00:00
Hey everybody, Mikki here. You're listening to Mikkipedia and this week on the podcast I speak to returning guest Associate Professor Jose Areta to unpack one of his most recently published papers that looks at a topic widely debated in the sports nutrition field and that is energy availability. Jose takes a clear physiology first approach to explaining

00:28
in our podcast what energy availability actually means first and foremost, why it has become such a dominant concept in exercise science, we revisit whether the current narrative has become overly black and white, and we explore the recent study which I've linked in the show notes that examines the effects of a short aggressive energy deficit in a bunch of healthy men across five days, including not what just happens at a whole body level but deep within the muscle tissue itself.

00:58
We discuss the hormonal and metabolic responses to rapid weight loss, surprising findings around mitochondrial protein synthesis, and what changes in muscle and connective tissue might actually represent. Jose also reframed energy deficit as a biological stressor, one that may be adaptive in the right context, and challenges assumptions around how common and harmful low energy availability for this short period of time truly is. So this is a nuanced, obviously

01:25
evidence driven discussion that cuts through the noise offering a more balanced perspective I suppose on energy deficit performance and long term health and is an exciting area to be as he continues researching in this field. for those of you unfamiliar with Jose, he's been a podcast guest before at the start of 2023 discussing energy availability and I will link that in the show notes.

01:52
Jose Areta currently works as an associate professor in sports nutrition and metabolism at the School of Sport and Exercise Sciences at Liverpool James Moore University. He examines how nutrition interacts with exercise to shape both performance and health, with a focus on macronutrient timing and composition, the role of supplements in optimization, and the hormonal and metabolic responses to energy restriction. And I have put a link to both the paper we talk about today

02:20
and where you can find Jose over on the profiles in his academic space and also on Instagram. Before we crack on into the interview though, I would like to remind you that the best way to support this podcast is to hit the subscribe button on your favorite podcast listening platform and leave us a five star review and share it with a mate. All of these are at no cost to you, but do a ton to help put Micopedia front and center.

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amongst literally thousands of other podcasts out there so more people get to hear from the guests that I have on the show like Jose Arita. Alright guys enjoy this conversation.

03:04
Jose, really great to catch up with you in your afternoon. Thank you so much for taking time. I'm super excited to speak to you about particularly the study that was published in the FASA journal in November 2025, but also more broadly your work in the area of energy availability and I guess the practical take homes and what we could, what we might understand now in the space for athletes. So thanks so much for taking the time.

03:34
Oh, thank you, Mickey, for having me here. And yeah, it's always a pleasure to talk all things, energy availability, adaptation to exercise and performance. So yeah, thank you. Nice one. And of course, what I'll do is I will link our first conversation that we had several years ago now about your sort of your line of research in the show notes for people to if they didn't listen to it at the time. But

04:03
For now, Jose, are you able to, before we dive into the study itself, can you explain about what energy availability actually means in simple terms? Because I do think there is a little bit of confusion around it. I mean, maybe I'm wrong, but I see a lot of different um people on the top talk about the

04:23
Yeah, well, it's, you know, I've been working in this topic for a few years now, and I suppose my own understanding of the concept of energy availability has developed as well as its usefulness to, you know, diagnose whether someone in the field or in the lab might be exposed to like something that could potentially be uh negative between inverted commas or something to which, you know, the body responds to.

04:49
I think originally the concept of energy availability was developed so as for people to take maybe more into consideration the fact that uh exercise is important to be taken into account as an outlet of energy from the body and consider the energy that is ingested relative to the exercise energy expenditure.

05:19
If I'm not going to go into the like the nitty gritty, the details of the definition, because you know, I think people might be getting a bit more confused about, you know, the actual concept of energy availability and energy balance for what is worth for, you know, the study that we're going to be talking about. I think we can roughly equate, you know, 45 kilocalories per kilo fat free mass of energy availability.

05:46
to energy balance. So we're going to talk about adequate or uh normal energy availability and we can equate that to energy balance. And when we are talking about low energy availability, we're going to equate it to energy deficit. think that's for your listeners is probably the most useful thing to take out from the conversation that we're going to have ahead. We can later talk about, you

06:11
energy availability, thresholds of energy availability, to what extent is useful as a concept that we can use on the field to diagnose whether someone is in sort of low energy or not. Generally, we cannot really use it because it is very, very inaccurate measurement. We can talk about more about that in detail down the line if you would like to. Thank you, José. so with low energy availability,

06:40
Is it, um that is something that obviously can be uh created through both exercise and of course, food intake, just for clarity of people. So it's like pulling both levers, if you like, of that energy balance equation. Jose, why has low energy availability become such a big focus in sport and exercise field over the last decade or so, particularly in like your, not just your group, but

07:10
there's been a lot of publications and I see a lot of discussion on it out on X and places like that. Yeah, I suppose the development of this concept as core in the area can be tracked back to the 90s when the concept was developed. Initially, this concept was developed to study oh female athletes that had amenorrhea. And the work of Professor Anne Louck did the first few steps of applying concepts that were

07:39
had been developed to understand the biology of animals in laboratory conditions and in pre-living conditions to study humans. And in this case, she was using this concept, as you were saying, you can decrease energy availability from decreasing energy intake or increasing exercise energy expenditure. Same as energy deficit, you can have an energy deficit from.

08:07
increasing energy expenditure or decreasing energy intake or a combination of both. um yeah, because it was not really understood, you know, why females had amenorrhea at that time, and you know, from the the increasing of participations of females in sports since the 60s, then they were like, okay, we need we need to understand this. One of the things that they were suspecting that was the reason for the

08:36
in Aria was that the fact that there was some sort of like energy drain. And so uh the work of Anne Lauch became sort of key m in developing the first research that was able to independently uh assess the effect of exercise from the effect of energy deficit on the development of some of the sort of key endoprain responses.

