PEM: measuring the threshold and understanding the cause

Emily Kate Stephens (0:03): Welcome, the delightful Dr. Rob Wüst of Vrije Universiteit Amsterdam is an exercise physiologist. This week, he joins me to explain his studies into the impact of Long Covid and ME/CFS on our muscles, as well as the threshold for post-exertional malaise, in a bid to understand what drives it and how we can prevent it. Such a pleasure to be talking to you today. So, what I think is quite interesting with the work that you do is that you seem to have this flow between things that you are discovering within the muscle and trying to establish the chicken or the egg, which way round these things are coming, is the abnormalities that you're seeing in the muscles the cause of something or the effect of something? Your first big paper that you did where you discovered that muscle abnormalities worsen after PEM in Long Covid. Can you give me an overview of the trajectory of that work that you've done and what you have found in the muscle abnormalities in Long Covid? And now you have brought in this cohort of ME/CFS.

Rob Wüst (1:39): So let's go back. I think it's already four years ago right now that I got a phone call five minutes before a lecture started. In the middle of Covid times, I was working from home preparing my lectures on slides. So doing this online teaching, and right before that teaching started, a clinician from the local hospital called me, and that was Michèle van Vugt. She's an infectionologist, and she works particularly with patients with acute Covid back then, because there was an acute Covid clinic in the Netherlands. She explained to me like, "Ah, we have these patients that keep coming back to us. They recovered from an acute infection, but they still are not recovered, and they still suffer from fatigue. They feel muscle problems, muscle pain. What is this? Can we take muscle biopsies? That was the direct question that she asked me, and I said, "Look, this is super interesting because I heard in my own environment also people who are suffering a little bit from these longer term problems of after acute Covid infection, and I thought, that's maybe interesting. Let's just talk again later. So we discussed later at more length, and then we decided that we would start a project with this, like a smaller student project. But let's just start small and see how big we can make it. So then fast forward a few months because we have to write a medical ethics application for this research, and we try to get some funding, but we didn't get it back then because I think the focus really on acute Covid and not so much on Long Covid yet. So, but we got the ethics in place, and we just started essentially. We just started with two master students in the lab doing a project. We take muscle biopsies and we see what happens. Essentially, that was the plan. But I already noticed back then that maybe there is something happening with exercise that exercise worsened this problem, so I quickly realised that maybe it's more interesting not only just to take muscle biopsies at rest, but also after this induction of post-exertional malaise, and that's something that we have particularly interest in right now because I'm an exercise physiologist and I do a lot of muscle research, and what we see in people with any type of chronic disease is that exercise is good for you. Exercise helps various diseases, heart failure, diabetes, anything. But not in this disease, and scientifically, that's super interesting for me. So that's how I, essentially, how we started.

Emily Kate Stephens (3:54): Is that actually the first? I appreciate that now you have also started looking at ME/CFS. But in terms of your studies, is that the first disease of this type that has that signature where exercise is not helpful?

Rob Wüst (4:08): Yeah, it's of course a little bit tricky because I didn't know back then about the effects of exercise and PEM in a patient with ME/CFS because it was just understudied. Not nothing that was known about this.

Emily Kate Stephens (4:18): But there aren't many other long term conditions like that you would say, and I think even in fibromyalgia, exercises

Rob Wüst (4:27): Yeah can be of course yeah of course I mean now we know that's I mean now I know at least that's these post-viral diseases fibromyalgia but also ME/CFS Long Covid probably also other diseases that are linked to viral infections Lyme disease, for instance, that's not a viral infection, but it is, but it's a post-infectious disease. Yeah, post-infectious disease, and maybe also sepsis. That we also see that not everything is you know when you when the body is dealing with a large inflammatory response, then having an extra stressor in terms of exercise may not be super. So now I know, of course, of other diseases where exercise may not be perfectly healthy and also is counter effective. But this was a disease that for me at least, was a new door because, you know, in my teaching to students here at the university, I always tell them exercise is good for you. Exercise is medicine, but and I think that still holds, and I now have to be a little bit correct, so to say, because it's still beneficial for patients with Long Covid and ME/CFS. But to a certain extent, if you exercise below the threshold, it's still positive. We don't because there's a difference between being completely inactive and being a little bit active. So, so let's talk about

Emily Kate Stephens (5:41): That threshold because that I think is possibly the holy grail for those of us that suffer from these conditions is being able to establish what that threshold is and how you can stay within it and whether there is any ability to move that. You've recently done a study looking at heart rate variability using wearable devices, and I'd love to talk to you about that study. But one of the primary things that you did at the beginning of that study was you established that what you call VT1, the first ventilatory threshold, and that is sort of your marker of where you think well, it's not even the marker of where people need to stay below. It's about 80% of that. Is it? Is it that they need? Well, let's talk us through a little bit.

