had a previous study where in untrained individuals doing exactly this, two hours at 65% VO2 peak did activate AMPK. And so where is 65% of VO2 max for most people? Considering most people's FTP is between 80% to 85% of VO2 max, if you're well-trained, this actually turns into about 85% of FTP. This is a kind of upper tempo type of range. Yeah, exactly. And that's one of the reasons that personally, I don't assign that much tempo riding unless somebody is like tired and we need a little bit of workload. That's okay. A little muscular load is fine. Or like when they're off the couch, it's a great time to do tempo. because you get some of this muscular adaptation. If you're not used to doing any intensity, this is actually a good stepping stone to help your muscles get used to this kind of workload. And this is one of the many reasons why. And just me and Coley discussed this particular study a bit before the podcast. If you look into what they're actually calling trained cyclists here, it was like, what, two hours? one ride your bike three times a week no that's that's trained cyclists oh yeah yeah so yeah so so there was a paper in 2000 looking at um looking at defining the different levels of cyclists like trained well trained um you know extremely well trained or pro or whatever in world tour or something like that there were like four bins of cyclists and like the bottom one was trained and they were basically riding their bike for an hour three times a week and so that's like that's what we would consider untrained um But- So these- Yeah, well, hold on. The second one, the well-trained, and this is what the McConnell study uses, well-trained cyclists. And so they're typically riding six to seven days a week from one to four hours. Which is very precise. But I think it actually goes to show that people who are riding fairly consistently, and this actually probably lines up with your coaching experience because it lines up really well with mine. where once people are riding that often for a couple months, all this kind of middle intensity benefit that you get from riding moderately hard from below 85% FTP, it kind of goes away. So yeah, my takeaway from this was that if you are one of these people that would get AMPK activation, from riding for two hours at 65%. You're also someone who's doing such small training volume that you probably don't need to be overthinking. The land of perpetual noob gains where you can just go have fun and get faster. And it's awesome. You don't need to overthink anything. But all this points to the second thing that this paper talks about as being a good predictor for MPK activation is low training load. So not having trained that much where you are less trained, you get more AMPK activation. And the more well-trained you get, the less AMPK activation you get because the author's note right at the top of the section, by the way, and I've been harping on this because it's Cellular Energetics 101. Quote, training leads to an improved ability to maintain cellular energy charge during exercise, unquote. And cellular energy charge means having a really nice, strong ATP to ADP ratio. That's it. So the review continues. Basically, untrained or lightly trained individuals have five times higher AMP concentrations at 65% VO2 max than trained people. and they have similar ampk activation they've got about five times greater ampk activation than trained people at fits at 65 vo2 max and so um and so yeah like for this like they they note um you know like they note the same thing about what well-trained people do um and um and so like uh oh what's my next oh yeah it turns out they know AMPK activation is great, greatly reduced after only seven to 10 days of training. And they referenced three papers with this. And I've read two of them, like even before, like before this review, I didn't actually read the third, but I know two of them really well. And I went, Oh yeah. Yep. That's it. I think one of them was the McConnell paper. Oh, the other one was the Granada paper that we looked at in Watchdog 41 with the crazy proteomics. So yeah, really cool stuff. Anyway. So, but this also circles back to exercise intensity, right? So the more well-trained you are, the less NPK signaling you get from middle intensity stuff because you're way better at maintaining your cellular homeostasis. Pretty simple. Yeah. All right. Ready for the last one? Okay. I think the last one is... probably the one that gets the most chat on forums and in cycling culture um i i think again coley this with with muscle glycogen i think this is this is something that you know never harms to step back take a step back here because i've with a lot of my clients i often assume they know what glycogen is um all right but actually yeah you're right so like so so the thing that is associated with activated AMPK is end muscle glycogen. So, or, uh, yeah, end exercise muscle glycogen. Like what are your glycogen stores at the end of exercise? And this is a messy picture. So, so yeah. So why don't you take us through a quick, uh, a quick tour of glycogen? So, uh, glycogen is, is how we store, um, carbohydrate and it's, it's the main fuel that we use for excess, like for excess, moderate and high intensity exercise. So your body will always use muscle glycogen first, and then it'll use other sources, fats and glucose, to make up the rest. Well, actually, not necessarily true. But basically, your muscle glycogen usage is highly related to... your um your ability to maintain cellular energy state and the higher you maintain it right the less muscle glycogen you use so the better endurance trained you are the better fatigue resistance you have and the less muscle glycogen you use at higher exercise intensities and it'll use like and it will preferentially use other sources like like ingested carbohydrates um you know bloodstream lactate like intramuscular triglycerides bloodstream triglycerides um like and but But it's one of those things where like in Wastock 40, we kind of talked about like, this is why eating doesn't necessarily spare muscle glycogen. Because it's more related to how trained you are. Given your fitness level, your muscle glycogen usage will be tightly correlated with your exercise intensity. Yeah, it'll be reverse correlated. So the more well trained you are, the less you use. Yeah, but I mean, given your fitness level. the harder you ride, the more muscle glycogen. Yes. Yeah. Um, right. So actually pretty much at energy, any fitness level, cause you can be super, super, super well-trained and you can like ride really hard and still deplete your muscle glycogen. So like, it's, yeah, it's not like you have infinite, um, ability to like be fatigue resistant. It's like, you know, cause we can watch the best in the world. Watch the tour de France and they still, they still have a bad day. Like if they overexert themselves. like rest in peace bagat jar. I, I, I was, I was pulling for you this year anyway. So, so let's get into the other important part about muscle glycogen is that you, you have as much as it is, it's a finite tank and it can't, it, once you start exercising, that tank can only become more empty. Yeah. You can't do anything to top it up and you can't. Yeah. Or the only thing you can do to slow down how fast it's depleting is to also slow down. Or reduce your exercise intensity. It's to slow down. To actually slow down. It's to slow down. Yeah. All right. So, yeah. So the last one here, end muscle glycogen. So there's a strong correlation between end muscle glycogen and AMPK activation. So this is a messy picture, by the way. So everybody put on your thinking hats and like. and focus on this because this is one of those things where in a podcast, I would hear it and I would go back like five times to rehear it. And so I hope we do a decent job the first time. So there's not a correlation between starting muscle glycogen and AMPK activation. And there's also not a correlation for rate of depletion. So to convert that to, our users it doesn't matter what you've been eating the previous few days as to how much ampk you're going to get out of it if you're looking at that factor in isolation and it also doesn't matter how hard you're riding so perhaps we can get ampk activation by riding its sweet spot for two hours or riding ftp for one hour hypothetically or doing like really high intensity intervals Exactly. And they actually see the same thing. They note that it's the same in normoxia versus hypoxia. And actually people with McArdle's disease, which is a disease where you cannot store glycogen or you can't store it. You can't use glycogen. That sounds horrible. Yeah, it's not fun. Actually, I think John F. Kennedy had it, if I'm not mistaken. So there's two things to consider here. And this is, this is one of the ways where people start to big brain it and big brain it the wrong way. So you can't just not eat and have low glycogen stores and then like have very active AMPK when you start writing. It does not work like that. So second, you also cannot just start writing with low glycogen stores. Like, you know, whether, whether you do it from like intense exercise the previous day, whatever it is, like starting with low glycogen stores doesn't help. Not eating anything doesn't help. So why does all this make sense here? Because I just talked about what we learned in Wastock 40, or what we demonstrated in Wastock 40, is the conditions that might draw down muscle glycogen are related to, but are not exactly the same as the conditions that maintain the cellular energy state, like maintain the cell's ATP stores. And AMPK, like as we've... said in the introduction is all about maintaining energy state right it's not about maintaining muscle glycogen stores or the whole body energy balance yeah and um and actually one of the cool things about this review one of the reasons that i rate it so highly is that they even note that that end exercise muscle glycogen levels are not the actual primary driver of ampk activity they don't actually expand on this so i will though um So what's happening here is that the conditions that create