09:05
that were associated to A-minorea. from then onwards, so what has become to know that the female athlete triad, which was this concept that talked about the sort of coexistence of eating disorders, low bone mineral density and A-minorea went to replace as one of the legs of the triad instead of being eating disorders, it went to be like low energy availability.

09:34
And so it's like low energy availability with or without eating disorders. So at that point, I think that's a key inflection point that typically is not talked about or is not talked about at all or often enough that, you know, the trial just replaced uh eating disorders and, you know, eating disorders are more like psychiatric condition. And in that case, it went to be more of a uh condition related to not having enough uh energy, thanks to the excellent work of Professor Anne Lausen.

10:04
And so I think that was probably the point. said, OK, energy is extremely important for the development of these sort of negative consequences. Let's call them, you know, like low bone density, suppression of reproductive function, and so on. And uh as the concept of the triad developed, you know, in 2014, there was this other theoretical model that had been developed.

10:33
uh pushed by the International Olympic Committee called the Relative Energy Deficiency in Sport. The Relative Energy Deficiency in Sport has at its core the concept of low energy availability. So based on this model, low energy availability is the sole cause of the whole range of functional and physiological sort of dysregulations that are caused by this one factor.

11:04
And that's why it's become really, really popular because they said, there's loads of athletes that have problems, a whole range of problems. And oh through the use of this model, then you can theoretically pinpoint the origin of the problem to low energy. And because all the problems that are highlighted by reds are so popular, they're so widespread.

11:33
that it seems to be an explanation for a whole range of different problems experienced by athletes. And therefore, a lot of people are interested in solving that problem, which is logical. And because there is this suspect, which is low energy availability, it has got a lot of attention. Yeah, OK. So a couple of things. And you did mention that we will talk about thresholds for low energy availability.

12:01
later, but it could be really useful, to distinguish between... I'm not sure if that's the right word, but I talk to a lot of people who say to me, I'm in low energy availability, actually what they really mean is that they may be in a calorie deficit because the two aren't the same, are they? And is it to do with the thresholds which... uh

12:26
I think, well, there's less energy available when you're in a calorie deficit because you're trying to burn the energy that's on your body to help improve body composition or whatever. So you're not taking in as much food, but it's not the same as just being in a calorie deficit, it? Well, know, it's well, then we have to go into the details. I can talk about this in quite detail, but...

12:52
You know, for all we know, low energy availability is equal to energy deficit. I'm going to go into more details about this. We did a review in 2021, publishing the European Journal of Applied Physiology, looking at all the studies that have sort of controlled low energy availability in a lab setting that are the only studies that allow you to draw some sort of like causal relationship between energy availability and

13:21
what's happening. And we saw a very clear sort of linear relationship between the degree of energy availability that an individual was exposed to and the weight loss. So, it's just like the less energy availability, the more weight loss. So, okay, these are short studies whereby, you know, you see the direct effect of energy availability quite directly and you can see,

13:49
at least for the short term, there doesn't seem to be any differences. Now, what happens is that one of the reasons why the concept of energy availability was proposed was with this idea that the body adjusts to being in a new state of energy, of a new state of energy. So you can, if you're exposed theoretically for long enough to low energy availability,

14:16
your body is going to adjust to that new level of energy by decreasing the amount of energy that it's using to maintain different systems. It's this idea of sort of metabolic adaptation. Therefore, with the idea that if you are in low energy availability for a prolonged period of time, you can reach a state of energy balance, but being a state of low energy availability, right? Because you're still in balance, but the energy that you have available is not

14:46
enough to maintain your normal physiological function. Your physiology has adapted to this sort of new state of energy. Well, now that theoretically is all very nice, but you know, in practice, it's very hard to prove that that is the case. You know, one of the things that one of the sort of few bits of evidence that might signal that that happens in a way that is quite direct, you know, experimentally.

15:14
uh is the results from the Minnesota Starvation Experiment from Ansel Keys, whereby people exposed to 12 weeks of a very severe energy deficit, by the end of those 12 weeks, the energy expenditure of individuals matched the energy balance. So by the end of those 12 weeks, they were in some sort of energy balance, but the energy availability was clearly not a healthy one.

15:42
that's a bit of an extreme case. Whether that happens with athletes to oh lower levels of energy deficit exposure is not that clear. uh This idea of metabolic compensation or the idea that the body is just the energy expenditure per amount of tissue is not that clear.

16:08
It is kind of intuitive, idea that, okay, if you eat less energy, your body adjusts to that new level of energy, but simply the body just gets smaller. You lose weight, you lose fat-free mass, you lose uh metabolically active tissue. And there are some really, really good studies looking at whether, you know, there's a decrease in the amount of energy, uh amount of different types of tissues and the...

16:37
that these data which you know have done MRI assessment that allows you to see the different types of tissues that the body has and so on, suggest that the level of uh energy expenditure per different types of tissues like very energetically expensive tissues like liver and you know like kidneys and heart and so on, doesn't seem to change that much.

17:06
Okay, interesting. And I mean, you alluded to it when you were talking about the place of low energy availability in this wider concept of relative energy deficiency in sport. Do you think that the conversation is a little bit black and white? Like deficit isn't great, energy availability is the thing that we need to focus on. Do you think it's much that the sort of dichotomous nature of that?

17:35
misses a lot of what might go on with with athletes, Jose? Yeah, 100%. I think, you we've been, we've written uh a critical piece about, uh you know, the actual concept of energy availability, well, not the concept of energy availability, but about the theoretical model of rats, basically explaining that there are quite a few sort of fallacies, you know, in the the in the model, and evidencing, you know, that the lack of

18:03
or the possibility of show causality with the existing evidence between the relationship between low energy and the things that are attributed to low energy. We're not saying low energy is not important or a potential stress factor, but we believe it's one among many others. The thing is that low energy has been shown to affect different end key endocrine axes like the

18:31
hypothalamic pituitary adrenal axis, coronal axis, and so on. And, you the effects seem to be rather clear because energy affects these axis, then people tend to go like, oh, if that hormone goes down or that hormone goes up, then it's energy. But then you have to be mindful that there are a lot of other potential, well, not potential, actual stresses in an athlete's life that can also modulate these pathways.