Rob Wüst (6:27): Yeah, because of course we don't know the threshold, and that's a real problem in terms of research, but particularly patient care. And the idea is always then, okay, just stay below that imaginary threshold that you determine yourself as being the threshold for PEM. And in our previous research, we went above it to go to maximal exercise. So we knew, okay, you go over the threshold, whatever the threshold is, you just go to maximum exercise. We've induced post-exertional malaise.

Emily Kate Stephens (6:59): And I read you saying that you actually have a bit of a ethical problem with doing that to people because you're constantly making them feel sick.

Rob Wüst (7:06): That's indeed a problem. If you ask patients to form a part of our research, to understand post-exertional malaise, we have to induce it, and that's also the reason why we're only using mild patients and not severely ill patients because we have the feeling that with more severely ill patients the pushback is bigger and maybe they don't recover fully and also then it becomes unethical for me to do the research that I want to do even though patients really want to participate they really say please take my whole leg off for research as long as I understand what's wrong with me. That's of course also unethical, but that's not go. That's obvious. But we would love to do muscle biopsies in housebound and homebound patients. That's I think one of the goals in the in the future. But to do that, the fact that we enter the room, we put all our equipment ready may already induce post-exertional malaise, so so we have to be very critical of what we want to do and what we can do. And there's this constant fight essentially: what do we gain with information, and what do we get? What do we let patients undergo? And that's the reason why we now, for instance, do a lot of the work on the studies that we have performed already, because we know that we can do a lot of work on this, and we don't have to ask other patients to participate. So, ethics-wise, it's actually good that we just keep the numbers as low as possible. But then the and then funding agencies ask us about the generality of the disease, you know, of the findings, and does also apply to patients with severe, yeah, children or adolescents with Long Covid, etc. Etc. So we get all these additional questions that you can only answer by looking into this properly. Yeah. So this is ethically difficult for us, and we don't take this lightly. Coming back to the start of this question is of course we want to understand what this threshold is. Our final aim is to increase the threshold as much as possible and shorten the duration of the PEM so that you are able to overcome these PEM episodes quicker and they become less severe. And therefore, it's good to have an idea about what the threshold roughly is. So what we did is that was a student project again, a master student who did an internship with a sports physician in the local clinic here in the centre of the Netherlands, and that clinic is very specialised on measuring heart rate variability. And you don't get heart rate variability measurements for no reason. You had to have a certain indication essentially to do this, so Kasper, our sports physician, thought that maybe by using heart rate variability, it tells you something about the recovery of patients or the inability to recover of patients, for instance during sleep, and that helps patients also with pacing strategies. So it is really in the setting of pacing. That we use these heart rate variability monitors to get better in an idea about when do people go over the threshold essentially and what are triggers for lower heart rate variability measurements and we use that data then just our student Twan, he was a master student here, very clever with data science, and he really took on the project and did a lot of data analysis using very specialised programmes. We don't talk about it now, but and what emerged from that was that this ventilatory threshold that we used to demark mild from moderate exercise tended to be the situation around which people had more difficulty sleeping. More the heart rate variability reduced after sleep. Their recovery after those type of exercises also took much longer in terms of heart rate variability. So we think heart rate variability tells you something about the recovery of the autonomic nervous system and particularly the way how the body is able to relax and the inability to relax tells you then something about the fact that you don't relax or don't recover properly, and this ventilatory threshold was then seemed to be the tipping point, so to say, and we don't know if that actually causes PEM in the patients if you go over it, but we see things in the wearable data that hint towards PEM.

