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Wust asked what an intense aerobic workout would do to the muscles in ME/CFS.
The chronic fatigue syndrome (ME/CFS) and fibromyalgia fields have produced some good muscle studies, but a recent study, “Muscle abnormalities worsen after post-exertional malaise in long COVID,” was something else indeed. The study leader, Rob Wust, has a double doctorate in muscle physiology and has been particularly interested in exercise intolerance, mitochondrial bio-energetics, and muscle metabolism.
Thus far, Wust has published three papers on muscle abnormalities in long-COVID patients. The first study of ICU COVID-19 patients found muscle fiber atrophy, metabolic alterations, and immune cell infiltration.
It was the second study, though, that really opened some eyes. This study—which was funded by a variety of sources, including the Patient-Led Research Collaborative for Long COVID and the Solve M.E.’s 2022 Ramsay Grant Program—did something simple but brilliant: it took muscle biopsies from long-COVID patients, put the patients on a bike and exercised them to exhaustion, and then took a second round of muscle biopsies, and dug into them.
The Results
The cardiopulmonary results were pretty typical – a reduction in energy production (VO2 max, peak power output), altered breathing patterns (possibly hyperventilation), plus the near-infrared spectroscopy readings found a reduction in “peripheral O2 extraction”; i.e. oxygen (read energy) was not being taken up by the muscles in normal amounts.
And how about those muscles? What happens to muscles when they’ve been worked hard but haven’t gotten normal amounts of oxygen (energy)? It turned out that a lot happened. The most obvious explanation – low levels of blood vessels feeding the muscles – didn’t pan out, as the ME/CFS patients had plenty of blood vessels (capillaries) feeding their muscles.
That suggested that the problems lay in the muscles themselves. Indeed, higher levels of glycolytic, type II muscle fibers that provide short bursts of energy but stink at endurance in the longCOVID patients provided one reason for their poor performance on the bicycle. Lower levels of an enzyme called succinate dehydrogenase (SDH) that activates the mitochondria provided another reason mitochondrial energy (ATP) production fell short.
Wust – like past ME/CFS studies – found that the long-COVID patients relied more on glycolytic or anaerobic energy production than normal.
Increased levels of metabolites associated with anaerobic energy production and a dearth of metabolites associated with aerobic energy production also suggested that the powerful aerobic energy production pathway had been silenced. The anaerobic rout continued with reduced ratios of citric acid (mitochondria) to lactate (result of glycolysis/anaerobic energy production) levels.
Again and again, the study found that during exercise, the long-COVID patients relied more on the primitive, inefficient, and ultimately toxic form of anaerobic energy production. That’s primitive, as in this form of energy production evolved before oxygen showed up in our atmosphere. We keep it around because it produces short bursts of energy. Anything longer than that and it runs out of gas and starts producing toxic metabolites like lactate.
The list went on – lower creatine levels, problems with lipid synthesis, high levels of oxidative stress, high levels of atrophied or dead muscle fibers with evidence of immune invasion – indicating the immune system may have attacked the muscles.
“It’s really confirming that there is something inside the body going wrong with the disease. It damages your muscles, it worsens your metabolism, and it can explain why you feel muscle pain and fatigue up to weeks after the exercise,”
All in all, the paper provided a gripping explanation from the perspective of the muscles of why physical exercise is so problematic in ME/CFS. As such, it HAD to be rebutted – and it was – but that’s for later in the blog. Next came the exposition paper that attempted to put the pieces together.
The Exposition Paper
In December 2024, Braeden Charlton, Rob Wust, and colleagues published a paper, titled “Skeletal muscle adaptations and post-exertional malaise in long COVID,” that explains what they think has happened to the muscles of long-COVID patients, and probably people with ME/CFS. They listed five possibilities (and rejected one).
Deconditioning – There is no doubt that in the more severely ill, deconditioning adds an exacerbating factor, but the authors noted there is no evidence that it’s causing the illness. (See “the Reply to the Reply” below for more on this).
Hypoxia refers to low oxygen levels. If the oxygen isn’t getting to the cells, they’ll turn to alternative means of producing energy: glycolysis and anaerobic energy production, which studies show is happening in these diseases. Note that ample amounts of oxygen are present in the blood but are not, in a subset of patients, being taken up in the muscles.
Mitochondrial problems could explain the reduced energy production found.