19:01
like sleep, stress, training volume or intensity, know, and, you know, we are a quite complex system that integrates all these stresses. And so I think that we need to move beyond a unicentric model. Energy is important. Study energy, I think, is quite relevant. But we need to look at, you know, all the key areas of an athlete's life.

19:30
that are likely to affect these sort of key endocrine axis that have a clear effect on physiology that are part of the athlete's life, like all the stresses. So it's not just energy. so people tend to think, oh, I'm not feeling good. I have reds or I have low energy availability. And we have the problem here that on the field, the assessment of energy availability are so uh

19:59
inaccurate. we can, in fact, it's not a criteria for diagnosis of reds by the actual em reds consensus statement. It's not, it's not something. So you have this model that is telling you low energy availability is the core problem, but we cannot measure it. And then it's telling you, look at all these other things that

20:28
look at the outcomes of low energy and then that's telling you that energy is the problem. But the thing is like all the supposed things downstream energy are things that are downstream. A lot of other things that are not energy as well. And they can be like known stressors for athletes. No, that makes perfect sense. And I'm curious, Jose, and we will actually get to your study, but how well received was your

20:56
Was the critique on Redis a conversation or a discussion point for you and in other groups like quite often or a lot of people on the same page? I'm curious. Yeah, it's really interesting to see that when em one writes something like critically inviting to a

21:19
reflection around the topic, sometimes the responses that you get, I they can be quite, quite different. Some people are like, like very welcoming or saying like, you know, the observations that we had didn't really match uh that sort of model that, we were, we were uh trying to use to fit, you know, what was happening. And we're very glad that there's all these new information that we can use to assess, you know, the problems. And then uh

21:45
you can see responses that are quite emotional around what we are saying, because I feel like lot of time people feel em personally attacked instead of like, why aren't they attacking anyone? We're just like saying, that we're trying to proceed in the most scientific way, which is like being objective, being critical, looking at the evidence, inviting people to look at the evidence.

22:11
And sometimes the response that you get is, well, it's not a response, it's more like an emotional reaction. And on that line, you can actually read the letter to the editor that has been sent to the journal in relation to our piece. And well, of course, we made a point in a reply path. But yeah, I think it's generating a debate where people are starting to open up.

22:38
to other ideas and to realize that maybe that model has a lot of what are called ad hoc hypothesis. And these ad hoc hypotheses are not able to explain what the model is trying to predict. Yeah, and I guess, and Aysa, the major point is if you're just targeting one area in the model, there's a lot of potential things that could be missed that therefore impacts on

23:07
the health and performance of an athlete. So that's potentially problematic. Jose, from a biological perspective, are humans designed to tolerate short periods of lower energy intake in your view? The question is if they are designed to... Yeah, evolutionarily speaking, like should we as a human be able to tolerate periods of lower energy intake?

23:36
Well, I think so. I think so. I think that we are adapted to be a hunter gatherer species and throughout the history of humanity, there's been famines. Actually, the worst famines have been a few years after we stopped being hunter gatherers. But during the hunter gatherer period, it's something that is natural not to have access to

24:06
constant and like availability of energy and you know movement and is essential for hunting and gathering food. So I think a degree of energy deficit is probably something that we are adapted to uh endure, which I'm not saying is the necessarily the optimal, but I think we have a through millions of years of evolution because it's not only the hominid evolution like, you know,

24:36
effectively, most species could be some sort of like hunter gatherer, you know, like, and so through evolution, we've evolved to the point that we've now have like all we're creating so much energy that we have available all the time, but it's not always been been the case. And I think that most likely we are adapted to survive, you know, through periods where there's not this

25:02
high energy availability all the time. But you know, of course you need to keep in mind that the demands of uh physical activity of a hunter gatherer are rather different from the ones of like a top elite athlete. But you know, taking into account those sort of differences, I think that maybe it's good to realize that, you know, if for some time you don't have

25:29
access to what you call the optimal energy is not something that necessarily you need to panic about. Okay, yeah, no, makes perfect sense. So Jose, with your study that was published in the FACEB journal, can you describe for the listeners what was the question that you were really trying to answer with this particular study before we sort of walk through the design? Yeah, for sure. So there were a few things that we were

25:57
trying to assess and it depends you which with which lens you look at the the this area you know what what angle because you can take like many different angles but uh considering your uh audience which you know I think they're more like um athletes or coaches or nutritionists and and so on and making it relevant to them you know there's there's a couple of things here what

26:26
First of all, because of what I was saying before in relation to the historical development of the area of understanding what happens to humans with low energy or athletic populations or physically active populations with low energy, there is not a lot of information of what happens in males. So the majority of data is in females because of historical reasons, because

26:52
you know, the lack of a menstrual cycle and the low bone mineral density historically is what's been driving the interest in this area because there are like very, very clear signals. So on the one hand, we wanted to see what and how are the sort of the endocrine responses to low energy availability in males. So that was sort of a secondary thing, which we thought was quite interesting. But the main thing was uh to look at what's happening in skeletal muscle.

27:21
when you overlay energy deficit on top of someone who is doing uh endurance type training. So you get someone who trains for endurance and then you withdraw the energy. So what happens to muscle? When you from past studies, like study from my PhD, for example, that if you put someone in an energy deficit, like muscle protein synthesis is reduced. And then if you do like weights type training that muscle protein synthesis can be rescued. And if you intake

27:52
protein, you can increase that muscle protein synthesis. But there were not a lot of studies really in looking at what the effect is of energy deficit on more granular responses to the muscle, particularly with the whole muscle phenotype change. Phenotype is the sort of the

28:21
the visible characteristics of the mass, visible in whatever technique you use in this case. We use an advanced technique of molecular biology called proteomics. In particular, we use a technique called dynamic proteomic profiling that allows us to measure hundreds of different proteins, the amounts and the turnover rates of these proteins in skeletal muscle.