continuous energetic stress to the point that you can activate AMPK are similar to the ones that draw down glycogen, but they are not always the same. So it's saying that perhaps end muscle glycogen is very tightly correlated with AMPK activation. Because of how hard and how long you go during exercise. Because of how hard and how long you have to go during the exercise to create that. But actually, it's a case of the causation. The correlation does not equal causation in this case. Yeah. So let's take it for example. Let's take FTP intervals. Like if you are capable of riding at FTP for an hour and like, let's say you're training, you're building fitness and you want to be improving something like this is very different from like maintaining and getting tapering and stuff like that. But now if you go out and you, if you can do an hour at FTP and you go out and you do a two by 20, this is so chill. Like, like it's probably not enough to like to. disturb your cellular energy state for long enough because you can handle this for an hour. Why do it for 40 minutes? You have to, and this is kind of like what Rory harped on in the last podcast, a smart guy that he is, progressive overload, right? So in order to get to more AMPK activation and this middle intensity signal, and that's one of the cool things about sweet spot and FTP work and threshold work, is that It is like a combination of high intensity and low intensity. That's why I call it spicy endurance. It's like right in the middle. You get a lot of the adaptations of both, including APK activation and, you know, what do you call it? Calcium activation and all that kind of stuff. And you get into big motor units and like the whole thing's great. So, yeah, but it's one of those things where like in order to actually do. this kind of exercise that's going to benefit you i mean just you know purely from an ampk activation standpoint you absolutely have to be able to main to hit your absolute intensity relative to you and you also have to be able to you know maintain that intensity for the right duration for you so this is where i've found that generally that the higher level of the athlete the more important being well fueled for these FTP and sweet spot efforts is because once your absolute power is higher and the duration that you can sustain that for becomes higher, you are going to need more glycogen to fuel that activity. And because as we've just said here, what really matters is that you can actually do enough work at a high enough power so that your muscles are getting tired at the end. it's almost, would you say Coley, it's like, you know, doing like must think of like muscular endurance, like how long can you do a, you know, um, an isometric split squat for, but you know, but it's just, it's, it's for, it's for a very specific task and, and you need to be able to, to, to, to do that specific task to your like, yeah, like, um, like your specific specific uh limitations yeah and this is one of the things that that we that is like you know we actually take for granted but it is one of the things that we individualize when we coach people is like you know how hard and how long can you do this okay well we're gonna have to go probably a little harder and a little longer next time um otherwise we we know for a fact from our training from our coaching and training experience that like if you just do the same thing over and over all the time and you're not seeing any improvements well you clearly need to try to like progressively overload it just a little bit, and you've got to be well-fueled for it. You cannot hack AMPK signaling by starting with low glycogen stores because you are going to be lacking the duration and the intensity to actually make this benefit you. The authors also note there is actually not a significant correlation with consuming carbs or anything like that. And they also note that any purported benefits of facet training are not supported by any evidence. Whoa, whoa, whoa. Have you not been on Twitter? I have, unfortunately. I try to just speak when spoken to on Twitter. Anyway, so this is our kind of like the big takeaways from this meta-analysis, is that we're looking at intensity uh we're looking at training load how well trained you are and uh and basically how hard you have gone for how long like to to deplete your muscle glycogen and so like so like for instance if you are um if you are training for yeah like ftp work if you if you if you do 40 minutes of ftp work and like that's pretty hard for you next time You do 40 minutes. It should feel a little easier and you should be able to do a couple more minutes. And so like you, so you keep progressively getting to the same, like to the same spot where your muscles feel like they have had that relative intensity because they can maintain that energy state for a while. Then it becomes more and more difficult as the glycogen draws down. And then you start to really get that signaling. But like for the first couple of minutes, like, you know, it's, it, it feels easy and it is easy. Right. Yeah. So. Um, so we're actually going to, it's like when, yeah, we're going to hold on. We're going to talk about that in just a second. Cause don't, don't stop the podcast here and like big brain. Oh, it feels hard. It's got to be hard. No, it does not happen like that. So, sorry, go ahead. I know. I was just saying, man, well, perhaps that, that, that can be your, your, your mental cue when you do get to the last five minutes of an FTP effort that it, that the magic does happen when, when you're going slightly extending your range. Yeah. I usually, I, Cause I, uh, I handwrite everybody's workouts. Usually, uh, whenever somebody is like reticent to do this or they just don't like doing these efforts, but I know they need them. I'll be like, look, the last couple of minutes where it's kind of sucks. This is where you make your money. This is where the magic happens. Um, and it's, and you've got to do the same thing to get there. Uh, and you actually cannot like get there pre fatigued. So like, you know, well, we'll get into it in a second anyway, because I want to, I want to talk first about the training load. Um, because, um, actually, you know what, we already touched on this. We're just going to move on. So like, let's get to our main takeaways. Um, because, you know, if you want to think about a ride being effective only in light of AMPK signaling, uh, which is one of many, don't forget that. Um, the first thing to consider with all of our practical takeaways here, before we get into the ways to not practically take away this, um, AMPK activation is not on or off. It's a range of activation because we're thinking about a proportion of your total AMPK proteins in your muscle being active. And so it's not like it's on or off, but it's like it's a range of intensity based on the range of how well your muscles are maintaining their ATP. It's almost like these things are just trying to make it more complicated to make it more. difficult for us to understand if only it could just be on or off i know it's not i wish it were a light switch there are so few things in the body that are um yeah so second thing absolute exercise intensity matters um so like if you are a if you're not riding that much if your volume is pretty low like if you're doing like five hours a week or something like that, you are pretty much in a state of perpetual noob gains. So as long as you're not overly fatiguing yourself, pretty much anything you do that feels kind of hard is probably going to be fine. But when you get really well trained, you've really got to start to focus and target this kind of stuff. So, yeah. So next thing is how close you get to fatigue matters, especially around threshold and just below. So I think here where we could perhaps give a really useful takeaway for the listeners is just to try and describe how close to fatigue that needs to be during these FTP and sweet spot efforts. Yeah, well, here's how I usually describe it. Because you do more FTP work than I do. So I want you to tell me about how you coach it and how you actually do it when you're riding. So I usually tell people to get to an 8 out of 10. And an 8 out of 10. some people could call this a nine, same difference, is where you have to really focus to keep the power up and you start staring at your computer. Otherwise, the watch are going to fall off. So how do you usually think about this? Because that's where I think you need to get to this point and then stop. Yeah, so I think the eight out of 10 is kind of more useful as a, like, before it gets hard, like how, how much does it feel I'm pushing? So I'd say when you're going up to LT1, it can just kind of happen. It just feels easy. You're just floating on it. Whereas once you start at FTP, even when you start the effort, you are actually having to concentrate to push against that gear. So that's why I'd kind of say 8 out of 10 is kind of useful for how it is whilst it's going along. I'd say for, for how, how hard it should be like within the effort. And then by the time you finished a session, it should be like, it is starting to become, yeah, quite. Yeah. You are having to really, yeah, it's grippy. You're having to concentrate. You're having to sort of use some of the, kick in some of those psychological cues of like. just, just give it another minute and just trying to distract yourself from, from the pain, embrace it. Yeah. But your breathing should be fine. It's not, it's not. Yeah. Your legs should hurt quite a lot. Um, but it's, it, I would say you are holding slightly back from that point of, of like, you know, it's, it's the end of a race, the end of a time trial, but it equally, it's not that far away from that either. Yeah. I would also say for higher intensity stuff, like let's say, Let's say you're doing like, you know, one minute race efforts, something like that. Like you're doing one minute full gas efforts to like get ready for a race where like, let's say there's a lot of one minute hills. And if you tether your one minute efforts to like your FTP, like let's say you've got to do it at like 