The bigger question is, “What is causing this?” The authors proposed mitochondrial problems that prevent oxygen from being taken up; problems diffusing oxygen into the muscles from the capillaries, caused by capillary blockage; a thickened extracellular matrix that surrounds the capillaries that prevents oxygen from getting out; or amyloid clots that are causing endothelial damage.
Autoimmunity and “Electrophysiological alterations” – It’s possible that β-adrenergic receptors (β2-ARs) could impair blood flows and impact the mitochondria. Allied with this idea is the possibility that increased muscle sodium content (which has nothing to do with diet) may be eating up ATP and causing intracellular calcium overloads, which further smack the mitochondria. (A blog on this is coming up.)
Central fatigue – where the brain turns off muscle activity is another, more distant, possibility.
The problem with the low oxygen uptakes lies between the arteries and the muscles, leaving, if I have it right, two basic targets – the mitochondria and the blood vessels.
An ME/CFS Interlude
Systrom’s invasive exercise studies found that the exertion problems in long COVID are nearly identical to those in ME/CFS. His studies suggest that blood may be shunted from the arteries into the veins before it reaches the muscles in some patients. In other patients, the veins are not constricting enough to deliver normal amounts of blood to the heart – preventing it from pumping enough blood to the muscles. Systrom also has uncovered evidence suggesting that the enzymes needed to power the aerobic energy production process may be inhibited.
Perhaps because they haven’t been studied in long COVID but have in ME/CFS, Wust et al. didn’t mention low blood volume, or the failure of ME/CFS patients to respond on a molecular level (gene expression, epigenetics, metabolomics, proteomics) during and after exercise.
While low blood volume does not appear to be a major factor, it is a factor. Systrom has found that adding saline IVs does improve energy production. A case report from Workwell found that regular use of saline IVs substantially improved one patient’s functioning.
Likewise, hyperventilation (rapid, deep breathing) found in some long-COVID and ME/CFS patients could activate the sympathetic nervous system which, by narrowing the blood vessels, could reduce blood flows to the muscles.
Affirmation
Wust’s “Muscle abnormalities worsen after post-exertional malaise in long COVID” study produced a stunning affirmation of ME/CFS and long-COVID patients’ experiences with intense exercise.
Exercise studies have played a key role in explaining these diseases.
From the beginning of my ME/CFS as a young man, it’s been the post-exertional malaise that stood out for me. While the day-to-day fatigue and pain kept me from functioning like I used to, my symptoms were kind of general and hard to explain. I was very, very tired, I was in pain, I felt like lying down much of the time, I had trouble concentrating, wasn’t sleeping well, etc.
Because these were symptoms that everyone experienced from time to time but were magnified greatly, they weren’t much to bite onto. It was a different story when I exercised, though.
Exercise had been an important part of my life, but now exercise produced an explosion of symptoms, some of which I’d never encountered before. Along with the increased fatigue and pain, came the heart pounding, the intense burning muscle pain, the feeling of contracted muscles, a weird sensation of thickened skin, dizziness, irritability, etc..Those symptoms really stood out.
From the beginning, I thought exercise studies would play a key role in explaining ME/CFS, and over time, through the work of Workwell, Systrom, Keller, Vermeulen, Cook, Hanson, Newton and others, they have been. The good news is that the Dutch team’s muscle findings (reduced aerobic energy production, increased reliance on anaerobic energy production, and others) in long COVID are in line with that past work.
Last Gasp of the Biopsychosocial Crowd?
However, they were a bridge too far for Bridget Ranque and 16 other researchers, who attempted to dismiss the study findings in “Reply: Muscle abnormalities in Long COVID.”
The study finding that very intense exercise harms the muscles does not mean that less intense forms of exercise will necessarily do the same. (Image from Gerald_Altman_Pixabay)
The authors did have one legitimate concern: their worry that long-COVID patients will misinterpret the findings and conclude that any exercise will harm them. As Wust noted, his study needs to be taken in context: it exposed long-COVID patients to a short but very intense exercise session that is literally designed to drive them into a state of muscular exhaustion. I remember during a similar exercise study my legs literally stopped moving the pedals. I have never engaged in that kind of exercise outside of an exercise study.
The GIST
- The ME/CFS and fibromyalgia fields have produced some good muscle studies, but a recent study, “Muscle abnormalities worsen after post-exertional malaise in long COVID,” was something else indeed.
