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

Press release:
https://www.amsterdamumc.org/en/spo...-long-covid-patients-has-a-physical-cause.htm
Unfortunately not as interesting or detailed as it could have been, IMHO.

Also
https://www.dutchnews.nl/2024/01/long-covid-patients-fatigue-is-biological-dutch-research/

 

https://twitter.com/user/status/1742869435067629757


Mild and moderate pwME also experience severe delayed PEM.

 

I hope others can help me understand this paper as it would take me a long, long time to the full thing.

It appears to be very thorough. The findings are eye-catching but also report numerous negative findings, including the absence of microclots in capillaries (I'm concerned when everything comes up roses).

I also like that the senior author Rob Wust has said they intend to look at MEcfs in the same way.
https://twitter.com/user/status/1742869435067629757


However, it's a bit surprising that no one else has seen signs of "severe exercise-induced myopathy".

@ME/CFS Skeptic reports CK was not elevated.

And it is a small study.

I am also unimpressed by the overclaim of:
“So, the cause of the fatigue is really biological. The brain needs energy to think. Muscles need energy to move. This discovery means we can now start to research an appropriate treatment for those Long Covid,” Van Vugt [a senior author] said. (see below)

Id be very appreciative any insight into the paper from those that have time to look properly

 

I took the tweet to mean they have plans for mild/moderate patients already, and hope to involve severe patients at some stage (which presumably is substantially more difficult due to the need for a biopsy). Might be wrong, though!

 

They are already studying people with mild/moderate ME and are planning to hopefully study people with severe ME as well.

 

https://twitter.com/user/status/1742980907634663856



“This paper is being discussed on the Science for ME forum: https://s4me.info/threads/muscle-abnormalities-worsen-after-post-exertional-malaise-in-long-covid-2024-appelman-et-al.36769/“

Rob Wüst: “Please remind me later. It’s a bit hectic today”

[Edit: can someone please remind him if I forget?]

 

My understanding is that difference in energy consumption of a thinking brain and a resting brain is minimal – energy production alone does not explain cognitive impairment in ME/CFS.

[edited typo for clarity]

 

They did show amyloid-containing deposits in the wall of a larger vessel (2nd panel A below). I don't think this was discussed in the paper but was mentioned in their recent talk. To me the vessel in cross-section looks like an arteriole, where the deposits are spread between the inner and outer margins, ie intima (endothelial cells, basement membrane) -> media (smooth muscle, internal elastic lamina) and adventitia (fibroblasts, ECM with unmyelinated small nerve fibres).



So, if the majority of amyloid-containing deposits are outside capillaries and lymphatics, have they been extruded from the vessels? Were they in capillaries but then those capillaries degraded, leaving the deposits behind and undegraded?

A probably more important question is how they are showing significant necrosis and yet no elevation in muscle breakdown products in plasma.

I can imagine that perhaps myoglobin might be down-regulated with tissue hypoxia (if that is occurring) so perhaps that might not then appear as myoglobinaemia/uria, but CK should be up. Is it not reaching (or impeded and slower to reach) the blood pool to be measurable? If capillary architecture is altered, with thicker basement membrane, perhaps that might limit transfer in both directions. See Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles (2023, Acta Neuropathologica Communications). Or less likely, is it being sponged by something in the blood and therefore not measurable?

 

‘Finally we’re believed’: Long Covid sufferers hail new research saying they should avoid intense exercise
People with long Covid tell The Independent of their relief over new research
https://www.independent.co.uk/news/uk/home-news/long-covid-intense-exercise-b2473174.html

I think the man continuing to work in the physically-demanding job is playing with fire.