150% or 170 or 130 or whatever percent of FTP it is. And you're doing these efforts and they feel super chill. you are not going hard enough. Like you are not getting this adaptation that you want. You are not, you're not. It's like when I see a client's doing training like this, or it's kind of like what you might be doing on a kind of unstructured group ride. I say it's, it's not, it's not like it's wasted. You know, it's not like it's, it's not negative training, but it's not, it's not negative training. It's not gonna, you know, directly make you slower, but all training has like, you know, a cost benefit and it's like maximal, it's like a very high cost for very low reward. So that's the kind of stuff you generally want to avoid. that's the kind of thing that I see with, uh, with people who, you know, do this kind of stuff. Cause I think a lot of people just want to go, how hard should I go for these? And I think some might be afraid to like really go hard. Cause well, first of all, it fucking hurts. And you also don't know, like, as, like, as you keep going hard and the watts start falling off, like, is, is this still doing anything? Can I, and I usually tell people, as long as you feel like you can still push hard, that's fine. Um, cause at some point, you know, like, and when you're, when your kind of legs leave you, or like you get to like your interval prescription, like for like one minute efforts for most average folks, I would probably give them somewhere between like four to eight. And for super advanced folks, I will probably give them between eight and like 15 on a long day. And, you know, sometimes we manipulate the restorations and like, you know, shorter rest means less Watts, but sometimes that's what we're going for for repeatability anyway. So, so if you are really going for it, you can be pretty much be assured that you're going to get some benefit as long as you feel like you can push hard with this stuff. But if you are, if you were like pushing kind of hard, but not really. And it feels pretty easy, but you just want to make it through your set. I would say you want to go harder and do less reps because I think that's going to be the higher quality training. Because if we tie it back to the AMPK signaling, what we're looking for is the energy state in the cell. Yeah, it is about you have to go. pretty hard well that's one of the reasons that stuff like you know stuff like 30 30s and 15 15s like these one of the reasons that these are beneficial is that they get into they make some big power they get into big motor units and um and kind of regardless of um you know, like of, of anything else, like, as long as you feel like you're pushing hard and you are creating horrible cellular energy state in your muscles, you are getting some of these benefits, a lot of these benefits. And like, that's one of the reasons that it, it benefits repeatability aside from like, you know, anaerobic capacity training, like. I think we did a Wastock a long time ago where repeatedly getting into bigger motor units, like we were talking about, this will lead to some aerobic adaptation in these bigger motor units. And that's one of the things that I look at when people come to me like, oh, I have really bad repeatability. And so we do all the aerobic training, but we also do this kind of stuff too. Just one thing this has got me onto thinking is when we talk about... FTP as a percentage, a fraction of your VO2 max. If someone who was FTP was a lower percentage of their VO2 max, that would perhaps imply that they need to target more the peripheral adaptations and you might be someone who was... might want to focus their training more on ampk activation potentially potentially but there's a lot of a lot of things where we could go wrong with this kind of thinking but there's a lot of ways we can go right for sure um i would say for somebody like this well first of all it's very difficult to actually tell even if you've got like wko5 um Uh, cause you know, in that, um, in the determinants of, uh, you know, endurance and well-trained cyclist paper from, you know, Coyle and Coggin and, and, uh, the other two guys who I forget, um, you know, they, they showed that the range in well-trained people is like, you know, it was like 65 to 85% is where your threshold is. It's huge. It's huge range. Yeah. Uh, but you know, for the most part, most people, uh, I, I've seen a couple of people in the 70% range. I'm one of them. 70, 75%. Most people are in the 80 to 85% range who have been training a long time. And, and one of the things that helps with this kind of stuff is actually just high volume. It really brings the stuff up and it's, you don't have to do the high intensity, although that's fine too. But like, you know, when, when we look at studies that have people exercising at 65% VO2 max, if you make it three hours, like clearly that's not your threshold, but for most people. Um, you know, it can be a range of like, so for some people that might've been like, it might've felt harder. That might've felt like more like sweet spot and they didn't make a three hours. It was not reported if that happened or like, you know, we don't know. Uh, maybe it's self-selected out people with a threshold of like 80, 85%. Um, and so, so like, I, I'm going to default to like, I'm going to say if you are pretty well trained, like below like sweet spot. like like 85 90 of threshold is probably not getting you any intensity benefits like like riding a tempo lt1 uh this is i'm getting ahead of myself with this but like i've got a note on this later about how not to big brain it but like like if you are riding at tempo just because you're making more lactate like you're over lt1 does not necessarily mean you are not maintaining cellular energy state um especially if you're well trained like some well-trained people can do absolutely ridiculous amounts of tempo work and you know go through a lot of glycogen but like first they're not gonna use enough glycogen to to like get fatigued i've seen people do like six hours of tempo work like without fatigue yeah and that's one of the things that like it costs it costs you it makes you like tired but it's not like this is back to that like cost benefit of all training and this is the sort of thing that has a really high cost for a six hour endurance ride with a coffee stop and get yeah get the same things yeah you're less tired and you're ready to go the next day for something harder um yeah so okay so let's get back to our main takeaways here uh we're almost through these so your starting glycogen levels don't matter to activate ampk but they matter for exercise intensity and duration they matter a lot for that and so despite that the review says like starting levels don't matter we know putting all the pieces together, they are actually critically important to getting really good high-intensity aerobic adaptations. So this is where just fueling for the work required is really key. And yeah, just from the more coaching I've been doing, almost the more I realize that if you get the basics of fueling right, It's actually something that even at a very high level, I've found that people don't do right. And if you can fix it, it really is just a game changer. Yeah, absolutely. Okay, so next we have total exercise duration is not critical for AMPK signaling. It is critical for many other things. And actually, Marinus, maybe you can say a brief word on this. Because when you started knowing me and my client who's coaching you, you started writing more. And you're not getting APK activation out of this, but you're finding that it does have a huge benefit, right? Yeah, definitely. So yeah, over the last year, it's my first year besides my coaching company, being more or less. full-time rider and i've increased my volume a lot and the first time i saw you know multiple seven eight hour endurance rides in a week and 30 plus hours i i thought it was i thought it was crazy um um but i i i thought i'd you know i just i'll have some faith in this i'll i'll give it a go and i was i couldn't believe how how much it made yeah the gains i got from it and um I've been using it with my clients, just these extra oversized endurance rides. What I find particularly amazing is if you really keep the intensity really easy and keep the fueling really high, like these eight-hour rides, let's think I've been doing them quite often. less than 50% of FTP, something like 45%, and taking on about 90, 100, sometimes 120 grams of carbs an hour. And I remember one particular occasion, just one recovery ride the next day, and I did a really good session of five-minute VO2 efforts, including five-minute PB on the first one. Yeah, it really does, does help. Yeah. Yeah. Okay, cool. All right. So I just wanted to sneak that in there too, into our Whatstock episode on other stuff. So, okay. So our last point, our last practical takeaway from this is that the less well-trained you are, the less any of this stuff matters. The more you can just go ride your bike, have a snack and have fun. But after a couple of weeks, you know. sometimes a couple of months for people, you know, you got to bring the intensity up because kind of riding at that like middle intensity at some point just stops benefiting you. And, and this actually goes back to our, like, you know, the cyclist training Bible, like the periodization one-on-one, like you start with easy stuff and then you like. add in some moderate intensity stuff, then you get to the hard stuff. Like there's a reason that kind of stuff works. Like from an AMPK signaling perspective, like that's, that's pretty basic. It's like a pretty simple progression. It's a pretty simple like intensity overload that, you know, it should work for a lot of people. And actually you, we, before the podcast, you and I were talking about one of your clients who's like, you know, still getting benefits from like the, the kind of moderate intensity stuff. And you're like, I want to keep rolling with this. I don't need to like overwork this guy. Yeah, absolutely. So a new client who I've, who I had, and he was relatively new to cycling. He