- The study found that aerobic energy production – the kind that relies on oxygen uptake – was inhibited in various ways. Higher levels of glycolytic, type II muscle fibers. lower levels of an enzyme called succinate dehydrogenase (SDH) that activates the mitochondria, increased levels of metabolites associated with anaerobic energy production, and reduced ratios of citric acid (mitochondria) to lactate (result of glycolysis/anaerobic energy production) levels all pointed to an energy production system that was overly dependent on the primitive and inefficient anaerobic energy production system.
- High levels of oxidative stress, atrophied or dead muscle fibers, and signs of immune invasion suggested that the short but very intense period of exercise had directly damaged the muscles.
- In 2024, the authors published a paper proposing 5 possible explanations for muscle problems found in long-COVID patients.
- After rejecting deconditioning, they concluded that low oxygen uptake to the muscles caused by mitochondrial problems and/or reduced blood flows to the muscle cells, an autoimmune reaction that impairs both blood flows to the muscles and/or mitochondrial activity, and/or problems originating in the brain (central fatigue) were likely impacting the muscles.
- ME/CFS studies suggest something similar is happening and add in additional factors such as low blood volume, hyperventilation, and the failure of ME/CFS patients to respond appropriately on a molecular level (gene expression, epigenetics, metabolomics, proteomics) to exercise.
- Recently, 16 researchers, many of whom are allied with the biopsychosocial field, attempted to dismiss Wust’s findings in a “Reply” to the study. They asserted that deconditioning produced the findings, that the symptom exacerbation seen in the ME/CFS patients was a normal response to exercise, and that the patient’s pathological response to their symptoms played a role.
- Wust showed that the ME/CFS patients had activity levels similar to the controls—and to the average American—that the symptoms produced were not normal, that numerous findings of the study were either not associated or, indeed, were opposite to those found in deconditioning.
- The biopsychosocialists arguments seem to be becoming ever more shrill and less convincing. For instance, Beatrice Ranque, the lead author of the reply, concluded that because normal physical examinations and routine test results suggest that “no organic impairment” exists in long COVID, psychological factors must be important.
- Meanwhile, at least five more muscle studies are underway in ME/CFS and long COVID-19, and a recently published invasive exercise study provided more insights into the pathophysiology of long COVID-19. A blog on that is coming up.
Workwell’s post-exercise symptom assessment of patients after their two-day exercise test for disability indicated ME/CFS patients who are in good enough shape to take the test invariably recover within a period of time. When David Systrom’s patients reach a certain level, he recommends his patients start an exercise regimen. Similarly, Health Rising recently ran a recovery story where Lucinda Bateman instituted an exercise regimen using sit-ups and low weights in a patient when he reached a certain level. I stayed away from weights for decades but now find that using exercise bands in short bursts is helpful. D. Hupin, one of the co-authors, found that personalized strength and endurance training, which did not result in PEM, was helpful in long COVID.
In his “Reply: Muscle abnormalities in Long COVID” Wust so easily wiped away the rest of their concerns as to make their “reply” seem like it was borne out of desperation.
Deconditioning? It was like déjà vu all over again (:)) when the authors trotted out the old and tired deconditioning trope. Because the patients were deconditioned, the authors asserted, the short but intense exercise regimen was going to produce muscle damage.
Wust pointed out that the long-COVID patients exhibited the same activity level as the healthy controls (5,181 vs. 4,727 steps/day for patients and controls, respectively) – about the same activity level (rather sadly) as the average person in the U.S.
Several physiological findings demonstrated that something different from deconditioning was at work: the different skeletal muscle alterations, the opposite mitochondrial substrate utilization (more carbohydrates), and the abnormal muscle findings found before the exercise intervention. The significantly lower gas exchange thresholds and respiratory compensation points indicated that effort was not a problem.
If Wust had included findings from ME/CFS, he could have added more objections. The deconditioning hypothesis originally turned on the fact that low stroke volumes were found in ME/CFS. Still, Van Campen et al. found that everyone with ME/CFS -whether they were bedbound or active – had similarly low stroke volumes, indicating that while low stroke volumes are part of the disease, they are not the result of being inactive.
Since everyone experiences muscle pain after exercise, what’s the big deal about muscle pain in the ME/CFS patients? Seeing this objection come out of the pens of some long-time ME/CFS researchers – who well know that PEM produces many other symptoms – was kind of sad.
The patients’ experience of their symptoms caused their distress. The authors used the Nath ME/CFS intramural study to conclude that the patients’ “experience of symptoms” and altered interoception, allostatic load, and perceived burden explained their response.