Emily Kate Stephens (11:22): Okay, so it's not necessarily then done on patient-reported PEM symptoms. It is actually done on the data. You had that alongside, didn't you? You had that diary alongside.

Rob Wüst (11:32): Exactly, we had a diary alongside. But the patient didn't mention that they really suffered from PEM. But we saw things in the wearable data that could hint essentially to this PEM. So that future work, and that's the plan. What we are hoping to do in the near future is to really see how PEM symptoms are linked to these heart rate variability monitors.

Emily Kate Stephens (11:57): Now you actually once you'd established that ventilatory threshold in your study, you actually found that 43% of patients went over that threshold just doing their daily activities. So we're not talking about them deciding to go for a run, and I think that is quite something that's quite pronounced because there is so much conversation about oh well you've got to ease off on the exercise, but so many of us know that some days you can't even hang the laundry, or there are certain things that are considered to be daily activities that shouldn't be pushing you theoretically over a threshold, but that in almost half of the people that you studied, that was the case in Long Covid, and was this looking at ME/CFS patients as well?

Rob Wüst (12:47): Only Long Covid.

Emily Kate Stephens (12:48): Okay.

Rob Wüst (12:50): So yes, that's indeed striking. Also semi surprising for me. But remember, this was also done as a in the phase of pacing. So of course the therapeutic, the reason they came to the sports physician was to get a checkup of their health and their ventilatory threshold was the submaximal exercise test we do, and also how to do the pacing and essentially patients have difficulty pacing because some activities, indeed, like hang up the laundry, walking up the stairs, you know, doing the shopping with two bags full of groceries, for instance, can already make your heart go up to a level that is at that ventilatory threshold. And in some patients, that ventilatory threshold is super low, and it's at the level of these daily life activities, and that's the problem.

Emily Kate Stephens (13:47): And let's go back then to look at some of the theories that you have discussed behind this, because one of the big things, and there you've had some back and forth on this recently, one of the big things is that is the deconditioning. So what you're saying there is you're not suggesting that people are going out for a run and pushing themselves over that threshold. They are just doing their normal activities. You've previously done a bed rest study. Have you previously seen that kind of PEM induced by simple everyday activities rather than what we classify as exercise.

Rob Wüst (14:27): Okay, so there are various levels of comments I want to put in here. But let's first start with: Did I expect this? To some extent, yes, because some patients are severely ill, or we call them moderately ill. So, if mild, we would say mild, moderate, severely ill patients. In the mildly patients are the ones that we typically study, but at this cohort, we also had patients that were moderately ill, and we classified them as having a very low ventilatory threshold at the level of their daily life activities. So, if you cannot perform daily life activities. In a normal way in a way that you would then become fatigued then we would classify you as a moderately ill patient and yes I think it was surprising but on the other hand I mean we also know that some patients are bedridden that is then of course severely ill and then even standing up may already give you orthostatic intolerance or POTS, and may in the lowest activities, then it can already induce some post-exertional malaise. So we know that there is a continuum of patients that we are around, and we typically see the mild patients because you have to come to hospital. You voluntarily participate in the study, so you are at least able to come to the hospital and actively consent to do an exercise test and a biopsy, so we are really looking only at the mildly severely patients. Now, of course, that is so. Coming back down to your question about deconditioning, it's a super interesting and a very important comment to make. Is that if you are a patient, you want to avoid post-exertional malaise, and there are two ways to do that. Is you can just stay below that level, or you can be completely inactive. If you are completely inactive, then you would expect that, like anyone else of us, would see the same effects happening when you are bedridden, at least on the skeletal muscle level or the whole body level. But patients are sometimes still relatively active, so we see we have the mildly affected patients, and therefore they are still having some step counts per day. So our cohort is not bedridden essentially, but still you could say is physical inactivity or deconditioning underlying the changes. We don't completely exclude this, but there is a level of things that are different. Things are diverging, and we know from our bed rest study that people who are undergoing bed rest do not develop PEM. That's just a how it works. If you are in bed for two weeks, you can get out of bed. You may feel a little bit quicker fatigue, but you would, with exercise, you would train up again, and you would be fit again.