really hadn't done the work that much. He started cycling in January and he'd been doing kind of like, what I think a lot of beginners do is just this like medium hard every day. And they find they can only do about eight to 10 hours a week because of that, because they're always. doing this high cost, low benefit training. So then I pulled him right back, got him to just ride endurance five days a week, day off, and then just once a week of this sweet spot or FTP type work. And in those first four months of being self-coached, he'd only improved by about... I think his FTP went from 250 to 260. And then with one month of increasing his volume a lot, doing less intensity, his FTP went up to 310. And then another month of, again, more volume and just still intensity, just FTP and sweet spot type stuff once a week. And now his FTP is up to 330. Oh God. Yeah. Establishment people hate him. Like get faster with less intense training. Yeah. Oh yeah. No, I mean, that's, I think that's a, that's a great thing. Cause like that's, that's clear as somebody who's benefiting from like just more of the basics and not overdoing it. Cause I think, I think one of the lessons that people should take from this is that the practical implications of everything. uh like i think honestly i think this is part of one of the reasons that the podcast connects with some people because i try to make sure that what we're talking about matches with people's actual real world experience because a lot of the time like if somebody goes oh well if i if i do x intervals because it's got you know it like clears more lactate like while i'm doing them or whatever i should be able to blah blah blah and therefore my ftp will go up and a lot of the time they don't see shit and no uh and so that's why um you know, when, you know, like the implications of all the AMPK stuff that we've been talking about, like, it's pretty simple. Like at first just do whatever, everything helps at, you know, then after a few weeks or a few months, you've got to start progressing, progressively overloading something a little bit. Um, and then. You maintain some intensity and you push out from your previous capability, slow progressive overload. And then for hard efforts like over FTP, you can't pussyfoot around this stuff. You've got to really give it a good whack or you're really not going to be getting much benefit out of it. If it's not making you... question why you know whether you really want it then it's probably yeah well i think also when it comes to like and this is the start of our like how not to do it um one of the ways how not to do it is like if you can do the exact same interval set at the exact same intensity several days in a row chances are it's not doing diddly dick for you like it like if you can like back to back ftp rides like adding time and zone like yeah that's great A lot of people can, a lot of people are, are not able to do that. So you've got to like, you know, spread it out a little more. And so that's one of those things where like, but if you do two by 20 every single day, or like if you do, if you can do like an hour and a half, a sweet spot and you're doing 40 minutes a day, like five times a week, why it's not doing anything. So, so I, I think the phrase like junk miles to me, like I, I think I would never call like, long, easy rides, junk miles. But I think, like, junk intensity like this is much more problematic. And the amount of clients I have come to me from having had previous coaches setting them four or five days a week of junk intensity, like, it's been really quite surprising to me. And I find it quite... irresponsible really of coaches to have been setting that people because it not only does it mess up your training and your progression but it's actually going to like mess up your everyday life like the carry through of that because it's such high fatigue and you're always being stressed about well I've got to be able to do these efforts today you're never getting to mentally switch off as well and I think that's really important and when you dial people back to you know you can't switch on once you're well trained you can't switch on a mpk four or five days a week year round yeah you have you have to have your easy days so you can yeah be fresh enough to go hard enough to get other signaling benefits from the easy days too it's not like a mpk is the only thing out there which i think i think some people forget about um like i i remember i had a discussion with somebody somewhere a while ago, they were like, oh yeah, well, AMPK is like the driver of mitochondrial biogenesis. And I'm like, it's not the driver, it's a driver. And it's like, he seemed to be, he, they, whoever they were, seemed to be one of those people who like had big brained it all in the wrong way. Because if you think AMPK is like the one true signal, it's like the one true religion for exercise adaptation and mitochondrial biogenesis, then a logical conclusion you could have is that every single ride needs to be done to absolute death and fatigue. Um, and you know, we've seen like hard evidence in this podcast so far that like, if like you're going to do a three hour ride and it's like, you know, I don't know, like 75% of FTP and like, that's, that's hard for you. And like you do three hours, four hours and you empty the tank. Um, you don't get much more benefit at all. from doing a four-hour easy ride. In fact, you actually get a lot more problems because it's so fatiguing. Equally, if you took a training program that's worked, that has intensity, let's say, one to three times per week, and you took away all the endurance rides and recovery rides around that, I guarantee you not get the same adaptation or anywhere near it. You do get a lot of really important adaptations from just riding easy that support the adaptations you're trying to get from the hard days where you are switching on AMP. And that's, I mean, and that's actually a really good point because, I mean, I've been saying this for a long time and, you know, because somebody really smart said it to me once and I was like, wow, boy, boy, was he right. And it's that, it's that there's no one intensity. There's no one thing that's going to like really improve you overall. Like you've got to do everything. Yeah. Um, so, and actually one of the other things, um, that you might think happens is like, uh, well, um, I like the, um, so like this is going to get into like exercise intensity and like tempo and stuff. Cause I think this is where, um, like in the, in the arguments I've had arguments, discussions, whatever you want to call them, I, they're, they're a little bit of both. Um, so, you know, the less well-trained you are, um, or sorry, the more well-trained you are and the less middle intensity workouts are going to actually activate this kind of stuff. And it'll just be the same benefits as lower intensity rides. And I've said this for so long. It's almost like I've been saying this for years at this point. Actually, I have. So for instance, let's dig into the McConnell study. About two hours at 65% VO2 max not activating AMPK for well-trained people. The well-trained people, for absolute context, riding 200 to 400. Oh, yeah. So in the study, it was not the same as the Eukindrup and Hawley definitions. They were riding 200 to 400 kilometers a week. So 120 to 240 miles. And in the 10 to 20 hours a week range. And they rode 120 minutes at 65% VO2 max. So this is over LT1, probably for all of these folks. Is this the carbohydrate feeding study? I do not believe it is. This is the not activating AMPK study from McConnell. So I looked into the paper's figures because I had forgotten what they looked like. And in figure four, we see everyone with a low level of activation at 30 minutes. But in untrained people, the NPK activation more than doubles at minute 120. And it's barely up. It doesn't pass the statistical significance test for the trained people. And it doesn't even pass it by eyeball. You would go, that's a little elevated, but it could easily be error. It's done nothing. Yeah. So these people are riding around 85% FTP on average, I would say. So if you're out and doing, and you're well-trained, you're normally riding, and like, let's say you're doing two to four hour rides to exhaustion at like something like 70%, 70% FTP or whatever. Cause I know that's where a lot of people will like try to peg their endurance rides. You're actually probably not getting nearly as much out of this as you should. And, and. you know, I would rather somebody like go out once or twice and ride sweet spot hard than like, you know, do this kind of like middling intensity all the time because of the fatigue and not a lot of benefit. And so like, and so I think at first actually, um, actually including in, uh, I originally heard David Bishop on the inside exercise podcast and he was talking about how like, you know, he would, yeah, he would want to do more. more like the easy rides over LT1 to get some AMPK activation benefit. And I'm like, oh, dude. McConnell himself, who's hosting the podcast, he's never put the numbers together relative to threshold, where it's like, oh, no, you actually don't get much at all, as McConnell's study showed. Did you just say he suggested doing easy rides over LT1? Yeah, over LT1. Because I also think that he wasn't considering high volume for a lot of people. not an easy, easy ride. I was just like saying, do, do an easy ride. Not easy. Yeah. It's like, it's like, do your easy rides like at tempo pace. And I actually, I have this discussion with some of my clients, some of them who've been training for years and years and years and years and years. And like a lot of them, you know, are, are kind of conditioned from their previous training and previous coaches or self training where they want to like get as many Watts out of every ride as possible. But, you know, Some of the diesel engines on some of these pros, it is unconscionable how hard they can ride for how long. And when you are out there kind of riding a little over LT1, kind of getting tired on every ride, there's absolutely no