28:46
Okay, so well beyond muscle protein synthesis and the standard things that we associate sort of measuring muscle with, I suppose, and getting right into that sort of cellular level mitochondrial type level. Jose, can you walk us through the design, just like pretty straightforward? What did you actually have the participants do, I guess? So, uh

29:12
This was a laboratory-based study. We've studies on the field about energy availability and energy deficit and so on. This is purely lab-based because it allows us to control everything. And because they allow us to control everything, they are quite intense to run. As I'm going to explain now, they're relatively short studies, but they require a lot of work because we control for everything. So this study.

29:42
In particular, we exposed our participants to three times five days of first, them being in free living conditions. So five days of living in free living conditions, five days of energy balance and five days of energy deficit. During the periods of energy balance and the period of energy deficit, we controlled energy intake and exercised energy expenditure.

30:12
throughout each five day period, our participants came to the lab to exercise and do 15 kilocalories per kilo of fat free mass per day of energy expenditure at around 60 % of VO2 max. So around 1000 calories of energy expenditure each time. And during the energy balance period, of course, the aim was for them to not gain or lose any weight. for them for the

30:38
for them to be in energy balance and in the energy deficit period or low energy availability, you pick whatever time you like best. We decreased the energy availability by 78%. So it's quite a drastic decrease in energy availability. Throughout this study, we took blood samples. Before and after each period, we took muscle biopsies. And we also did assessments of body composition using DEXA, using BIA, so bioelectrical.

31:08
impedance analysis. And we also did assessments of resting metabolic rate. And when they are exercising, we took measurements of respiratory gases to look at substrate use. And then with regards to the measurement of things like ensuring that they were in, I guess, energy balance and or, and I guess that would be the initial thing, looking at their RMR,

31:38
applying it for physical activity factor using doubly labeled water? how did you, I guess you wouldn't necessarily do that, but what would your, how do you do that? So yeah, I should have mentioned now that you say double labeled water, we gave them uh a precursor tracer called deuterated water. instead of like both the hydrogen and the oxygen being labeled as just the hydrogen, so it's deuterium oxide. And that was for the

32:06
proteomics technique. In terms of how we knew they were in balance because we gave them the diet. We made prepackaged diets. We knew the level of energy expenditure that these individuals were going to have in the lab. And then we give them the amount of energy that they would need to maintain their sort of normal physiological function. So we didn't do a further assessment on top of all the ones that I told you because

32:36
we knew that exactly what was coming in and out of their bodies. And Jose, just so the listeners get an idea of what this 78 % sort of deficit would look like. I'm not sure if you can think of a particular participant or just in general terms, like roughly what might the difference have been in terms of the calories that they would have been consuming in balance versus the calories they would have been consuming under those

33:03
low energy availability conditions. So it's basically like a fifth of what would be required to be in energy balance. So you're thinking that on average after five days you'll have a deficit of em well over 10,000 calories. Yeah, wow. Well, they must have been starving. In the name of science, obviously.

33:33
And it wasn't, and only five days. Were you a participant, Jose? Yes, I was a participant, yeah. Yeah, yeah, yeah. That's often the case in the exercise science world. Yeah. So why did you choose such a large deficit over a short period of time? Is it because you wanted to get the most bang for the buck in that sort of space of time?

34:02
Yeah, so the main thing was to look at what happened in muscle, basically. And of course, we didn't know what was going to happen because we approached the research in such a way. We're doing this analysis of proteomics to see, let's see what we discover. We had a hypothesis and our hypothesis was confirmed in the end. But there was

34:33
uh Yeah, that was the main thing. oh So we basically trying to hit them with a hammer, you know, say, okay, is there going to be a difference? We know that this is not something that it's psychologically valid. We're not trying to look at what people are doing in the real world for like white loss interventions or what an athlete might be experiencing or like any sort of uh individual might be experiencing.

35:00
even though there are people who are doing these sort of things, but it's not that we're sort of trying to approach this research question with what's like a best practice sort of thing. But we're trying to look at the physiological response to being in sort of in this condition. And because these studies are so hard to conduct, because of all the control that is required, it's really heavy burden on the participant.

35:30
and on the research team, you know, controlling, we could do this for maybe for a longer period of time, eh but it's, and the deficit to be less pronounced, but we didn't have the resources to do that also, particularly because we're giving these participants W-level water, sorry, heavy water, like neutralised water, and that's quite expensive, know, the tracer is very, very expensive. uh

35:59
doing a month of that with a participant is not viable in terms of the cost of the study. Yeah, no, that makes perfect sense. And Jose, you mentioned both DEXA and bioelectrical impedance. How do the two differ for what they would be measuring? Because I know a lot of people out there will be thinking, well, BIA, they're sort of similar, but obviously there are reasons for using both.

36:30
Yeah, so Dexa gives you like a three compartment sort of result. It gives you information on fat free mass, fat mass and bone. Dexa was originally developed to look at bone mineral density and in sports science or like sports nutrition we used to look at other components, but it's a lot more precise.

36:56
a lot more reliable and accurate when looking at what's happening in bone. Anyway, we weren't particularly looking at bone because we know that in a week, it doesn't matter how severe your deficit is, you're not going to be able to pick it up with DEXA. But the things that fat-free mass, the DEXA picks as fat-free mass, uh a lot of things that are not necessarily the tissues that we're interested in or doesn't give you really reliable or relevant information.

