Muscle abnormalities worsen after post-exertional malaise in long COVID, 2023/4, Wüst, van Vugt, Appelman et al

Jonathan Edwards said:
Well none of you have shot it down yet.
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While thinking of this, we need to be bear in mind the "something-in-the-blood" observation, so if those studies are valid there ought to be an ACh receptor/mechanism relating to the cells they tested. Off the top of my head I think myoblasts, fibroblasts, PBMCs and endothelial cells have been assessed in different ways and I think all would qualify on a very quick look.

Related, have we already "formalised" an equivalent of Koch's Postulates that any hypothesis for ME/CFS needs to satisfy? If not we should start a thread for discussion (I believe the term "Edwards' Postulates" would be up for grabs :)).
 
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Helene said:
Would be interesting to try it again now after a break of a couple of years to see if I'd get the same initial reaction.
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I've posted about my experience with Pyridostigmine Bromide a few times in the past, i've been taking it for around 5-6 years now I think - prescribed by neurocardiology in an autonomic clinic. Where my experience may differ to some is that I take ~2x the max dose usually recommended for POTS, which is ~5x what some of the larger POTS trials have used when looking for effect, though still some way below the maximum recommended dose for MG. It did require very gradual increments due to side effects but they dissipated a week or 2 after each bump.

Funnily enough last weekend, for the first time in years, I forgot to take my AM dose before going out to get some groceries. I was light headed during activity, completely wiped on my return and then really, really suffered that evening with painful, heavy legs & the wired but tired issues. That would be a very normal "immediate" response before I was taking the Mestinon, but normally now only occurs when I'm on my feet for hours not minutes. Or if I tried to repeat that baseline level of activity during a spell of PEM, when the threshold to trigger these issues is lowered.

None of this seemed particularly contentious to me given the circulatory abnormality and the immediate effect Mestinon can have on that. What I've been less clear on is why the delayed PEM I experience since taking Mestinon is also greatly reduced, in respect to severity and duration. Overexertion that would previously trigger days of being hopelessly fatigued and bedbound, with swollen lymph nodes, sore throats etc. is now just a day of inconvenience from some fatigue & cardiovascular wobble. Mestinon is the only intervention among many that's helped with PEM for me, short of just not triggering it in the first place.
 
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Rob Wüst replied to my email. He is going to look at some further comparative staining. He was aware of the cross-binding to nerve.

I think this is worth sorting out in detail. It may not have anything to do with cholinesterase but if not I think we need some sort of explanation for the strange distribution of staining if it is amyloid.
 
Jonathan Edwards said:
Which something in the blood observation are we thinking of?
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Agree the nano-needle findings seem to be parked. (Odd). A couple of others immediately to hand are:

Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome (2017, JCI Insight) —

cells [myoblasts] exposed to ME/CFS serum displayed a metabolic change involving amplified lactate production under conditions of energetic strain
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Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2020, ImmunoHorizons) —

Adoptive transfer of serum from 10 patients with ME/CFS produced a similar fragmentation of mitochondria and the associated antiviral state in the A549 [adenoCa lung epithelial] cell assay.
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A549 has nicotinic AChRs. See Nicotine activates HIF-1α and regulates acid extruders through the nicotinic acetylcholine receptor to promote the Warburg effect in non-small cell lung cancer cells (2023, European Journal of Pharmacology)

To the best of our knowledge, this is the first study to demonstrate that nicotine plays a pivotal regulatory role in metabolic reprogramming as well as regulation of pHi homeostasis in A549 cells via activation of nicotinic acetylcholine receptors and can therefore aggravate lung cancer progression.
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SNT Gatchaman said:
this is the first study to demonstrate that nicotine plays a pivotal regulatory role in metabolic reprogramming
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This might be worth digging deeper into given Prevalence of and risk factors for severe cognitive and sleep symptoms in ME/CFS and MS (2017, BMC Neurology)

Mij said:
"Our findings suggest that people with ME/CFS who are smokers, or have a low income, are more likely to report severe cognitive and sleep symptoms."

How is smoking relevant?
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Jonathan Edwards said:
'An interesting question that the presented facts pose.'
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That thread discusses the confounders: social, educational etc.
 
SNT Gatchaman said:
Agree the nano-needle findings seem to be parked. (Odd). A couple of others immediately to hand are:
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Bit of a rag bag I would say. If someone can isolate a blood extract with a defined molecular mass that consistently does something different in ME than controls I ill be convinced.

It is a cogent point that effects on cells might be mediated by ACh receptors on many cell types.
 
Jonathan Edwards said:
If someone can isolate a blood extract with a defined molecular mass that consistently does something different in ME than controls I ill be convinced.
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Is this doable? The same blood swap experiments, but an array of samples, sorting and swapping according to mass (or size)? I mean, it’s a too obvious approach not to have already been considered, isn’t it?
 
sneyz said:
Is this doable? The same blood swap experiments, but an array of samples, sorting and swapping according to mass (or size)? I mean, it’s a too obvious approach not to have already been considered, isn’t it?
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Identifying the molecular mass fraction that contains your active agent is a routine part of confirming that it exists. You can use ultrafiltration methods or columns.