benefits from that. And all this data shows it. You might get some benefits from other stuff a little bit, but it's better if you ride hard when you're supposed to ride hard and ride easy when you should ride easy. And doing the middle intensity all the time, junk intensity, just like you said. I think another cue you can perhaps tell yourself if you're caught on a ride doing that and thinking that it's going to help you, just ask yourself. Could I win a race by riding off the bunch at this intensity? And if the answer is no, then it's not going to work. Well, maybe you could win Unbound riding at that intensity. I mean, actually, I think one of the other things to consider here is kind of like we said of needing good glycogen stores and having low glycogen at the end of your ride. I've seen also be bandied about as one of those things like, oh, you've got to have low glycogen at the end of every ride to get all your maximum aerobic benefits from it. And that's absolutely not true because that's the sprinter before the lead out train again. It's not necessarily the fact that you've got low glycogen at the end of your ride. It's the fact that you were able to perturb your cellular energy state. And if you go in fatigued enough that you cannot ride. many hard watts to the duration that your cells can maintain that energy stress. Let's say you're absolutely fucked and you're exhausted and you go out and you ride four hours at tempo pace, but it's like you could easily in a race do seven or eight at that pace. You didn't do anything. I don't care how low your glycogen stores are at the end of this thing. You did nothing. You made yourself tired. It also just doesn't sound like fun. No, it's misery. Like, why would you do that? It sucks. It sounds awful, yeah. And so, like, that's the junk intensity thing. That's the black hole of middle intensity. And you probably, like, spending time glycogen depleted is going to, especially if you don't replenish it quickly when you get home, it's really suppressing your immunity. Yes. You get sick a lot. You get injuries. Um, yeah. Like you get, you get, um, you know, hormonal problems, like, uh, like people who are in like chronic energy state. Like if you, like if you're grumpy, if you got brain fog, um, and one of the things that people don't want to talk about a lot, but I will like you lose your sex drive. Like it's, it's, it's horrible. And like, and my, a lot of my clients actually tell me, tell me about their sex drive. Like it's up, it's down, whatever. And I'm like, okay, well, this is a good clue. Um, and so, you know, and you know, if you're a person who generally when you're not training, doesn't have high sex drive, like maybe it's not a good market for you, but like for a lot of people it actually, it actually is. So, um, um, and so, but, but, but back to the immune suppression, if, if, if that, if, if being, you know, glycogen depleted even did slightly, you know, augment the stimulus from the training. If it means that you're going to get ill even once more per year, lose one week of extra training per year, that tiny augmentation of the stimulus has already been canceled out by that week of training. Well, and if you come back from that week of training really strong because you never rest, I mean, I'd say that was probably beneficial. Some people need to lose that week of training, but most people don't. You're right. Um, especially if you're like a professional athlete, um, you know, riding at the level you're at, you know, losing a week, that can be a lot. Um, and so, um, and so actually, and it could mean, it could mean you miss a race. Could mean you miss a race. Could mean you miss an important result, uh, or more, um, you know, team connections, stuff like that. So like, uh, another way to do this badly is like to start every workout glycogen depleted. Um, and to also think that like, if something feels harder, it is harder. But like I just said, if you cannot ride hard enough to create these, these, uh, this energy stress from your exercise, uh, is if you like, if you're, if you're like, man, my FTP Watts are down today. Like I'm going to ride, you know, if I can only do like sweet spot today for like 40 minutes, normally I can do FTP for 90 or not 90, like an hour. like you are it this is not a good workout it's not you have to be able to ride hard enough the absolute intensity matters like we said um so don't so don't uh yeah try and do your ftp efforts that aren't like on terrain that doesn't suit you like if if you know you produce better power on a climb and you've got a climb that's convenient and close to you And then go and do that. I don't think you have to do it on the trainer. It's certain. Yeah. Well, I would say that unless you have problems pushing on flat ground and that's a skill that you need, like then, yeah, we're going to, we're going to, I would do both. Um, I would be like half your intervals. I want you flat ground where, where you feel uncomfortable and half of them like go uphill where you feel really good. Um, but I would also say, uh, cause I actually dug into that normoxia hypoxia study about absolute exercise intensity. Um, where they saw the, you know, big improvements in AMPK activation at like the 72% of normoxia, but not at hypoxia is the same exercise intensity. Um, right. So, um, so in that study, um, the participants who ate 90 grams an hour, um, versus zero versus 45, actually, was that the normoxia study? Um, oh no, sorry. Yeah. That was, this is the one from, this is the one from, uh, uh, Wattstock 40. where we looked at how eating food doesn't impact your cellular adaptations. So people who ate 90 grams an hour saw a big bump in P38 activation. We're going to talk about that in another podcast. But they also saw a huge bump in calcium, CAMK2 activation for three hours of tempo riding. I did look into that more. It looks like they're about LT1 because it was about 208 watts for people with their VO2 max and average was 60.5, which sounds like about LT1. And then this is their study with the performance test at the end. And they took the muscle biopsies after that sub-maximal exercise. You could have hypothesized that perhaps the extra carbohydrate feeding was meaning that it canceled out the difference because it enabled them to do that test at the end at a higher intensity. But actually, all the biopsies were taken before they did that high intensity test. Yeah, so it was just like after riding tempo. Yeah, so the easy riding was done either at the same intensity. But you still got more adaptation by having more carbohydrate. So even if it doesn't make you do more work, it's still giving you more adaptation, which I thought was quite interesting. Yeah, I thought it was really interesting too. It really benefits you. Because one of the other ways that I conjured to big brain this kind of stuff is to ride fasted. Because when you get out to like... when you're out near the end of your threshold intervals, it feels hard, right? And so one of the ways to misinterpret this would be to go, oh, everything that feels hard is activating AMPK and getting that intensity activation. That is absolutely not the case. So you cannot do this. Your RPE does not match your cellular things because your brain is integrating so many different signals, but your muscles are just like, Am I working or am I not working? Like what's going on here? Like, am I working hard? Am I working moderately? Am I not working that hard? So if you can't push hard, you are not going to get the adaptation that you want from like, you know, the intensity that you're trying to achieve, even if it feels hard. Yeah. So like, and the same goes for like riding facet or with low glycogen or any of this kind of stuff. Like it just doesn't work. Especially for AMPK activation, there are some other ways that this could potentially give adaptations. But I want to do this in another Wattstock and mostly tell people not to do it. But if you are going to do it, I will give you some guidelines and what the actual stimulus could be. But for AMPK, there's nothing here. There's literally zero. Don't ride fast. Don't restrict carbohydrate intake. Don't do everything hard just because it's hard. Especially once you become better trained, you are potentially screwing yourself in the short term and long term by making everything too hard, not eating enough, or not training to the intensities that your body is capable of. I'd say it's the sort of thing that you can maybe get away with more if you're if you're training less and or you're less ambitious so a lot of these people the instagram influencers or like that you might see that are promoting extreme you've seen more of them lately than i have so please yeah please tell me about them well well so yeah if like frequently i'll i'll get clients saying oh no i've got a mate or i've seen this person who's you know on a ketogenic diet and they seem to be doing great or they're doing all these fasted rides and, and it seems to be really working for them. Um, and I, even in the past, you know, pros used to do, I, you know, not, not long ago, Bradley Wiggins was cited as, as having done six hour fasted rides. And, um, so there is, there is a lot of stuff out about it there, but I would say that, yes, it's the more, the higher level you're trying to. uh compete at that the more careful you have to be about this you absolutely have to be careful because especially like the like uh once you get very strong like the energy deficit that you create energy demand it's huge like and you you you look at like kilojoules per week way more than i do uh so like you know i i wouldn't be surprised to see you doing like 30 000 kilojoules in a week and like you know how long does that take to eat back 