Wust pointed out, though, that the Nath paper did not explore any of those topics and, in fact, provided “multiple physiological explanations for ME/CFS pathophysiology, including autonomic dysfunction, differential cerebrospinal fluid catecholamines, and metabolite profiles, and lower post-exercise cortisol responses”. Plus, it confirmed Wust’s findings of lower °𝑉𝑂2max and impairments in skeletal muscle mitochondrial metabolism”.
“Ranque” Desperation?
The biopsychosocialists are still out there, but seem to be more of a fringe element, and their arguments seem to be becoming ever more shrill and less convincing. Take Beatrice Ranque, the lead author of the reply to Wust. In “Why the hypothesis of psychological mechanisms in long COVID is worth considering,” she fell back on the weak argument that because normal physical examinations and routine test results suggest that “no organic impairment” exists in long COVID, psychological factors must be important.
She hit that theme again when she pointed out that “self-reported persistent symptoms poorly correlate with objective long-term organ damage”, and when she wrote because “debilitating and persistent symptoms…are not fully explained by damage of the organs“, therapeutic interventions should follow those recommended for “functional somatic disorders”. Her conclusions – which completely ignored the molecular findings in long COVID – were embarrassing in a disease as new and poorly studied as long COVID.
It’s no wonder, though, that Ranque was so bothered by a study that found plenty of “organic impairment”. With objections like Ranque et al.’s to the Appleman/Wust long-COVID study, people with long COVID and ME/CFS have little to worry about – and indeed, with a mess of ME/CFS and long-COVID muscle studies coming up, things are probably not going to get any easier for them.
More muscle studies are underway.
Upcoming Muscle Studies
Two major ME/CFS muscle studies funded by the Open Medicine Foundation are underway. One will take a deep, deep dive (genomics, proteomics, metabolomics, phospho-proteomics, ultrastructural analysis, mitobiogenetic markers) into muscle samples from ME/CFS patients. The other will take muscle samples before and after a two-day CPET exercise test and, among other things, assess levels of citrate synthase (which Systrom has found depleted in ME/CFS before), gene expression, metabolites, and proteins in the muscles.
Plus, Paul Hwang of NHLBI and Avindra Nath are continuing to collaborate on their WASF3 muscle cell findings. Rob Wust’s Solve M.E. Ramsay award examines muscle biopsies before and after exercise in ME/CFS, and David Cosgrove at Cornell scored an NIH grant to analyze ME/CFS muscle biopsies using new technologies to “identify changes in cell-cell communication (ligand-receptor) pathways involving myogenic, endothelial, and immune cells and their spatial organization between control and ME/CFS muscles” and assess the role blood vessels play.
Things are moving quickly. Last November, Leitner and Singh took invasive exercise testing to a new level in long COVID. A blog on that study is coming up.
Thanks as usual Cort, this is all very interesting. I really wish though that once again authors would make comparisons between long COVID and fibromyalgia and not just ME/CFS and long COVID. Do you have any information on whether similar data have been found in FM? As you note, that would have even further strengthened the argument in the reply to the editorial authors trying to cast doubt on the study results. It seems to me too that with the strong pain and exercise issues also present in FM it only makes sense to include it – is there some reason why these findings would apply more to ME/CFS? I just find it so frustrating that FM is being left behind, in study funding and in application of results from long COVID.
Frank I could not agree more, they definitely need to add fibromyalgia to these tests.
Check out the german start up called “Mitodicure” and Prof. Klaus Wirth.
Couldn’t have said it better. These are my concerns as well.
I feel the same way. Not so long ago we still heard about fibromyalgia in those types of studies, but lately it feels like we have been forgotten, or considered irrelevant.
As I understand it, the main symptom of FM is pain.
Pain is not a universal symptom of ME. The top diagnostic for ME is PEM, whereas gentle and increasing exercise is beneficial to FM sufferers.
Am I wrong? Not sure about LoCo.
Brilliant! Thanks for the reporting.
Just commenting to point out two confusing typos that may need fixing?
“Plus, two hallmarks of deconditioning – decreased filling pressures and reduced peak CO2 – are opposite to those found in deconditioning.” Deconditioning opposite to deconditioning? I think one of those is meant to be long-COVID/ME
“Plus, ‘The significantly lower gas exchange thresholds and respiratory compensation points’ indicated that the reduction in aerobic functioning found was not effort-independent.” – Do you mean not effort-dependent? Sounds like you’re saying those effects were dependent on effort by saying they’re NOT effort-independent.
Again, thanks for this 🙏 good news for the community.
Both fixed! Thanks!
