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

Indeed, but I worry that the interpretation of this recent paper supports that view - it suggests that PEM is all about inflamed muscle.

My limited experience of Long-Covid/PASC in the sense of being kiboshed for a couple of months or more each time has nothing to do with local muscle symptoms suggesting inflammation. It is more like feeling the life has been sucked out of one by a Dementor. There seems to be weakness in the sense that going upstairs is like climbing a mountain but no hint of muscle pain or soreness.

 

What nonsense. He's going to continue telling his patients their PEM is actually DOMS and they should just push through with "rehabilitation".

 

Interesting comment from Alan Carson, President of the FND Society, asking for a bedrest comparison.

He should read the analysis here. someone here (@ME/CFS Skeptic ?) has already pointed out the long Covid patients averaged 4000 steps a day: bedrest is not a relevant comparison. Plus, as Rob Wust, Jonathan Edwards and others here have pointed out, PEM is not the same as delayed onset muscle soreness.

Maybe I’m overgeneralising, but psychosocial enthusiasts always seem to respond with generic, knee-jerk criticisms. I don’t understand why they don’t just read the biomedical research that makes them uncomfortable: they might find real reasons to criticise the methodology (or might not). It’s almost as if they’re not able to operate outside their own bunker, or just don’t feel the need to engage properly with other scientists – never mind patients.

I’m a big fan of scientific debate and criticism, but it's only useful if it's thorough and thoughtful, not regurgitating vague criticisms in the hope that one will stick.

Anyway, I suspect tthat the RW bedrest study will settle Alan Carson's concerns on the bedrest point.

 

Thanks for your reply; unfortunately mine won't be of the same quality!
I recall the Group at Griffith's University publishing that they'd found certain genetic differences in a receptor. Wengzhong Xiao [OMF Harvard] review the data, in one of the Stanford Symposiums, and said that it didn't add up.
I'm impressed by the group at Griffith's University and, to me, they could do some good/great research. So GWAS data might just save a whole lot of --- around. I think Jonathan may have insightfully pointed out recently --- people in labs are desperate to find something i.e. after all that hard work. GWAS might just provide a reality check --- abandon this -- and thereby an opportunity to the re-focus on more promising research areas.

 

I don't think you're over-generalizing. They are incapable of accommodating any new information that challenges their biases. Period.

 

They rely on poor research to support their own theories, which logically must mean that either they can't do better, so would be unable to critique other research, or they are aware of the poor nature of their own research and don't want to point out flaws in research that most likely already exist in their own.

 

I wonder if it's even worse than that, with some of them not actually invested in their theories at all. They're invested in their ability to hoover up grant funding by telling policymakers what they want to hear.

 

This is receiving a lot of traction on X which is fantastic, but it's also getting mixed up in the messaging. I've been reading from researchers who are responding to the study that 'injury' is caused from 'intense exercise' when it can be brought on by walking.

 

The small cumulative factors must also be clearly stated.

 

Todd Davenport commenting re Carson's tweet too
https://twitter.com/user/status/1743344271951003937

 

In my eyes the problem is less that "this isn't what you see in healthy or deconditioned people", but rather that an inactive control group (and also a bed-bound group of PEM patients) provides a further level of control and helps you further analyse the existing data (that doesn't mean the group by Wüst didn't do excellently well with the extremely limited means given in LC research funding and others can now work on replication). Having a study of "LC with PEM vs. healthy controls vs. inactive controls" can in that sense be more robust than one study of "LC with PEM vs. healthy controls" and one study of "inactive controls" due to small differences occuring in the lab that could introduce some noise, because nobody sensible could anyways think that PEM is related to deconditioning.

I've also seen some responses to Carson's ridiculous tweets (not sure if it makes sense to respond to someone about metholodogy when said person clearly doesn't care about methodology to begin with and is only driven by his own beliefs rather than any evidence) which then responded with claims that this study proves causality. Unfortunately, even with replication we'd still not be there yet since the study only shows a strong correlation between PEM and these muscular abnormalities, which however is different from causality. As an example it may for instance be that autoimmunity causes both PEM as well as exercise induced muscular abnormalities via different mechanisms and that the findings are linked via autoimmunity rather than the one causing the other or vice versa.

 

The responses to Carson's uninformed tweet are just great. He's really getting roasted. It's clear he didn't look at the study and tweeted that to try and dismiss it out of hand. These patients were not on bedrest. I'm sitting here with a similar step count as the people in this study and I'm profoundly sick compared to controls who walk only 1000-2000 steps more. Absurd life-destroying symptoms after exertion like sore throat, pain everywhere, flu-like malaise, heart issues, insomnia...

 

https://twitter.com/user/status/1743241329738395749


https://twitter.com/user/status/1743286301053358339

 

That is of course always possible or maybe likely in some guess, but I guess I prefer in general to think that people are deluding themselves rather than that they're being consciously venal and deceptive. that could be a naive perspective, however.

 

They did see the amyloid deposits (or whatever they might be staining with Thioflavin T) in LC before exercise. Not really a huge change after either (excepting those three outliers with very high densities).



I suppose the baseline high amyloid deposits density in LC would be pretty easy to try to replicate for anyone who has frozen LC muscle biopsies, which I think we've seen a few studies of. Replication could involve a different stain (seems like Congo Red is the older standard). I wonder if that's something that the Patient-Led Research Collaborative would fund. Is anyone connected with them?

 

Can someone explain what he means by: "...must of course have a mechanism - i think thats where the issues of inference become key- but of course maybe your other data speaks to that" What inference is he talking about here? Can someone clarify? Is he suggesting these findings are similar to what happens in DOMS?

 

This paper seems like it might be relevant to the amyloid in muscle question: TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

Abstract: A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here we show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.

 

Indeed. At least this data seems like something that could also be explained by variations occuring in the lab (taking a biopsy from a different location, some slight differences in applying the staining etc) rather than necessarily a faulty exercise response. On the other hand it might also be that exactly those 3 outliners are exactly those people you want to be studying in such a heterogenous condition. Typically I'm far more impressed by large difference in a subset of people, than small differences in everyone often established by some of the AI/ML classifiers.

Indeed, seems like an excellent idea. The main problem will probably be that most of those studies wouldn't have assessed for PEM and given the heterogeneity of LC and the many patients with a short duration of self-resolvent symptoms, very mild symptoms or only a cough, one might need very large sample sizes to detect meaningful differences (and controlling for a recent Covid infection seems to be a larger problem in the microclot studies). Technically some of the PolyBio studies could address this (this Polybio study is using some kind of in-vivo imaging technique to look at something similar https://polybio.org/projects/evalua...fibrin-pet-imaging-peripheral-blood-analysis/, whilst this study is collecting biopsies and then staining them https://polybio.org/projects/immune-activity-and-microclotting-in-long-covid-peripheral-neuropathy/).

 

I would guess he is trying to lay the ground for the "of course there is something going on in the body but it's how the brain interprets it that is the problem" line of psychobabble hardware/software, 'definitely not cartesian dualism' waffle.