So actually, this gets to the last point about how not to big brain this shit. And potentially, this is like the worst and dumbest way to do it, which is why I left it for last, because I can't imagine many people would consider this. But this is also what not to do. If you think that leaving your cellular glycogen levels low after you're done training and restricting carbohydrates, you might think that this could help activate AMPK. Does not. It absolutely does not. So like while you're starting glycogen levels have nothing to do with AMPK activation, because you've got to like work hard for a while to get this to happen. And your end exercise activation does because of the intensity dependent way of how you get there. So the question is, if you stop working out and then you don't eat to keep your glycogen stores low, are you keeping AMPK more active? No, definitively you are not. So what happens when you stop exercising, like, cause, cause in a lot of stuff where, where you look at like concurrent training, a lot of people say, and I've said it myself, your AMPK activation level is slightly above baseline for a couple hours after you're done exercising. It's like 10% more while like during intense exercise, it's like, you know, hugely more like 10 times or five times or whatever. It's like, like after you're done exercising, AMPK activation goes damn near baseline levels. And like barely statistically significantly higher, like barely. And so you're not getting anything by restricting food. And actually you are screwing yourself in the long run because you are like, you know, this is a good window to like rebuild your glycogen stores. This is called the glycogen window for a reason. And like, yeah, if you don't have intense exercise to do for like a week, it's less important that you, you know. eat within this like half hour, hour after exercise. But like, if you've got a double day or you got hard stuff the next day, you absolutely need to take advantage of this. And by, by restricting food here, you are not helping yourself in the least. And, um, I think back to what you're saying about, uh, AMPK only being activated for like pretty much whilst you are that, that, that higher exercise duration. That's why we find in well-trained people, there is kind of quite a narrow window of intensity that is going to work well for this. And that is stuff that's above sweet spot and up to and at around FTP. And even over it, yeah. Because if you go too much over it, then it's like you can't do enough work potentially once you're well-trained. Well, that's what depends on... Now, cause now we're in a question of like, what motor units do we want to train? Because, you know, when you are doing FTP work, like you are recruiting more motor units as you go and you're training them up. But like for most people, like there are a few, a handful of exceptions. But for most people, like if you are only doing threshold work and then you get into a crit, most people are not going to be good at repeatedly accelerating. And I remember back when I was racing crits, like I was not like that. It took me like five to. five to six races to really feel like I could really race. And the one year I actually did deliberate training of like repeated sprints for like an hour, um, five seconds, 10 seconds, like every minute or something like that. Uh, I like now we are, I was like max intensity short likes and repeatable. And so like, I would do, I don't know, like 60 more, like a hundred sprints. in training by the way this is very hard it requires a lot of rest afterwards um but like when i got to races i could race like i could race two or three crits back to back like without losing my height and repeatability because i had trained my big motor units um and one of the reasons is like yeah ampk activation um is a big one, but also the fact that those motor units are being recruited at all. And so they're like building glycogen stores, they're building mitochondria, they're becoming more aerobically trained. Like, because it's not just like FTP, because this is an easy one to think about. But like when you're doing five minute efforts, if you're doing them for like race efforts, you want to get better at like smashing five minute hard hills. You got to do five minute efforts. Like if you do them a little sub maximally, that's fine. But like, you've got to get pretty damn close to being like at the end of your limit for these things. You can't do them just kind of like, oh yeah, this is totally fine. I was breathing out of my nose for five minutes. Like you probably, unless you're like moderately trained, you are probably needing to actually really go hard to make these actually benefit you. So Coley, can I put to you a kind of hypothesis potentially? Big brained way that you could perhaps pick apart. So one thing I've heard a coach saying is that the reason the sort of works at slightly above FTP works to like, so, you know, doing eight, 10 minute intervals, slightly above FTP, how this would work to increase your FTP is that you want to be getting into the motor units that are responsible for riding slightly above it to then make your FTP higher effectively. Pick that. Why does that not work for the listeners? Why that does not work for the listeners is basically your FTP is much more linked to your VO2 max than it is to your motor units being aerobically trained. like by a 99%. So if you've raised VO2 max, you are going to raise your threshold. That's why VO2 max is the ceiling on your threshold. So if you are training the motor units just above your FTP, the way that this would raise your FTP is if it is raising your VO2 max. It is not because you're training bigger motor units. That is absolutely a thing for sure. But when it comes to the actual muscular adaptation, like does this also train the muscles to a good degree? Sure, it does. But it's like, it's short. It's shorter than you can do at threshold. And if you do them just barely above threshold, you know, you're missing a duration component here. Duration is such a huge driver of exercise adaptations like at and below threshold. And, you know, just above. So like, if you can do, you know, if you do, if you go out and you do a bunch of 30 minute time trials and you, and you can hold your threshold for like 60 minutes, like, is this going to raise your VO2 max? Or, you know, train your bigger motor. It'll train your bigger motor units a little bit. Yeah, sure. Is it going to raise your VO2 max for most well-trained people? No, it won't. So like the number of people I've seen try to do this, like, and, you know, pull your FTP up from above, like. This is what VO2max work does. It's not a motor unit thing. Just being aerobically trained does not, and you might think, oh, it clears lactate. Therefore, if I can clear lactate more, therefore I will raise my FTP because FTP is where you stop, where you can't clear lactate anymore. But the lactate comes as a secondary consequence of other conditions. Like that happened first and then the lactate comes. It's not like your body's making lactate obligately and then suddenly, okay, now I can clear it. My FTP is higher. It does not work like that. So does that make sense? Yeah, yeah. It just explains why a lot of what people might call... pull workouts don't don't work oh interesting um and actually i would say that's the same thing for lt1 like like oh you want to raise your lt1 like right above it a lot like no if you want to raise it you ride just below it or decently below it a lot and way below 100 yeah Uh, well, a hundred Watts for you, but for me, it's like 20, 30. Um, but like, yeah, like my, my LT1, like a hundred Watts. And if I go out and I do a three hour endurance ride, I'm going to do it at like 70. Um, cause that's all I need. And that that's, and that's it. Then I rest, I recover and it's higher. Like I've, I've raised it like, you know, uh, you know, 10 or 15 Watts since I like started doing more riding again recently. And like, you know, it's, um, it's, it's. It's, it's a pretty simple process. Like you don't need to, you know, the pulling it, pulling it up is like something that happens if you're kind of well-trained, but like, I swear to God, most people, if you go back to doing the program that you did when you were first starting training and you tried to do it now that you've been training for three, four or five years, it's not going to work. So, um, so we've gone on. Pretty damn long. So would you like to get to some of our listener questions before we wrap this up? Yeah, absolutely. Yeah, that'd be fantastic. All right. Okay, I got to roast somebody. When I ask for questions on the podcast on like a topic, when people ask me questions not on the topic, I usually skip them. But we're not going to talk about cramps. This is AMPK activation. We're not going to talk about cramps. What is AMPK? We got to that one. Oh, actually, this is actually not a bad one. Thanks, friends. If fasting, apple cider vinegar, and smoking elevate AMPK, why can't I just do that and be Tadek Pogacar? 