37:26
And what we know is that if you are dehydrated or you lose em fluid, and we know that there's like quite marked fluid shifts when someone goes in an energy deficit, the DEXA picks that as far as free mass. So we added a bioelectrical impedance analysis, which we use a pretty good em BIA equipment that is validated against uh MRI. So it's a very good

37:56
piece of bioelectrical impedance analysis equipment that we've got, mainly to look at shifts in body water, which the BIA gives you that information. So if we see a change in fat-free mass, we can say, how much of that is coming from water? Jose, so firstly, did the intervention do what you expected in terms of weight loss for the participants?

38:24
over the five days? Yes. on average, well, first of all, we must say that the intervention was successful in the energy balance uh period. There was uh no change in weight. So, during the free living or energy balance period, the response was consistent across all participants. Same with the weight loss. There were no outliers in any way.

38:54
And the weight loss was quite pronounced. So on average participants lost nearly three kilos of body weight and around 2.1 kilos were of fat-free mass. it's a lot of, you know, people would think automatically, oh, that's a lot of muscle, but you know, fat-free mass is not necessarily muscle as I was explaining before. And that was 1.2 kilos of water that produced from the five days of the energy deficit.

39:22
and fat mass loss was around 0.8 kilograms, so quite a pronounced fat loss. So if you multiply the amount of tissue lost by the energy equivalence of each tissue, you can work out quite quickly that the majority of the energy from the people's energy stores was derived from fat. Yeah, yeah. oh

39:51
Also interesting and probably that might be different from what people would understand really because of your point when people hear fat free mass, they immediately assume muscle because of potentially the way these things are measured either in, you know, um free living conditions or oftentimes in laboratories. And what about hormonally? What happened to things like leptin, um thyroid hormone, IGF-1?

40:19
Yep, so we measured loads of things in blood from we took venous blood like every time the participants came into the lab, which was each day they exercised basically. And we measured a whole range of uh endocrine markers and metabolic sort of markers. The endocrine markers that we looked at, you know, I don't have the paper in front of me, on top of my head, you know, we measured

40:49
leptin, insulin, IGF-1, T3, testosterone, insulin, and probably some other that I cannot recall right now. But those are the key ones. And we saw that the responses are what we were aware of, that for the most part, what we expected. And basically the body signaling that is going some sort of like energy preservation mode.

41:14
You see leptin was decreased, IGF1 was decreased, T3 was decreased. We didn't see changes in testosterone. That's really interesting because testosterone is used as a primary marker of low energy availability in the RETS model. When there are no other stressors like psychological stressors, the effect of low energy in testosterone is not all that clear.

41:43
the fact that we didn't see changes in testosterone was to me, it was surprising, then I realized that what is not that surprising because there's that red link that people make between energy and energy only and decreasing testosterone is not that straightforward. In line with that, we saw changes also in metabolic markers like increase in free fatty acids, increase in

42:12
ketones and increase in glycerol. On average, you could say that people went into some sort of small degree of ketosis. I think that the average ketones by the end of the fifth day was around like 0.4 millimoles or something like that. So that's normal. Ketones like beta-hydroxybutyrate tends to go up when people...

42:37
go into energy deficit. you could say that any energy deficit diet is a ketogenic diet as well. Ketogenic diet. Yeah. And Jose, would you consider those changes in the hormones that we just talked about? Is it dysfunction or is it adaptation? Well, I tend to think that that's an adaptive response. And this is a point that I made a few times. We tend to think, I think because there

43:06
as you were making reference to before, there is such a black and white thinking that um I think that it is a physiological response that if maintained through a long period of time, that's going to potentially not be the best for you. But it is a physiological response. the fact that leptin goes down is not necessarily a

43:32
pathological thing or the same that IGF-1 goes down. It's response to the current state. like, you know, if you go for a run and do intervals and your heart rate gets to 190, it's not that you have like any sort of uh maladaptive tachycardia. You you're responding to a stimulus. So I think that we should start thinking about endocrine responses as like signaling a response to a stressor.

44:02
uh in this case, an active deficit. And of course, um the major, I guess, one of the key differences with what you looked at was changes at that cellular level in the muscle proteins. So can we talk about that, um what happened at that muscle level, what you found? Yeah, I think this is the most interesting part of the study and I love how we've been slowly

44:29
building up and teasing your audience by like, we've been like, what, like 40 minutes into this conversation, you're already now talking about that. that's happening. All right. Here we go. we- Got to keep them hooked in, We had like, we saw like two very distinct responses in skeletal muscle. So we look at

44:54
two separate things. So it's part of the same sort of technique, they're like, in a way, they're like two different bits. So the technique, as I was saying before, is proteomics. But we looked at two things. We look at the muscle protein synthesis and the muscle protein synthesis of individual proteins with this technique. And we look at the abundance of individual proteins.

45:20
They are like separate things, but they should be telling you the same story in a way. the muscle protein synthesis, we um identified around 700 proteins, individual proteins that we could look at, this protein, this synthesis rates are going up, and so on. And then we can look at where those proteins are coming from and sort of infer, or not infer, but uh

45:50
allocate them to the classical skeletal muscle pools. say like people will study muscle protein synthesis, look at myofibrillar pool, sarcoplasmic pool and mitochondrial pool. So we did that. In addition to looking at each individual protein, we can look at that. And what we saw is that the sarcoplasmic pool, which is like the of the pool of proteins that are sort of floating around in the muscle for to explain it in lay terms.

46:19
didn't change throughout the study. So it didn't decrease or increase during energy deficit. Same with the myofibrillar fraction. Didn't increase or decrease. But the mitochondrial pool didn't change in the free living or energy balance conditions, but it increased during the energy deficit condition. So instead of there being a down regulation of muscle in any way, the myofibrillar and the myofibular

46:47
and the sarcoplasmic pools were maintained and the mitochondrial pool was actually increased in terms of like synthesis rates. So there was an increase in the synthesis of mitochondrial proteins. So when we look at the abundance of proteins, we saw basically the same thing. So there were two key responses, was it an increase?