Dr Ranque’s forename is Brigitte and not Beatrice ( I know cause I’m french and she’s one of the important player with a lot of institutional weight here in the long covid/ME-CFS medical community…)
And I for sure hope this kind of study will provok a shift in her belief system , although I doubt it.
What we need is more studies then a critical mass of data then a new medical consensus…
Fingers crossed !
TY for the great summary Cort. Any new abnormal findings can potentially provide missing pieces of the puzzle, so I applaud this researcher’s initiative and findings.
However, the dogmatic escalating commitment of a dwindling pocket of other “researchers” to the psychological dismissals of patients and their complaints helps no-one (aside from giving doctors license to excuse themselves from doing deeper investigations into possible underlying physiological causes of our symptoms). However, an easy dismissal of a complex/unknown problem can be a powerful incentive for a busy doctor – who has a never ending line of “lower hanging fruit” waiting at the door.
Incidentally, “escalating commitment” is a known psychological phenomenon whereby once an individual makes an (even slight) commitment to one side of an argument, their commitment to their chosen position will often escalate when challenged (even by facts), probably due to a desire to “save face”. If the “Psychosomatic Dismissers” are so bent on blaming the disease on psychological phenomenon – even in the face of mounting physiological scientific evidence to the contrary – then perhaps they would also be open to accepting that their refusal to accept contrary scientific evidence is also (or instead) a psychological phenomenon (due to escalating commitment)?
Does this sound familiar?; “Since I don’t personally know the cause of your symptoms or disease, it must all be in your head (and implicitly – therefore I won’t waste my time looking any further)”. I have always considered this “all-too-handy/common” presumption by Clinicians to be a combination of ignorance and arrogance that is beyond the pale. It is enough to make a desperate patient scream, cry, or (eventually) just give up consulting doctors/whipping a dead horse.
Thus, I am disheartened when anyone considered to be a “researcher” pays any credence to psychosomatic dismissals. Even if there might be some small partial truth in theories that “some patients’ perspectives or coping strategies may act to exacerbate their symptoms”, promoting it as if it was the only or core root cause (while rejecting scientific evidence to the contrary) will only act to reduce the call and funding for real research, and the onus upon Clinicians to take these diseases (long Covid, CFS and Fibro) seriously.
This is just my take, based on 30 years of seeing innumerable Clinicians/Specialists – some of which were likely highly skilled in their fields – but whose skills were (by and large) “rendered useless” by their (medical culture pre-programmed) psychosomatic dismissals, simply because standard cursory lab screens for (other) common known diseases showed/show nothing definitive. If anyone’s thinking is irrational or unsound here, IMO, it is not the perpetually dismissed and frustrated patients’.
This will be my last post here.
Frankly, I am sick of all the talk and going round in circles in research. Gosh, we’ve had all sorts of theories over the years – HPA dysfunction and TH1/TH2 in the early 2000s, a retrovirus got thrown in that got us all briefly excited, rituximab excited us then flopped, neuroinflammation got me excited for a few years until I realised recently it was another interesting theory going nowhere….
I have had an albeit mild form of this illness for nearly 35 years. What pains me much more, however, is the suffering of my 17 year old daughter over the past two years.
I am sick of the broken promises , of the trials that seemed to promise so much but never started, or started and failed.
I think there’s a good number of charlatans in me/CFS circles, unfortunately.
My son is 26. He is me/cfs free. He’s never had the condition and I hope like anything he never does..
I never imagined, in 1990, that I might have a 17 year old daughter with me/CFS in 2025, and there’s STILL no treatment. Not even treatment that can help, let alone cure.
So….. maybe the illness IS psychosomatic. Or perhaps, more likely, so complex that it will always defy modern science.
In the meantime, I hope and pray that my daughter will heal, in time. After all, I got significantly better over time. Probably 85% of my former health. I have been able to
live a pretty good life
Thank you for your work, Cort. I hope
One day that your persistence will be paid off with some meaningful progress.
Good luck to you all, and God Bless
Sorry you have to go through this but science takes time and progress isn’t linear. It’s a discussion and there will always need to be many theories to find the ones that are actually correct. That’s the scientific method. If you wanna blame anyone for the lack of progress, blame the lack of funding. If we had the ability to actually test all hypothesis thoroughly, we’d likely have been -much-further along years ago.