The answer is because you're not actually exercising when you do it. Like exercise is the real thing. Because your energy state is not compromised. The energy state of your cells is not compromised. Yeah, like smoking isn't going to activate AMPK in your quads. Yeah. I don't think. Apple cider vinegar. Does apple cider vinegar activate AMPK in your muscles? Like that's strange. I couldn't imagine that would happen. I've heard it reduces the insulin response to food. Well, I mean, based on the fact that... I've never... Perhaps this person's getting confused. I think he's taking the piss a little bit. I've damned with him a little bit. He's a little, you know, for a German, he's a little sarcastic and I appreciate that for a German or anybody really. Okay. Are intervals at the end of a zone two session really beneficial for muscular endurance or is it just mental? So like in light of APK signaling, let's consider this. Is it better to do intervals at the end of your ride or like, you know, potentially throughout or at the beginning when you are more fresh? What do you think? Definitely, in terms of AMPK, it's better to do them at the start of the ride so that you can produce that high enough power output for long enough, as we said, is necessary. Because if you leave it till the end of your ride, for example, you might have depleted some glycogen, because believe it or not, even easy riding does deplete glycogen. Mostly fat, but yeah, a good amount of glycogen gets worked. Mostly fat, but yeah. So you're not going to be fresh enough. to do high enough intensity for long enough to be fatiguing the relevant muscle fibers in a way to actually create the change in energy state in your cells to activate AMPK that we're looking for. I would say for somebody like you, for somebody with endurance as good as yours, Like you, you barely fatigue as you ride for a couple hours. Uh, and so like, no, you start to feel better. Yeah. And so for you, like I would want you to do them when you feel best, um, or like throughout a ride, cause it's not going to be nearly as important. Like, and you and, um, you and our mutual friend, um, you know, like, like you guys can both do like a five minute max effort every hour during a seven hour ride. And they're basically going to be like within like 20 Watts of, of every other effort. As long as you've been feeling well. Yeah, exactly. I would say for most people, yeah, do them while you're fresh. If I were going to go do hard efforts and on a long ride, as badly aerobically trained as I am, and as well strength trained as I am at this point, I would want to do them right off the bat when I'm nice and fresh, and then I can get a snack and spin easy. Because otherwise, yeah, I can't ride hard enough. Not that it would matter that much for me as trained as I am, because I am in the quote unquote trained. category and not well-trained. So, um, do long, low cadence efforts at like 60 to 75 RPM near sweet spot. Are they good for large motor unit endurance? No, I would say maybe, um, so are you getting into larger motor units when you do this? The answer is yes. Um, how large, I think it depends on the muscle force and all that and how fatigued they are. Cause as you fatigue, you recruit more. Uh, but I would say you want to, um, I, I personally would rather do harder, like actual, like efforts over threshold at like normal cadence. Cause it's, it's so much more specific to your race demands. And I pretty much only give people like low cadence stuff like this. If it's a deliberate weakness, like if somebody is having trouble climbing a mountain at like 70 RPM at the end of a race, but I know normally if at the end of a race, like on flat ground, they can do normal power and their power outputs reduced. Like, yeah, we're going to train them to like, you know, like do the low cadence that they are complaining about. that they, that they are not strong at. So that's the one time I would really do it, but otherwise I would rather use like specific efforts. Yeah. I think this comes back to what we've mentioned throughout the podcast is that, uh, you want, um, like it is about the absolute, uh, absolute power, not, not, and the, the, the absolute metabolic rate. the power output is what drives that and, and the cadence, whether it may, if it makes it feel harder, it, it doesn't mean that it doesn't change the, the metabolic cost, you know, the total energy demand on, on your cells. And that's what's matters for. So if we, if we are strictly talking about AMPK, then, then doing them at a lower cadence isn't, isn't going to affect that. Yeah. Yeah. It actually would spread out the, the metabolic load throughout more muscle fibers. By riding in lower cadence. Yeah, because if you're doing 300 watts at 70 RPM versus 300 watts at 110 RPM, the 110 RPM fibers, they have a greater metabolic load. Yes, yeah, yeah. Because mostly, it would be a higher proportion of type 1 fibers the higher the cadence. But that also depends on, because somebody else actually, the next question is, is there a difference in behavior between type 1 and type 2 fibers? And I would say it depends on the person. Like you have probably a whole lot more, probably have twice as much and as many slow twitch fibers as I do or more, um, I mean, relative to even muscle mass. Um, and so like I might be 80% fast twitch at this point and you're probably 80% slow twitch, but like, you know, how many of those muscle fibers you're using at any point is a good question. So like, cause here, here's one of the things that I want to do in a myths episode actually is I want to discuss with people about how. Just because you're at a certain exercise intensity does not mean you are recruiting a certain type of muscle fiber. And also some interesting takeaways I was getting from that carbohydrate study was just that you're getting still almost as much fat oxidation in the type 2a fibers as you're getting the type 1 fibers. Yeah, we did a podcast episode on that on cross-country skiers whose type 2 fibers just about equal as their slow-twitch fibers in terms of fat oxidation and aerobic capacity. Yeah, yeah. There's just more data to illustrate the point. No, yeah, you're absolutely right. Okay, we did this. How do min-max the mitochondria adaptation? What is a min-max? Minimum. Maximum? Yeah. Oh, here we go. Min-maxing is a character building strategy of maximizing a specific desirable ability, skill, or other power of character and minimizing everything else seen as undesirable. What's the question? How do you min-max the mitochondrial adaptations? Is it what? Get them. Apparently this is a gaming or a programming thing, and clearly neither of us do either of those things because I really don't know what this means. I'm checking out the wiki article on min-maxing, and I don't. Yeah, no, we're going to skip this question. Sorry, sorry, listener. We're too stupid. We are too dumb to understand this question. Oh, God. Sorry, folks. Okay. Maybe write into, yeah, Elon Musk as a podcast. Oh, God. Please know which intensity and volume distribution do you prefer for adaptations for one day road races? Okay. So I've talked about this on the podcast before. My answer is I don't consider just intensity or volume distributions before I do the planning. I plan for somebody's ability to recover and what they need in terms of like aerobic adaptations or otherwise for specific races or whatever. And so I, it's not, They're not factors I ever consider when planning. It would be like planning what percentage of carbohydrate, fats, and proteins you're going to eat for the next year. you know you would never do it because right because you might get sick and like exercise less but you're like oh god i've got to get like 90 carbs today and for my but you're like you're on like 3 000 kilojoules because you're like because you're like resting and recovering and like oh god i don't have any fats or proteins no you're gonna stick to the plan so you're gonna stick to the blood that's a great analogy um yeah so yeah i don't really do it like that um so if i have two hours to ride will i maximize adaptation by going as hard as i can i think everybody knows the answer to this one but let's uh yeah let's answer it it depends of course because if you're how well trained you are if you've never on how well trained you are yeah if you've never been when you bite much then then it is perfectly ample Although I would suggest why would you ride as hard as you can when you can ride easy and still improve really fast and build up less cumulative fatigue so that when you are more well-trained, you're ready to do the really hard stuff to actually kick on again. Yeah, actually, and having that kind of perspective on it I think is really helpful too. we uh discussed earlier it can only take seven to ten days before uh what what you need to elevate mpk ampk uh well or the yeah the significant significant reduction in ampk activation because yeah you get a significant reduction ampk activation after just seven to ten days because that was one of the earliest things that was ever found in endurance training like as an adaptation it's like oh look more mitochondria oh look yeah better control of the energy state like And by the way, energy state, this is not like some modern thing. Like I have books here from like the seventies, which, and they're talking about like, you know, the adenalate state of the cell and stuff like that. Like actually, here we go. So this was like a conference and like contributors. Here we go. Control of citrate synthase and mitochondria. Where's my favorite one here? The citrate cycle and the regulation of energy metabolism. Metabolic control in mitochondria by adenine nucleotide translocation. The cellular energy state in this stuff, this was put out in 1967. This is not a new concept. This is old stuff. This is absolute bottom of the barrel. like cellular bioenergetics, one-on-one stuff. So like, this is not like some, yeah. And that's exactly why we should just forget about all that and just listen to our, I want to actually, Marinus, I want to ask you about this though. Cause, cause like, I think in, in terms of like the modern training cycling sphere, it seems like, like not everybody obviously, but like some of the, some of the more louder folks have forgotten about this stuff or like they don't emphasize it as much as I think they should. Yeah, yeah, I completely agree, but it's just, it's like whatever is, it doesn't sell to just, yeah, it's not sexy. It's not sexy as like lactate and fats and like fasted training. Yeah. Yeah. There's no product to buy or there's no like. Yeah, there's no like image to sell. And like, and I'm not trying to sell my image with this stuff either going like, Oh, look how smart I am. Like I learned this from other people. I learned this from like the people who studied this stuff. Like I am, I am like, I am just a messenger. I don't do research. I have research projects I would like to see on this kinds of stuff, but like, you know, I don't, I don't research. I read other people's research and I, I, I try to make it into useful advice. So, um, and that's why you're not as, uh, rich or famous is he going to go sell me that he's got a richard meal and i've got a rolex it's okay it's only several magnitudes of uh orders of magnitude difference in price um anyway so okay so last couple questions um um uh something about nutrition high or low carbohydrates or just some days low and some days high uh yeah we kind of touched on this like don't this does not help ampk