Emily Kate Stephens (17:01): That's the massive difference, isn't it, between your bed rest study, where people are then able to incrementally recondition themselves. That's the huge difference in these conditions. That the PEM is not improved by, you know, greater reconditioning. So

Rob Wüst (17:18): That completely different aspect. So an astronaut in space does not get PEM, and therefore, so looking at PEM and deconditioning are two completely separate phenomena at the body level. One can lead to the other. To avoid PEM, you become inactive, but it doesn't mean that then it's causative.

Emily Kate Stephens (17:37): Okay, and in terms of what you're actually seeing in the muscles, in the physiology of it, you proposed in a talk that I saw you give recently four other theories that are some from your data and some from other clinicians' data: local hypoxia, electrophysiology, autoimmunity, and central fatigue. The local hypoxia, you can actually see that in the biopsy testings that the biopsies that you've taken. Can you?

Rob Wüst (18:08): Yeah, technically you can, but it's super difficult. So let's just go through this theory in more detail here, because one of the theories is that somehow the muscle becomes less perfused or gets blockages, and in the literature, people have suggested that some of the microclots that people find in the blood can block capillaries.

Emily Kate Stephens (18:27): And that amyloid clotting, you are now thinking, might be in play in this.

Rob Wüst (18:31): Well, so that's a theory. That's a theory that other people have found.

Emily Kate Stephens (18:35): Okay, it's not something that you've started looking at.

Rob Wüst (18:37): We start looking at it, but we never find that evidence. So the evidence that those clots are blocking larger vessels and capillary flow, we do not find any evidence for it. But the fact that we cannot find it doesn't mean that it's not there. We just cannot find it. So so if someone else finds it, then that theory can be true. But we do know from other people's work, and we start looking at this as well in a little bit more detail, is that there are endothelial problems. So the capillaries, so the smallest blood vessels in your body, may become problematic and cannot sustain the flow or are becoming disorganised. There are various theories in the literature how the flow in the smallest blood vessels can be altered. So even if it's not blocked, it can still cause problems with perfusion. And then what happens is that tissue behind those vessels are not getting enough oxygen and enough energy, and that can cause fatigue. Now the problem is a little bit with this theory is that yes, you would that would be similar as going up to the mountain.

Emily Kate Stephens (19:50): Okay,

Rob Wüst (19:51): If you go up to a mountain, you also get less oxygen, and the body will then adapt. So one adaptation is to make more capillaries. To just get more blood vessels, because that's a one way for the body to deal with hypoxia, with low oxygen levels. We don't see that

Emily Kate Stephens (20:11): No

Rob Wüst (20:12): So much. You know, it's not that certainly there are more capillaries. It's not that they're less, but they're the same or less essentially. But it's super difficult to test this in theory, and also we're now testing some other trying to circumvent this theory with trying different. If this happens, then this would happen, and as a result, do we see this happening? Yes or no, and we don't see a lot of evidence for it. But there is this idea that at least a problem with endothelial, so that's that is around. So there is, but you simply don't know yet if that's the causative problem. Also, there is a there's a problem with PEM because PEM means that there is an acute worsening of something upon exercise, and that also makes it difficult because this theory of hypoxia or endothelial dysfunction or ischemia reperfusion injury or blockage of capillaries is true. Then you should also see it worsening with PEM, and we just don't know that.

Emily Kate Stephens (21:13): Does that suggest then that it might be more to do with? And I don't know if you can see this in your biopsies, but I know that it is a big area of research for you generally. Is it more to do with the mitochondrial dysfunction or an issue of energy production in the mitochondria?

Rob Wüst (21:32): Yeah. So again, that could link with this problem with oxygen flow and energy flow to the muscles. If there's a problem there, of course, you know, in the places where these energy is being used or oxygen is being used, you should see difference there. So it can easily be an effect. So the mitochondrial problems that we see in our muscle in the muscles of patients with Long Covid can be the effect of the problems occurring in the bloodstream, or it can be happening on itself. There, it's more the problem is primarily there, and then it's a

Emily Kate Stephens (22:06): Cause for other. It's a cause

Rob Wüst (22:07): Exactly, exactly. With the current study design that we have, we cannot distinguish between the two because we don't know whether changing. You would then have to change, for instance, one thing or the other, and see how the other affects. That's one way to do this scientifically, but those studies are very invasive and super difficult to do. So it would, for instance, be that you would want to improve mitochondrial function and see if the endothelial blood flow changes, or if you improve blood flow, if the mitochondria function improves, okay, and those studies are super difficult to do.