47:16
in mitochondrial proteins, proteins associated to oxidative metabolism. the proteins that the muscle use to sort of fuel oxidative uh metabolism, that is generation of energy with the use of oxygen, which is all mitochondrial sort of pathways. And then we saw a decrease in proteins of the extracellular matrix.

47:44
particularly proteins associated to collagen. So those were the key responses that we observed in muscle. Yeah, so with that, with the changes that you just described, what is the meaning of the changes to the collagen proteins, Jose? Yeah, well, we don't fully know. And again, this depends how you look at it, because if you look at it from a

48:13
you know, the angle of like, oh, things are negative, you know, and then we think like, oh, that will, that means that someone is going to have some sort of injury because they don't have enough collagen in their muscle. eh I try to avoid, you know, drawing conclusions that don't have much support. eh Otherwise, em the way that I see it and based on other research in monkeys, there's studies

48:42
looking at lifelong energy restriction in monkeys. And they've shown that these monkeys maintain a better quality of muscle without the inclusion of collagen within skeletal muscle. So this is called skeletal muscle fibrosis. So that's a normal uh response to aging in muscle. This is like this age-related fibrosis, which um this

49:08
lifelong calorie restriction in monkeys have shown to counteract in a way and for the monkeys to maintain a more youthful phenotype in their muscle. That seems to be something maybe related to what we are observing that this energy deficit is decreasing proteins in muscle that otherwise would accumulate and make, you know, sort of interrupt the normal

49:38
matrix of the muscle, but we don't really know if that's that or something else. It's the first time that this type of response is shown in humans. So I think this opened up quite an um exciting frontier to understand what's actually happening to the extracellular matrix with energy deficit. Yeah, for sure. And with the other change with the mitochondrial changes,

50:07
mitochondrial protein synthesis, does this suggest that the muscle continues to adapt to exercise even during this significant energy deficit? So it's not a detriment, this is actually like an adaptive process. Yeah, that's the way that I tend to see it. m Again, this can be seen in different ways, but um even the lack of changes in sarcoplasmic or m

50:36
myofilic protein synthesis when the body is having such a drastic response to energy deficit is telling you that the body is still maintaining the spending energy in something that is quite energetically expensive and therefore that's probably important. You know there are other studies that have shown a decrease of sarcoplasmic protein synthesis and myofilic protein synthesis with energy deficit.

51:03
some really good research shows that, well we didn't show that, we showed something else and we've gone em a bit further by looking at this more like granular detail analysis of what's happening at a qualitative level in muscle and we see this increase in pathways of generating energy despite the body is in an energy deficit. oh particularly in the mitochondria, you know when

51:33
we look at protein by protein what actually happened. And we see that there's like three key pathways in the muscle that were upregulated. The better oxidation, which is the pathway of sort of breaking down fats for them to be oxidized in the mitochondria. The TCA cycle, which is the basic cycle of breaking down acetyl-CoA.

51:57
in the mitochondria and the electron transport chain. So, them three pathways, all the proteins that we measure, most of the proteins that we measure tended to increase, which is fascinating. And the body is responding to this um exercise and energy deficit despite being in a uh disadvantages sort of situation in terms of like energy availability, sort of signaling that the body

52:25
is maintaining the functioning of that eh system despite not having enough energy. Yeah. And Jose, obviously, anything you'll say is likely speculative because the studies may not have been done. But would we expect there to be differences if you were to do this in female athletes at the same age, different age, or whatever? What do we know about the...

52:54
measures that you measured, what do we know about sex differences there, if we do? Well, there's none. Yeah, okay. The closest thing that's been done to that is looking at the activity of, I think it's like a few enzymes, one of them being cytochrome C oxidase, which is a key

53:20
uh mitochondrial enzyme and despite there being energy deficit the body maintained the activity of the enzyme. lack of change when there's a severe energy deficit is telling you something again that the body is maintaining the capacity to do that but you know in terms of specific skeletal muscle responses in females I wouldn't know, there's no research so that would be really interesting to see.

53:49
Yeah, for sure. And where do you draw the line that's sort of adaptive to a point where it could be problematic? Is it just a time thing, like five days? Maybe it would be interesting to know. And of course, this is anything we talk about here is purely speculative, but what would have happened if it was 15 days or that kind of thing? is that what you'll think?

54:12
Yeah, no, I like that, you know, the fact that you use sort of the terminology that that sort of the rest consensus statement uses that they try to differentiate between uh adaptive and problematic low energy availability and sort of saying like, oh, if you do a little bit, you know, maybe um it's resulting in positive adaptations. But if you overdo it, then that turns negative. Well, I think that is not as simple as that. And I think that's why I don't I think we should stay clear from using those those

54:41
terminologies of like, um adaptive and problematic. think the terminology itself is problematic because something can be both uh adaptive and problematic at the same time. And there is no like, it's good here and then from there onwards, it turns bad. It's not like uh Anakin Skywalker turning into like Darth Vader or anything like that. I think it's more like, um you can be adaptive and

55:10
problematic at the same time, you know, because we're, for example, making reference to what's happening in skeletal muscle and maybe from a skeletal muscle standpoint, it could potentially be positive. But then you have to look at what's happening in bone. And, you know, in most cases, we saw a decrease of em in P1NP in this intervention. P1NP is a marker of collagen formation, not bone formation. It's used as a protein marker of bone formation, but it's collagen formation.

55:40
And of course we saw the Christian collagen in muscle as well, but imagine that it was a marker of bone, you could say like, it's affecting positively the muscle, but not the bone. So you're having like some positive effect somewhere, but potentially a negative effect somewhere else. And so this is something that we have to become realistic because

56:03
again, it's not all black and white, it's not all good and bad. No, it's just like we have to understand that that's why I try to stay clear from like thinking of things, good and bad necessarily, because the body doesn't know good and bad, the body responds to stimuli. And that's why we're approaching this study from a sort of physiological standpoint, trying to understand how the body responds to this energy deficit. I think, you know, for

56:32
what's relevant for your audience, I think that it's important to realize that there are different things that you have to take into consideration when you are exposing yourself or someone else to a degree of energy deficit, that you have the physiological considerations and then you have the psychological considerations. And I think that you need to understand that energy deficit has both.