Thankyou for this interesting discussion and summary of clinical findings about pem. This reflects my personal experience of trying to exercise. I have cfs/me. I recently did a ‘return to exercise’ program with an educated physio who encouraged me to rest and pace whilst doing small amounts of specific exercises. By keeping well within my exercise tolerance and aerobic limit ( which sadly is very low after 18 months in bed or a chair, with infrequent trips out), I found I felt better. And very slowly I could increase my exercise levels. They’re still way below a person without cfs/me however.
As a former judo instructor, I’ve found the loss of energy to be crippling. I’ve tried ‘doing more to get fitter’ and ‘pushing through’ simply made me crash so badly. I’ve had to learn the new boundaries and how to pace effectively. None if it was psychological! Although the side effects of having a life changing illness definitely has a psychological effect. I’m so pleased there is a growing body of evidence to support the experience of so many sufferers and hopefully there will be a solution found in the future. Thankyou so much researchers.
Hi Matthias, whishing you and your daughter all the best. I had a time a couple of years ago, where I felt overwhelmed by the variety of research topics as if there was no clear way forward.
I do not feel this way anymore: To me, much progress appears to happen, and I am writing this just in case it might buoy up your mood to see someone viewing it more positively due to the reasons below.
My current view of ME/CFS existing research is, in short, that ME/CFS is probably a complex cascade dysregulation in the body, of which research has already uncovered many puzzle pieces in the body, but is still looking for the “main switch” (and root of PEM). My bet is also on an epigenetic element to the disease.
What makes me hopeful is that:
a) Results are increasingly being replicated, the same topics start to come up various studies which also shows in the fact that Cort is increasingly able to make connections and crossreferences between studies
b) tRat research technology has made leaps that allow for detailed research that was not possible 10 yrs ago (like Maureen Hanson’s urine metabolome studies, or Prusty inventing his own tech for looking at viral interaction with cells). Only now can we look that closely at some things.
c) That the ME/CFS research community is, in my eyes, remarkable for the fact that they seem to be defined not by elbow competition, but by a spirit of truly wanting to solve ME/CFS and cooperation (take as an example the Stanford Working Group Meetings where international ME/CFS scientists freely share pre-publication results with each other)
d) That only since the Pandemic, ME/CFS started to be officially recognised, and only recently have official guidelines been changed in some countries to no longer treat ME/CFS as a psychological illness (like with the NICE revision in UK, or in 2024 revision of German guideline).
e) That the increased recognition of ME/CFS has been reflected in donations like the foundation who awarded a prestigious medical grant to Akiko Iwasaki, or that crypto tycoon chipping in.
f) The role of viruses also emerging in other fields of research (e.g. MS, dementia research…)
f) Here in Germany, I’ve noticed a lot of change in media reporting: Whereas before the Pandemic, reporting was about zero or wrong, now there’s a steady online media stream of both sympathetic portrayals of patients, including reporting on research, both actually including 95% correct descriptions of the disease. Âlso, since the Pandemic, ME/CFS awareness and allies have been built among politicans of all parties.
So I agree, it will be complex and difficult to solve, and does not yet guarantee a treatment. I am pretty much stuck at severe ME/CFS right now. And there is still much to few research funding. But I truly believe that conditions for solving ME/CFS have never been better than today.
I hope this cheers you up maybe a little. And if you feel like coming back after some time away, I’ve always appreciated your comments!
Kind regards
“that research technology”, not “tRat research technology” 😉
Thank you JR
Hi thank you for writing this.It makes lots of sense to me.I’m diagnosed with fibromyalgia.My symptoms are:-I feel like I’ve been poisoned,been to the gym after not going for a long time and that I’m bruised everywhere.Also I’m always exhausted and have cognitive problems.I have also got sleep problems.Sorry I’m having difficulty writing anymore brain won’t work properly.Thank you very much for helping me try to understand x
I forgot to say I feel like I have flu all the time
Feels like we’re going in circles. No major progress towards a treatment. Sparse studies producing only tiny leaps forwards. The underlying cause of the disease still essentially unknown. It realistically seems like we’re 20+ years away from an actual effective treatment that significantly affects our quality of life. I’m 25, have had ME since age 13, and the outlook feels hopeless.
Thankyou to Cort, the researchers, and those who take this devastating disease seriously.
Yes, it is mostly small steps – I guess that’s the way science mostly works: the findings slowly build on each other – but in a way we’re seeing remarkable progress. Take the muscle biopsy studies, though. Wust’s was the first to assess the muscles after exercise and he found a bunch of stuff. In general it validated what we know but it did so at the muscle level – so now we have validation of the turn to anaerobic energy production at several different levels – 2-day CPETs, invasive CPET, metabolomics and probably others.