Emily Kate Stephens (22:46): So then, in terms of what you can actually see, have you seen in the muscle some of these other theories of the calcium changes or the collagen changes? What have you seen in that physiology?

Rob Wüst (23:03): So when it comes to the electrolyte changes that we describe in a recent overview paper or review paper, is that they are mainly based on work from Germany. There have been some studies suggesting that there are differences in ME/CFS occurring with sodium load, for instance, in the muscle, and that can change the excitability of muscle, and therefore you cannot activate your muscles properly, and that may make you more fatiguable or early fatigable, or you cannot produce the same amount of force, etc. Etc.

Emily Kate Stephens (23:34): You're not a clinician, but theoretically, if you see that kind of deficiency, is it something that could be addressed with supplementation, or once it's in the muscles, is it not such an easy fix? Yeah,

Rob Wüst (23:48): This is a bit of my this is a personal feeling about this theory. Is that I have the feeling that, and I don't know if this is true. So this is pure speculation right now. Is that the body is able to maintain its ion concentrations in the blood within super tight boundaries? Sodium potassium concentration in blood are in super tight boundaries. Calcium as well, because there are various regulatory systems in place to get rid of it via the kidneys or by intake of the foods, uptake in tissue, etc. That's super tightly regulated. So changes in sodium concentration in muscle, I find it difficult to ascribe it as the core aspect. It must there must be something else that makes these changes happen, because otherwise it will be there is a system in place that brings it back to the normal concentrations again.

Emily Kate Stephens (24:47): So that is suggestive of disruption of autonomic function.

Rob Wüst (24:52): For instance, yeah. That and but then it would be a. It's an

Emily Kate Stephens (24:57): Effect.

Rob Wüst (24:57): An effect exactly of something else. Happens, but I don't know that because it can easily be that there is indeed something wrong with an ion channel in the disease, and if the ion channel is then suddenly the most important aspect of the disease, then it is a causative problem again. So as scientists, we constantly deal with: is it a cause of the disease, or do we see it as an effect of something else? And that's annoying for a lot of people, including scientists and including patients themselves too.

Emily Kate Stephens (25:27): But I think I like that you say that you have this that you're still sort of in this dichotomy of which is it because there are a lot of people who have come out and said this

Rob Wüst (25:39): Is

Emily Kate Stephens (25:39): The problem, and you say, yeah, but if this is the problem, then theoretically, if I just took that, I would be fine again, and I'm not.

Rob Wüst (25:48): If for instance, I can just give you some examples too. So this mitochondrial dysfunction, I think we can all agree that if you improve mitochondrial function, your body function will be better. That's without saying. The problem is a little bit that Long Covid is not the same as a genetic metabolic disease, for instance. There are some similarities, and there are some really clinically there are some good similarities even, but it's not the same as patient who lacks a gene in a particular mitochondrial protein, and as a result, is it a cause and effect? How does a virus then change mitochondria all over your body? I don't know.

Emily Kate Stephens (26:30): Yeah, what has it infiltrated?

Rob Wüst (26:32): Exactly.

Emily Kate Stephens (26:35): In terms of that, now that you've brought the ME/CFS cohort in this recent study. Can you tell me about the differences that you saw? Tell me about the differences that you've seen in the ME/CFS and and Long Covid.