I am sure it will have been considered, but just like a dose response curve for a drug it is in a sense the minimum one expects for proof of existence of an active agent. I think the nano needle study made some comment about crude fraction but to be believable one would want it to be repeatably found in a specific fraction.
 
Forskning.no writes about the study today, Changes in the muscles of patients with long covid worsened after exercise,
and for some reason spends half the article on how exercise «might still be the road to recovery». Bente Frisk, who is a fan of the Lightning Process and claim that patients recover using her groups similar approach is interviewed.

Recent thread on Bente Frisks and others work using micro choices/mindfulness/LP/similar, with links to other work by the same grouo:
First trans-diagnostic experiences with novel micro-choice based group rehabilitation for low back pain, long COVID, type 2 DM, 2024, Kvale+
 
Midnattsol said:
Forskning.no writes about the study today, Changes in the muscles of patients with long covid worsened after exercise,
and for some reason spends half the article on how exercise «might still be the road to recovery». Bente Frisk, who is a fan of the Lightning Process and claim that patients recover using her groups similar approach is interviewed.

Recent thread on Bente Frisks and others work using micro choices/mindfulness/LP/similar, with links to other work by the same grouo:
First trans-diagnostic experiences with novel micro-choice based group rehabilitation for low back pain, long COVID, type 2 DM, 2024, Kvale+
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What a disappointing article with a lot of mess. Another expert from the article is professor emeritus Omdal who has researched into fatigue, but emphasised many times that his work does not include ME. I don't think he understands that PEM is a different symptom than fatigue.
 
Kalliope said:
What a disappointing article with a lot of mess. Another expert from the article is professor emeritus Omdal who has researched into fatigue, but emphasised many times that his work does not include ME. I don't think he understands that PEM is a different symptom than fatigue.
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Agreed. It's the second time Omdal has been interviewed on (potential) biological underpinnings of fatigue (although I don't see why he would be a choice on this specific article) and one of the Norwegian proponents of graded exercise therapy/CBT have also been interviewed (last time at least Vogt but I think also Wyller?).
 
David M Tuller
Interview with Dr Rob Wust

Presentation:
In early January, Nature Communications published a Dutch study called “Muscle abnormalities worsen after post-exertional malaise in long COVID.” The study caused a buzz among patients, clinicians, and other researchers and generated extensive news coverage. Called. (I wrote a blog post about it here.) The investigators identified significant biological differences after an exercise challenge between long Covid patients with post-exertional malaise and matched healthy controls who had recovered from COVID-19. I spoke about the paper’s findings with Rob Wust, one of the main authors and an expert in muscle metabolism at Vrije [Free] University Amsterdam

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https://www.nationalgeographic.com/premium/article/post-exertional-malaise-me-cfs-exercise-energy
“For many people with long COVID, a major symptom is difficulty with exercising, because when these patients push past their limits it can lead to a devastating cycle of fatigue that boosts the risk of worsening their condition.

These issues with exercise, which is known as post-exertional malaise (PEM), are also the defining symptoms of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

Now a new study, published in the journal Nature Communications, provides an explanation for this feeling of exhaustion, suggesting that patients with long COVID experience a range of changes in their body after exercising, including widespread muscle damage, changes in muscle composition, and disrupted energy metabolism.”
 
Braganca said:
https://www.nationalgeographic.com/premium/article/post-exertional-malaise-me-cfs-exercise-energy
“For many people with long COVID, a major symptom is difficulty with exercising, because when these patients push past their limits it can lead to a devastating cycle of fatigue that boosts the risk of worsening their condition.

These issues with exercise, which is known as post-exertional malaise (PEM), are also the defining symptoms of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

Now a new study, published in the journal Nature Communications, provides an explanation for this feeling of exhaustion, suggesting that patients with long COVID experience a range of changes in their body after exercising, including widespread muscle damage, changes in muscle composition, and disrupted energy metabolism.”
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Here is an archived link to the article mentioned above:
https://archive.is/rd7Pm
 
I was wondering, has any muscle necrosis been seen in pwME in a post mortem/autopsy? I would have thought that would have been fairly easy to spot ... or am I missing something? Would an advanced technique be required to see something like this? Or did they just not know to look?
 
I don't think patients were biopsied following exercise challenge, but instead at rest.

Mitochondrial abnormalities in the postviral fatigue syndrome (1991, Acta Neuropathologica) —

Scientific study of the postviral fatigue syndrome (PFS) has been bedevilled by the difficulty indiagnosis and the absence of fibre necrosis on routine histology. Nonetheless, diffuse or focal atrophy of type II fibres has been reported, and this, although non-specific, does indicate muscle damage and not just muscle disuse
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In spite of this evidence of viral involvement, muscle biopsies from our carefully selected group of patients showed none of the histological features of inflammation or necrosis. Ultrastructural examination, however, revealed obvious mitochondrial damage, suggesting for the first time that this may be the pathogenesis of PFS.
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Postviral Fatigue Syndrome: Persistence of Enterovirus RNA in Muscle and Elevated Creatine Kinase (1988, Journal of the Royal Society of Medicine) —

Histological and histochemical investigations of muscle biopsy specimens from PFS patients have revealed a number of non-specific abnormalities, primarily, scattered atrophic fibres, type II fibre hypertrophy and occasional single fibre necrosis.
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