activation or like or the intensity because you cannot like we said you cannot maintain the high intensity you need for the duration that you need to to make all the signaling work so so what i'd say um as to like high constantly high carb or periodized is is what i find as well as like ecologically with with my clients ecologically what um I think maybe I overuse this and or misinterpret that word, but I mean when it comes to applying in a real world setting, real life, that it is quite hard to... If you can say to people that before these one to three harder rides a week... before them in the 24 hours before the two to three meals, three, four meals before that, you really need to focus on getting in enough carbohydrates to load your glycogen stores for this hard session. You're losing me. Get to the point. Because if I'm getting lost at this point, the listeners are getting lost. Okay, so what I'm saying is that you need to focus on carbohydrate intake before your hard sessions. Before your endurance rides, it doesn't really matter. High carb, low carb, medium carb, it doesn't really matter. I think the person was asking around, should I be high carb, low carb, periodized? Should some rides, would you benefit from low carb for some rides? I would actually say no, but you don't have to. I say no, but what I'd also say is... Like if it's just an endurance ride. You don't have to go like 15 grams per kilogram body weight the day before to fuel for it. No, no. So I just say just the day, just make sure you're generally in energy balance and you're eating a good healthy balanced diet with enough protein and enough micronutrients. And then if it's just endurance ride, you don't need to sweat it. It doesn't matter. Like if you want to have like two avocados because you love avocados and have a bit less pasta. Do that. It doesn't matter. Yeah. two avocados that's a lot but yeah yeah yeah but some sometimes you crave it or like there's a whole pot of hummus used by date is tomorrow you like and you can't have half a pot can you've got to finish off so like or like block of cheese it's really nice like you just want to have that like it does it doesn't matter if it's just an endurance ride that's right yeah you don't yeah fuel the work required um but like yeah but i i think i think also like yeah to go to go to our previous point like you can't um You don't get any extra benefit from like under fueling. And actually you can get, especially from your hard rides, you can actually get reduced benefit from under fueling by a lot. Yeah. It's not a way to, there's no hack though with the new. No. And in fact, there are very few hacks in general. Well, I mean, sometimes I feel like I'm the hack, but like, but I mean, there's like no bio hacks here. And I, so I think, cause like all this stuff comes down to like, All this stuff supports the very basics. Fuel well, get consistent, quality, hard training sessions when they need to be hard. You don't have to destroy yourself every single day. And AMPK and KMK2 and calcium, these are two of the big ones for aerobic adaptation. There's a lot of others. I can probably name three, four, five right off the bat. But these are the generally well-studied ones and the most well-implicated ones. They like to, to use the knowledge with these, right. Um, it just requires just the basics, just nailing the basics, like write easy when you got to go easy. So you can write hard when you need to go hard. It's, it's, uh, probably like the best takeaway for this whole thing. So, um, anything that you think we kind of forgot to touch on, or did we kind of, uh, did we kind of beat this one to death as usual? I think the one last thing, which is actually quite important, but we should be able to cover quickly, is just to say that from these studies, when you find more AMPK activation, that doesn't necessarily translate into performance. Actually, because we had talked about this beforehand, because actually in the review, they looked at different ways to look at AMPK activation. And they looked at phosphorylation of different sites because AMPK is a trimer, which means it's got three subunits that come together to make the whole protein. And they looked at acetyl-CoA carboxylase phosphorylation as like a target for AMPK activation. And a lot of the times when we see moderate AMPK activation, we can see a lot of ACC activation or phosphorylation and or which would actually deactivate it and turn off that like that. that anabolic pathway in favor of AMPKs, like catabolic pathways. So, so like, yeah, a lot of it doesn't translate directly to performance. And actually in the, the authors note that too, where like, especially in the, like the early aughts. They were doing, uh, and you know, even into the teens, like a lot of people were doing like MRNA studies, like, oh, we've got more MRNA for this thing. Therefore we should get more benefit, but like, it doesn't translate to performance. They didn't even translate it into like more mitochondrial density or enzymes or like cytochrome C or citrate synthase or like, you know, mitochondrial respiration function or anything like that. Like they just went MRNA, good enough, done. So. And the authors actually note one of the other things that in the future people should do is actually measure the ATP-AMP ratio or just the AMP concentration in general for the cells. And that would actually help the context of all this kind of stuff a lot more. But that's also one of those kind of academic things. But generally speaking, that's one of the reasons that sometimes... It's hard to pick a good representative study for the stuff that we talk about here in Wattstock because I'm looking for something that can connect all the dots. And I try to be upfront with shortcomings of studies. And if people want to criticize that and say it doesn't say what you think it says, that's totally fine. But yeah, you and me, we're trained scientists. We're doing our due diligence. You differently than me. I'm from biochem. You're from exercise fizz. you know, we have the same mentality, uh, with all this stuff. And, um, and we, and I think we have higher, high standards too, but it's difficult to like maintain the high standards sometimes, or sometimes like for our, you know, for our first study from 2001, you know, it was like, there was a lot of stuff that like, you know, people went, Oh, why would you want to do this? Like we already know XYZ. So yeah, highly contextual, but like, yeah, I agree that, um, you know, sometimes some things don't necessarily translate. from their cellular activation into performance. So that would be something else to do. And I didn't see a ton of great studies on AMPK activation and improved endurance performance that I thought were good enough to really include here. So we didn't. I guess we'll both just have to go back and do PhDs, Coley. I'm good. I feel exactly the same. You and I are busy enough at this point. Personally, I would rather be working with people and getting the very general coaching knowledge than drilling down and spending five years on this one specific aspect of performance. I'd rather have a holistic level view of all of it. Yeah. You just want to be able to get a phd student like tell them what to do and just get them to go and do it that would be nice i have helped people design studies before for this kind of stuff and you know it's a lot because i do get um i do get a lot of uh like master's students phd students reaching out like asking me to help design this stuff and i'm always happy to help and i appreciate when they asked me um because uh you know because because i think that that like they because i think people like you and me Like we, we can bridge the divide enough on this stuff. And we've got enough of a perspective on both sides of the equation that like, I think, I think people like you and me, you know, obviously not everybody needs it, but like when people ask, I think, I think we can help sometimes, but we also know how difficult it is. I do try. Yeah. All right. Well, Meredith, thanks for coming into pinch hit for Kyle today. So. I, yeah, I knew this was going to go a little long. It's been a pleasure. Yeah, it's been a lot of fun. Because you and I, we always, whenever we talk, we go long. So I knew this was going to be a longer than usual episode. But thanks, everybody, for listening. Really appreciate it. And if you want to reach out to me or Marinus, just shoot me an email, empiricalcyclingatumail.com. If you like the episode, if you want to share it, that would be great to support the podcast. And if you want to share the podcast on forums or with friends or whatever, or if you want to try to give us some cliff notes on that, that's also fine too. And if you want to donate to the show, remember we are totally free content. You can donate at empiricalcycling.com slash donate. And if you want to become a client, we are always taking on clients, students, and professionals. We are, of course, negotiable for our rates. We know that you don't make a ton of money. And if you want to consult with us too, we are always looking to consult with people. It's always a lot of fun. And so shoot me an email, empiricalcycling at gmail.com, especially right now because it's late August, actually early September. And so this is like transfer season for coaching. Um, and so it's, it's, uh, it's pretty busy. So, um, if you want to at least start a conversation, if you're thinking about it in a month or two, uh, please just let me know. And, um, or if you want to reach out to Marinus too, um, I can, uh, I'll leave links up in the show notes to Marinus too as well. So if you like, if you like, uh, what Marinus was talking about today and like his previous episode, uh, yeah, feel free to reach out to him, but we're on the empirical cycling podcast. So empirical cycling is the way to go for coaching. yeah anyway so instagram empirical cycling if you want to ask questions um on for the podcast episodes thank you for all of our listeners to asking those great questions and uh give me a follow for the weekend so with that we'll see you all next time