Rob Wüst (26:51): So what we quite early on we realised that Long Covid and ME/CFS had lots of similarities, and as a result we thought, okay, let's see if we can also include a cohort of ME/CFS patients, and there was also something else going on in the Netherlands of a ME/CFS cohort, and there was lots of research being built around ME/CFS, but that was actually perfect timing because it could fit perfectly with our Long Covid cohorts. So what we wanted to do is to see: do we see similar things happening in patients with ME/CFS? So that's pretty early on. Reviewer comments always said, "Ah, that's completely different diseases. How do you say this? How can you say this? This is unproven, etc. Etc. But we were pretty early on had this idea that they could link, and now everyone sort of acknowledged that they are two parts of the whole umbrella term, and they're not exactly the same disease, but they have an umbrella term and with a pillar of Long Covid or post-Covid syndrome, other ME/CFS conditions, but also, for instance, Lyme disease and some other post-viral diseases. So we know that they share some similarities, and we thought, okay, well, let's see what we if we can also include it in there, and we got some funding from patient organisations to really push that push this forward. So that was really nice, and actually, we're about to publish those results. We're working on the last changes of our preprint right now, so we're hoping. So we're hoping that it will be published in the next month or so, if everything goes well. And in there, we compare at least the change that we see with Long Covid people with ME/CFS who already had ME/CFS diagnosed before the pandemic started. They're a completely different type of patients as well. Longer ill for longer are probably better able to deal with their PEM because they are dealing with PEM induction for such a long

Emily Kate Stephens (28:38): Time

Rob Wüst (28:38): For such a long time exactly. And yeah, well, maybe there are some similarities or differences. We are studying that right now, and we see some similarities in terms of their exercise capacity. It is very low, but also other aspects in skeletal muscle that we are now trying to finalise.

Emily Kate Stephens (28:55): Do you see differences within that skeletal muscle, or can you not say that at this point?

Rob Wüst (29:00): Well, so we see. I mean, of course, the patients have been ill for longer, and you can see

Emily Kate Stephens (29:05): That in the muscle fibre.

Rob Wüst (29:07): So there are differences, but we don't know whether that's due to the fact that they've been ill for longer, or whether they have for this different disease. So that would require us to do another study in five years or six or 10 years' time with our current Long Covid population to see whether they reach the same values as the ME/CFS people would have.

Emily Kate Stephens (29:26): Yeah.

Rob Wüst (29:27): So yeah, we see some differences here and there, but the question is: Is it the duration of the disease or is it the disease itself? Super difficult. Again, trying to work out cause and effects. Yeah. What is causing the things that you see? And I think as a scientist, it's really important to keep thinking and find arguments for factor A or factor B because that really helps making it clear what you're looking at.

Emily Kate Stephens (29:53): In terms of other scientists out there who either you have worked with or you have been reading about, who do you think there is out there who's really doing exciting work in this field?

Rob Wüst (30:08): Yeah, that's a good question. But I can name more than 10 people that are that I really like. I don't want to. I mean, if I don't mention a name, it will be it also to be bad, so I don't. I think I should not say certain, you know, certain names.

Emily Kate Stephens (30:27): Tell me areas that you think have real potential for actually holding a key. Obviously, the research that you're doing you consider to be absolutely crucial for us moving forwards. But your research in conjunction with what other research do you think might hold the key for us? Yeah,

Rob Wüst (30:42): What I really like is really biomedical research. So finding the real cause of the disease in terms of biology, I think that's a crucial thing that has been understudied so far. And of course, you can do a lot of questionnaire studies, and I think that's also important. But it doesn't give us the answer to what is causing the disease, it kind of gives hints to which direction to look for, of course. But then we need to find the biology of that of those problems. Is it something in the immune system? Is it the viral persistence that is causing the disease itself? Whatever the disease is causing, that's where I think the field should be moving towards. To is there maybe a diagnostic criteria that we can find for patients that we can use to diagnose patients.

Emily Kate Stephens (31:25): A biomarker, an actual biomedical diagnostic criteria, rather than a symptom reported criteria.

Rob Wüst (31:32): Exactly, and I think that's where the field is moving towards now. And I think in the past people have tried to study that mainly based on symptomology or questionnaires or for other simple things, but it's now also time to dive deeper and do the really nitty gritty molecular changes and and biomarker studies and looking at the different disease hypotheses.

Emily Kate Stephens (31:58): But that's a really good point when you say looking at the real nitty gritty, because it's not, you know, we all had the blood tests that says there's nothing irregular in your normal blood tests. But what you're talking about is actually looking at the looking deeper or looking at the more specific things.

Rob Wüst (32:15): Exactly, exactly, and I think that's where everyone in the field now moves towards, and everyone does it from his own perspective and his own interests. So, and that's also super cool because I'm an exercise physiologist. I looking at from an exercise perspective, but someone else looks at the disease from an immune perspective, and puts all his scientific life and his scientific work in understanding the immune changes, and that's super important too.