57:00
and you have to not confuse them too. And I think when energy deficit itself becomes the target, that's probably a problem because you have to be thinking in terms of performance and health first. Yeah. So if you are focused on the energy deficit to the point that your performance is decreasing, then that is problematic and it's not the energy itself. It's like how you're approaching the problem and it's not the energy.

57:31
Yeah. Yeah. And I suppose it's to your point, like the system is just going to respond how the system responds. And there may always be trade-offs rather than, yeah, trade-offs if one thing occurs, something else might be happening in the background. I'll say very quickly, because I'm aware of the time and I know you want to go for a run. No, no, that's really respect that as a runner myself. And so you mentioned right at the top, and I know we discussed this in our last

58:01
um conversation, but I wonder whether people won't appreciate just the complexity of measuring energy intake and why that affects this whole energy availability question, if you like. can we sort of delve into that real world problem? Yeah, of course. Yeah. And this is going a little bit beyond, you know, the study that we were mentioning before. So

58:28
The thing is like the concept of energy availability was developed to be used in studies like the one that I was just talking about in the lab, where you control everything. Your participants come and you give them, we gave them, I don't know, 60 kilocalories per kilo of fat free mass per day of energy intake. And then we know they're eating that much. The thing is that with the development of the area, people were quick to take that concept.

58:54
thinking that that magic 30 kilocalories per kilo of biomass threshold was going to tell them that people might be running into some sort of problem if they were below under that threshold and use that assessment, that formula to assess the energy availability of people in the field. now, from using a tool developed to study something in the lab to

59:22
you sit in the field, we have a huge problem. that huge problem is mainly related to the lack of accuracy in the assessment of energy intake and energy expenditure. There's a whole range of other problems as well, because the energy availability formula, for example, does not consider the need and non-exercise activity thermogenesis. So if someone is walking 30,000 steps a day,

59:52
and that's not exercise, that's physical activity, that is not considered in the formula. And that is plainly wrong because the body, again, doesn't differentiate between physical activity and exercise. But let's assume that you're working with an athlete that does whatever, 5,000 steps a day or something like that because the rest of the day they're busy exercising and so on. And that's not so much of a problem. Then you have the problem of the error of assessment of energy intake.

01:00:22
mainly. So you have errors of assessment of energy intake, have uh errors of assessment of exercise energy expenditure, and you have error of assessment of fat-free mass. The main contributor to the error is the energy intake. Then you have the exercise energy expenditure, and then you have the fat-free mass assessment. We've written a paper on this that has not been published yet, but hopefully we're going to

01:00:52
finish some stuff up. we've thought about this a lot, basically. The error of measurement of energy intake is on average. So the systematic error of measurement of energy intake is around 20%. That's what of minus 20%. So people tend to underestimate by 20 % what someone else is interesting.

01:01:23
Then you have the error of the energy expenditure, and then you have the error of the fat-free mass. So when you add up, that gives you a very, very noisy measurement. So what happens, or what's been one of the main issues why low energy availability became such a widely talked about topic, is because by using the assessment

01:01:51
of that was developed in the lab to measure in the field that started to result in a lot of measurements under the value that sort of rigid threshold of 30 calories per kilo of fat tree mass per day. But you have to consider that first of all we don't know if that threshold applies to everyone, what the duration of the energy availability and the main thing

01:02:20
is that most likely, because of the error of measurement of, that I just talked about, there's an underestimation of the actual energy availability of a person. So when you compound all the problems that exist from the use of this assessment in field conditions, you quickly start to realize that it's not a very useful measurement for you to understand what.

01:02:47
energetic state that someone is in.

01:02:52
And I've seen papers looking at, I'm pretty sure I saw one paper that suggested that 60 % of recreational athletes are in a state of low energy availability and it was cause for concern. I remember thinking as a clinician who has hundreds of people in person and many more sort of online thinking, really that seems...

01:03:19
That seems like an overstatement to me given what we know about the population, I suppose. Yeah. Yeah. Yeah. So there is uh a 2018 review paper in Sports Medicine talking about the prevalence of low energy availability in different populations. And they have a table there consistently. Most people in the populations reported are like well over 50 % of the population is like

01:03:48
under low energy availability and it seems like it is a problem for absolutely everyone. And I'm not saying that there's no people out there that are eating less than they should. That's definitely a problem for some people. But from it being a problem for some people to it being a problem for everyone, there's a big gap. And that's something that we need to be mindful of, that you cannot really trust that measurement to diagnose that someone is under-eating.

01:04:17
uh fuel based on what they need for their sport. Yeah, yeah. And I will say that most of the time when I'm talking to people, they're always reporting to me their very best day uh of what they eat when we're chatting about it. Jose, do you think dipping into energy deficit within a day is something that we should panic about? No.

01:04:41
em No, really. think that if you're working with an athlete, the main thing that you have to have concern over is the amount of muscle glycogen they have for whatever session they need to do. If you're concerned about them being able to hit the numbers and the volume of training they need to do.

01:05:07
carbohydrate availability is key and how much muscle glycogen there is in their bodies. If for whatever reason an athlete falls under a level of uh energy availability or a degree of energy deficit within a period of a day, I don't think that is a major topic of concern. I must say that the research in that topic is very limited.