Now that that question has essentially (I believe :)) been settled the question is where the breakdown is – and the list is not short but it’s not that long either – and that’s where the next research will go. For me, I’m very encouraged by all the muscle studies.
For the past 30 years or so, we’ve had two small teams – working out of the UK and Italy if I remember correctly – working on muscles in ME/CFS. Now we have 2 major muscle studies from the Open Medicine Foundation, two more from the NIH (WASF3/Cosgrove), Wust’s ongoing work, plus Klaus Wirth has come up with a way to explain the extreme debilitation and a new invasive exercise long COVID study just came out.
The difference between where we are now and where we were 2 years ago is just remarkable. Of course, finding a treatment is a different thing we don’t know what future findings will provide in that area – but we are making ground.
I don’t think the difference in the last two tears is ‘remarkable’ at all, but I admire your positivity.
Certainly we have had some new and interesting research.
I was quite positive about Polybio, but now I am not so sure. Amy made a very categorical comment in a LA Times article that I thought was less factual and more propaganda.
Thanks for your response. I’ve just reread my comment and it was unnecessarily terse and pessimistic – apologies for that.
I’d been reading some discussion of me/cfs on forums containing doctors which had thoroughly depressed me. It’s truly painful to see many medical professionals still not taking the disease seriously, dismissing sufferers as lazy/liars/mentally ill. If only they’d take the time to actually read through some of the research.
The work of Klaus Wirth does in fact give me some hope. His theory of me/cfs is certainly compelling.
This site really helps keep me sane. Thanks again.
Exactly, well put.
I wouldn’t even guess when we might properly understand this illness or have treatments.
I have got my hopes up far too much in the past
Hi Mark, if you want to have a look, I just left a comment above, summarising some reasons to be hopeful about ME/CFS research. I also feel pretty much stuck right now after 12 years, the last 2 of them severe, but the the points above are what gives me reason to be hopeful.
And as to the research in this blog, I feel it’s actually a pretty big deal that there is tangible scientific evidence for PEM. It wasn’t there 10 yrs ago, making it so easy to psychologize the disease. Now we have tzat more and more from various studies: This graph from Maureen Hanson’s study always cheers me up: https://x.com/DrMaureenHanson/status/1624786614764425216 🙂
Hey, I’ve just read your comment – thanks for writing it. I was having a rough day and it cheered me up a little. Sorry to hear of your situation. There’s so many of us out there living through similar ordeals – it’s somewhat comforting to know I’m not the only one suffering.
Germany really seems to be a leader in producing cfs research and raising awareness for the condition. It’s indeed encouraging to see building evidence of measurable physiological disturbances. Hopefully as time goes on medical professionals will be forced to take our condition more seriously, and not simply dismiss it as ‘psychological’ – as it seems many sadly do.
Hi Cort, don’t forget all of Professor Newton’s research ( https://me-pedia.org/wiki/Julia_Newton) when you write the next blog.
It is not Vermoulen but Vermeulen 🙂
In fact, a breathing disorder can explain everything. I think hyperventilation has a medical reason, not a psychological one. If your oxygen intake is not going well, it works both ways. Then I come back to the brain stem.
I really should have looked up his name (lol) – I am probably never going to remember it right.
Righto regarding Dr. Newton. Haven’t heard much from her lately but she did an awful lot.
I suspect that when medical researchers actually start studying fascia and it’s role in circulation and nerve conduction, we’ll start putting more puzzle pieces together.
I know it’s not psychological- I was always someone who woke up at 5:30 to do yoga and hiked a couple of miles after working all day. I also meditated daily for years before the injury that triggered my CFS. I’ve never had depression or anxiety, although I did get an ADHD diagnosis last year at age 52.
I do mixed workouts-a little bit of weights, a little bit of walking, a little bit of dancing, a little bit of isometrics. But if I overdo activity I crash and have the insomnia and tachycardia and all kinds of malaise. It’s a very fine line to walk, to exercise just enough to feel better and not worse.
Has anyone tried a PEMF mat? If so, did it help?
Very interesting. Research over years frequently comes back to the same problem with mitochondria. Analysis of complex pathways is useful. I wonder if there will ever be some deep research into the cause ? And if there is a causative
agent / s, then that might provide an approach to treatment ?