Emily Kate Stephens (32:42): The crossover is really important as well because you've mentioned that you think that you might be able to see a change in the muscle that suggests there's an autoimmune situation.

Rob Wüst (32:55): But for instance, it so that really makes us work together, and that is that I think is also super nice as an exercise physiologist to work together with immunologists to see what they how they look at body function and explaining post-exertional malaise because it could well be that there's a big immune component of PEM and that you know this the fact that it's that it takes sometimes a day or two to get induced, and some people have fever-like symptoms. That's a sign that maybe there is also an immune component to the disease, and that sends something interesting because then suddenly we have a match. It's like you know you hear something at a conference about an immune talk, then you think, oh, this is interesting. Let's see how where we can find common commonalities, and also then try to work together to find that where this commonality and this common problem for the disease. And I think that really is really helpful in this type of stage of the disease that studies is to get this cross link between different people. People looking at brain immunology. We talk with people who are a super nitty gritty idea about brain function, and they can explain brain fog, and that then I try to integrate my work with their work, and I would not have been able to do that if I would look at a different type of disease.

Emily Kate Stephens (34:13): Yeah, that's fascinating, isn't it? So it's basically all of the crossovers of all of the different body systems because it's interesting. I speak to people who are looking independently at all these different things, and someone says, "No, it's definitely in the prefrontal cortex, and someone says, "Definitely in the muscle. So that is possibly one positive that this collaboration.

Rob Wüst (34:34): That's actually maybe important because I see I hear this more often that I that it's in the muscle. I don't think actually it's a muscle disease, and that makes it also makes me sometimes a bit of an outsider because Long Covid is not a muscle disease. It's it may reflect on the muscle function and symptoms relate to exercise capacity, and therefore it's important to look at muscle as well. But to find the cure of the disease, I'm not 100% sure. We should be looking inside the muscle, but with our work, we can take muscle biopsies, and therefore we can look inside the body. It's super difficult to take a brain biopsy; not possible in healthy people. You have to die first before you can take the brain out. Same for your heart. If you want to look at heart function, you need to wait till someone dies before you can take the heart out and look at the cellular structures, but with skeletal muscle, we can do it. We can actually take the muscle out when someone is still alive. So that gives us a hint into the tissue alterations that we see with the disease, but it doesn't mean that disease is there.

Emily Kate Stephens (35:36): Yeah.

Rob Wüst (35:36): Only.

Emily Kate Stephens (35:37): So it's also a window into those other areas that you can't necessarily see, and trying to work out that traffic flow of cause and effect, and what has come from where or is going towards that. I really, really appreciate your humility when it comes to that as well, because just that idea that we can all work together, and actually everyone's work can feed into each other. Perhaps we do then have a chance of actually working out what is going on in these situations,

Rob Wüst (36:04): And I think that's important because it is it's a multi-systemic disease, so we have to work together to find that common cause because it's not going to be, you know, maybe in one. Eventually, it will be somewhere. So someone will be discovering the cause of the disease, but until there, everyone looks at it from different perspectives and try to uncover what we well what we see and what it means. Yeah,

Emily Kate Stephens (36:33): Amazing! Thank you so much for your time today.

Rob Wüst (36:37): Welcome.

Emily Kate Stephens (36:42): I actually had the pleasure of meeting Dr. Wüst in person earlier this year, and I really appreciate the humility and spirit of collaboration with which he approaches his work. He doesn't believe that these are muscle diseases, but does believe that we can learn what these diseases are by looking at this physiology as part of the greater picture, and this is my usual plea to please feedback and share your thoughts, what you would like to learn about. I am still working through all of your requests and endeavour to get to as many of them as I can. Thank you for continuing on this path with me. Thank you for listening to Make Visible. Please do like, follow, or subscribe to listen to our next episode, where we'll be uncovering more insights into complex chronic illness. This was brought to you by the team at Visible, a group of scientists and engineers whose lives have been affected by energy-limiting health conditions. We're building wearable technology that's helping 100,000 people measure and manage their complex chronic illness. To find out more about what we're working on and how Visible could help you. Visit our website at makevisible.com.

‍