01:05:38
However, there are studies that are observational studies that have provided a degree of link of people having a degree of energy m within their energy deficit to changes or to having lower sum markets that are also associated to low energy availability. But there's no research showing causality, showing that if within a day you deep

01:06:07
those sort of energy availability below a certain threshold then that will result automatically in a maladaptive endocrine response. So I think that overall the most important thing is the level of energy balance you have over a longer period of time. I don't think

01:06:35
but we don't have very little evidence to be honest um to understand that this sort of within-day energy availability or within-day energy balance is a major factor of concern. Okay, nice one. And if we just sort of look forward, Jose wrapping this up, like what do you think we still don't understand about energy deficit and adaptation? Like what questions do you

01:07:04
do you have around this? And where are you and your research group taking what we already know and moving forward? Yeah, well, I think it's really interesting because it's inevitable to chuckle when you talk about this because one of the main things that probably sports nutritionists are known for is because they can maybe manipulate someone's body weight or body composition.

01:07:32
with the idea that that's going to lead to an improvement in performance. But there are no proper scientific studies looking at the effect of weight loss interventions in performance outcomes. And I think that there's no proper research on that, proper blinded scientific research or properly counterbalanced and so on. That's the other thing, that it is very hard to blind someone that you're

01:08:02
putting them in an energy deficit. And you have to take into consideration the beliefs, both of the participant and the research team. Because there's been some research projects coming out in the last couple of years from teams that are, let's say, aligned with the idea that

01:08:31
low energy availability results in decreased performance. But then we know that there's placebo and there's nocebo effect and nocebo effect is quite powerful. uh And I think we need to understand in a more sort of neutral way whether a degree of energy deficit can improve or decrease performance. It's probably going to be different for different individuals in different situations.

01:08:56
I that's one of the, I would call it a low hanging fruit because it seems something that would be intuitive to research. The thing is, it's very, very difficult to control properly. So I think that that is probably something that the field desperately needs, but we need good research that is conducted in a way that is unbiased by people who don't necessarily

01:09:24
attach their identity to the research idea and in a way that we can discuss the findings in a rational way, trying to look for whatever best outcome is for the person, for the athlete or for whatever individual you're working with. Yeah, I think that's quite important. Yeah, it sounds like an impossible

01:09:54
It seems like an impossible wish there for you, the way that you're talking about it, like, that it's never going to happen. But who knows? It might. Yeah, it will. Yeah, good. And so what can we expect from you and your lab over the course of the next couple of years? Obviously, you just mentioned the paper that's still coming together. What other projects do you have on, Jose? Yeah, we have quite a few things going on, some of them related to energy availability, some not.

01:10:24
we're looking at skeletal muscle responses to low carbohydrate availability. So we have a quite significant study coming, you know, we're still putting it together. So it's going to take a little while. We have quite a bit of research on muscle glycogen manipulation of muscle glycogen and performance, which is pretty cool. We have some work on exogenous ketones em at the minute. So we have some publications in that topic, of adaptive responses to em

01:10:53
using exogenous ketones for recovery. Yeah, those are the main things. There's a few other things, yeah, just that I think summarizes what we're working on at the minute. That sounds great. And you mentioned muscle glycogen. And of course, there was that big review paper in January looking at glycogen versus glucose and what's most important sort of...

01:11:21
if you like, that determines um performance. Do you have an opinion on that, Jose? Yeah. Yeah, I think uh some of the things that that paper proposes are quite extreme. I must say that I'm not aligned with that. Some of the things of the basic physiology that they are explaining um is not that controversial, to be honest. And we know if people go like hypoglycemic, that's

01:11:51
that's more important than having a lot of muscle glycogen. So you can still have a lot of muscle glycogen, but if you go hyperlysemic, you are not going to be able to exercise anymore. So when it comes to maintaining glycemia and being able to exercise, then, you know, that's not news. Then I think the idea that only with a little bit of carbohydrates without having high muscle glycogen, that you're going to be able to perform at a high level, particularly in like endurance sports and so on.

01:12:21
I very much doubt that. so I'm not particularly, I don't buy in that idea, to be honest. Yeah, And it's so interesting, the, I guess, sports nutrition, exercise physiology, and what it means for the athletes, such a fascinating area that we're continuing to learn. And of course, in no small part to what you're doing, Jose, and the work of your lab.

01:12:49
Thank you so much for taking the time to speak with me this afternoon. Can you just let the listeners know, and of course I'll put it in the show notes, just where they can find out more about what you're doing and if you're, I see you on X, if you're on any other sort of social platforms, Jose, if you've got the time, given what you do. Yeah, no, I'm an advocate to share information for every possible.

01:13:17
means, of course, you know, time is the enemy. I don't think X is the best platform anymore. You know, it's been morphing into some sort of like hatred and violence-ridden platform that is maybe not the best one for sharing uh scientific information. I think LinkedIn has become a bit more suitable for that type of information. you can find me in LinkedIn.

01:13:44
recently I opened an Instagram account to try to give Instagram an opportunity to reach maybe people that are not in other platforms and they are still interested in the uh type of work that we do. Of course, that's got a bit more of a personal twist where I share maybe things that we're doing in the lab or talks that I give and so on. Probably I'm going to post this podcast link there. yes, you must. So I must. Great.

01:14:14
Yeah, and you know I have a university website, I'm working on a personal website that is going to be available eventually, but for now those are the places where you can find me. Wonderful, Jose thank you so much and you're very generous with your time, I've heard you on several podcasts and I always love listening to what you and your team are up to and I really appreciate you taking the time with me this afternoon as well.

01:14:42
Thanks Jose. Great, thank you Miki. Pleasure to chat.

01:14:57
Alrighty, hopefully you really enjoyed that and I'm always excited to learn about what more research is coming out of these laboratories which really are at the cutting edge of understanding energy metabolism, performance, health and all of those super fascinating fields. And if you've got any questions, comments, queries, hit me up. I'm over on Instagram, X and threads @mikkiwilliden, Facebook @mikkiwillidennutrition, or head to my website, @mikkiwilliden.com.

01:15:27
and scroll right down to the bottom, pop your name in the box down the bottom and jump on my weekly email. Alright guys, you have the best week. See you later.