 

https://www.ad.nl/gezond/onderzoek-...g-covid-heeft-lichamelijke-oorzaak~a6d2a09a5/

https://www.nu.nl/wetenschap/629672...k-lichamelijke-oorzaak-postcovidsyndroom.html

Could only get the headline for that, the rest is paywalled. Source:

https://www.trouw.nl/zorg/fietstest...-covid-gaan-achteruit-na-inspanning~b5f69a94/

https://www.volkskrant.nl/wetenscha...raadsel-van-patienten-met-postcovid~b0b67980/

https://www.telegraaf.nl/nieuws/774...-bij-long-covid-fysiek-en-niet-tussen-de-oren

Seems like all the major Dutch outlets reported on this. The only one I couldn't find an article for is NRC. Sorry for the text/linkdump btw. I can divide it in separate posts tomorrow if that's preferable.

 

Merged thread

Independent: ‘Finally we’re believed’: Long Covid sufferers hail new research saying they should avoid intense exercise

https://www.independent.co.uk/news/uk/home-news/long-covid-intense-exercise-b2473174.html

EDIT: Sorry for the duplicate - I could not find this thread so didn't realize that a link to this article in the Independent had already been posted.

 

With the press consistently framing this study as proof exercise is harmful for people experiencing PEM, it wouldn’t surprise me if our friends in the BPS bubble make their displeasure felt soon.

 

The absolute increase in amyloid-containing deposits after exercise testing was similar between controls and patients, which suggests maybe there could be a problem clearing them or whatever happens normally, rather than a problem of too much being deposited (unless the amyloid-containing deposits were associated with capillaries in controls, which isn't clear in the study).

Do we know why amyloid-containing deposits appear after exercise and how they are cleared?

 

yes, I assume Knoop & Co. will push back soon. Maybe they'll even come up with "eight anomalies" in the paper!!

 

@Snow Leopard ?

 

I'm discussing the paper on a Dutch forum and it honestly feels like I'm talking directly to one of them. The same bullshit about psychosomatics not being explored. 30 years of research yielded nothing. No one says psychological diseases aren't real, yada yada yada. Even brings up PACE as an example of good work that's been done.

Having been reading your articles and this forum in general I feel I was trained for this discussion for years luckily.

 

Is anyone aware of comparable - amyloid and/or some of the other findings in this study - pre-post-exercise muscle biopsy studies in overtrained athletes (who also seem to have problems recovering after exercise)?

 

Good to see this. Replication required.

So, what do pwME have to prove intense exercise is contraindicated? The 2 Day CPET, and the invasive CPET results are two sets of findings.

Off the top, do we have any other findings, post intense exertion?

Maybe the intramural NIH studies will reveal something....

 

I think we have to ask whether these are in fact 'amyloid deposits' or at least in what sense.
Note:
1. we have no evidence of any amyloid deposits actually in people in ME or Long Covid. The 'deposits' reported by Pretorius are deposits in tubes or on slides from plasma that has already had any particles centrifuged out.
2. Amyloid deposits normally take months or years to form. They are not present in normal tissues. They form in situ in the tissue outside the blood vessel lumen. If amyloid deposits were a problem in Long Covid then one would expect to see them before exercise and be very lucky to see any visible increase after.
3. The bright dots and lines in the pictures do not look like typical amyloid deposits in other conditions. If they had come from within vessels they would have had to be endocytosed or phagocytoses and transported. They ought to look like haemosiderin granules in macrophages do, or something similar. These do not look like that at all. From what I can see of the pictures the only thing they look a bit like is nerve fibres.
4. None of these important issues were alluded to in the video presentation.
5. If normal control muscle shows a similar increase in 'deposits' then presumably they aren't very important.
6. Thioflavine T, as far as I can see, is a stain for a particular protein. Unlike birefringence-based methods it does not actually show the presence of amyloidogenesis - i.e. protein stacking or polymerisation. Thioflavine T has become very popular as an amyloid marker but it has also been criticised. I do not know much about it since it was developed after I moved from histochemistry to other areas. Proteins capable of stacking as amyloid are normally present in tissues as part of plasma exudation during inflammation, but do not stack. Muscle exertion is known to produce a degree of inflammation and for certain types of exercise overt damage.

I think it would be useful to have an expert histochemical opinion on these images.