Hi Cort,
Since 2010, I’ve been researching muscle weakness and have confirmed two diagnoses: ACTN3 gene deficiency (R577X variant) and post-polio syndrome. A third possibility, dysferlinopathy (DYSF-related disease), is currently scheduled for evaluation. https://www.mdc-berlin.de/news/press/developing-crispr-therapy-muscular-dystrophy
In the process, I’ve also discovered that there are many other potential factors, most of which appear to have epigenetic markers.
Hi Sieglinde, just to clarify, do you mean you have been doing general research on which diagnoses have a connection to muscle weakness; or do you experience muscle weakness yourself and have confirmed your own diagnoses?
I have an acquaintance with post-polio, who, remarkably, has the very same problems with hand/arm movements being particularly taxing in typical “cleaning” movements, that I do with ME/CFS.
Hi JR,
I have a clinical diagnosis from a specialist in the UK affecting my leg muscles, making it difficult for me to walk up hills or climb steps. I also have a DNA-confirmed ACTN3 gene deficiency. However, I believe my skeletal muscle weakness, particularly in my arms and shoulders, may be related to Dysferlinopathy (DYSF-related diseases), as I have the DYSF gene. Hopefully, this will be confirmed with a biopsy soon.
I struggle to lift my arms beyond shoulder height and find it difficult to do tasks that require bending forward. Driving long distances while holding the steering wheel is also challenging.
Thank you Sieglinde, good luck with the biopsy and best wishes!
Hehe, with severe ME/CFS, everything IS exercise. I am still puzzled why I have not more muscular loss, attribute it to the constant state of nervous system overarousal kind of keeping up a probably constantly enhanced muscle tonus, and or constantly operating at the muscular capacity limit even with small tasks.
I have a friend with mild post-Covid ME/CFS, who discovered there is actually a safe threshold below which he can safely do mild exercise.
But discussion of exercise benefits should never, ever forget that this works only in patients, who are functional enough that exercise time does not take away from needed resting time. In many, particular in patients wired to be active with high nervous system arousal, in my opinion much more benefits can be derived from truly learning how to rest, and when instead trying to exercise, the benefits if true rest will instead be lost.
Secondly. my friend who benefits from a clear exercise threshold, does not experience the phenomenon of exertion-limits masking nervous system hyperarousal the way I do, which can also make exercise dangerous because exercise itself can cause a pleasant hyperarousal that will then mask safe limits.
Thirdly, as I’ve said before, I think the perspective benefits of movement of the body should not be limited to just exercising and strenght building. In my opinion, keeping the fascial system fluid, circulation and so-to-say “the juices flowingq and the body mobile are health benefits of movement that have nothing to do with strength building, but may actually be more important for a chronic illness patient.
For me with severe ME/CFS, walking stretches/mobilisation in my flat in the morning, stretches against the wall in the evening if I can, and one full body muscle relaxation practice at rest is what I incorporate into the day if possible.
As for rest versus exercise, the timing may also matter: Not to forget that for some patients, there seems to possibly be a “window of opportunity” right at the start of postviral illness where resting can in the optimal case lead to full recovery. My best friend’s co-worker recovered fully from post-Covid by following Charité Berlin’s (the university clinic where Scheibenbogen researches) instructions for rest in the convalescence phase and breathing exercises provided by Charité, sticking with determination to her couch and fending off relatives’ initial insistence that she exercise. Today she does heavy physical work renovating her house.
Of course I do not advocate total immobility. However, in my opinion the following might sum it up:
In ME/CFS, exercise is body maintenance (and I suppose might have some antinflammatory infects). Rest however has a potential to be curative in particular close to early onset.
To me this makes sense as I imagine resting early on and avoiding all risk of overexertion may give the body system the opportunity to calm down, while on the other each event of overexertion that causes PEM will kind of “fire up” the disease process anew.
As for the “allostatic load” (= kind of damage from chronic stress?) argument, it goes to show that BPS views can be rather undifferentiated: According to a European survey https://www.europeanmealliance.org/documents/emeaeusurvey/EMEAMEsurveyreport2024.pdf , I think 12% of ME/CFS patients reported traumatic life event/stress as an initial trigger for onset of ME/CFS, while stress itself is an epigenetic mediator, an immune event and a known initial trigger for various autoimmune diseases. So, the fact that those patients report stress as a trigger still does not mean that ME/CFS itself is psychosomatic, just that in 12% of patients, an additional layer of possible stress damage effects could be expected too due to their history, and that this stress possibly (co-)functioned as the immune or epigenetic trigger that caused initial outbreak of ME/CFS.