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

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".
Jonathan Edwards said:
If something serious was going on in muscle I think we would expect a simple CK to show it.
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@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)
Dolphin said:
https://www.dutchnews.nl/2024/01/long-covid-patients-fatigue-is-biological-dutch-research/
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Id be very appreciative any insight into the paper from those that have time to look properly
 
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Kitty said:
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!
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They are already studying people with mild/moderate ME and are planning to hopefully study people with severe ME as well.
 
Simon M said:
“So, the cause of the fatigue is really biological. The brain needs energy to think. Muscles need energy to move.”
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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]
 
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Simon M said:
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).
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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).

Screenshot 2024-01-05 at 9.12.02 AM copy.jpg

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.

A larger percentage of long COVID patients displayed small atrophic fibers and focal necrosis, which increased significantly after exercise, indicating an exacerbated tissue damage response in patients with long COVID.
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Neither did we observe an increase in muscle breakdown products, such as creatinine and creatine kinase, in the plasma of both groups.
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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?
 
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Although the majority of people infected with the SARS-CoV-2 virus recover within weeks, a small group develops post-covid. Complaints in patients with long Covid include the so-called post-exertional malaise (PEM), which involves extreme fatigue after physical, cognitive or emotional exertion, as well as serious cognitive problems (brain fog), fatigue and exercise intolerance.

Boundaries
Going beyond the physical limits of that fatigue is usually not a good idea. Brent Appelman, physician-researcher in infectious diseases at Amsterdam UMC: "Because complaints can worsen after physical exertion, some classic forms of rehabilitation and physiotherapy are actually counterproductive to the recovery of these patients."
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https://www.ad.nl/gezond/onderzoek-...g-covid-heeft-lichamelijke-oorzaak~a6d2a09a5/

Researchers from Amsterdam UMC and the Vrije Universiteit (VU) Amsterdam have specifically looked at patients who suffer more from their complaints after they have exerted themselves emotionally or cognitively: post-exertional malaise (PEM). They did this by having people cycle as fast as possible for fifteen minutes.

The study included 25 people with post-Covid and 21 healthy people who had Covid but subsequently fully recovered. A day later, blood and a piece of muscle tissue were taken. This material was compared with material taken one week before the bicycle test.
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https://www.nu.nl/wetenschap/629672...k-lichamelijke-oorzaak-postcovidsyndroom.html

Cycling test shows: muscles of patients with long Covid deteriorate after exercise
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Could only get the headline for that, the rest is paywalled. Source:

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

Dutch scientists unravel the major fatigue riddle of post-covid patients

Many post-covid patients become sicker and more tired after the slightest exertion. Amsterdam scientists have discovered that this has a physical cause. The power plants in patients' muscle cells function poorly and their muscle tissue dies.

Ellen de VisserJanuary 4, 2024 , 11:00 am
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https://www.volkskrant.nl/wetenscha...raadsel-van-patienten-met-postcovid~b0b67980/

VU sports scientist Rob Wüst says that they saw abnormalities in the muscle tissue of patients with long Covid. “At the cell level, it could be seen that the mitochondria of the muscle, also known as the energy factories of the cell, function less well and that they produce less energy. Muscles need energy to move.”

“The cause of the fatigue is really biological,” says Michèle van Vugt, professor of Internal Medicine. While the healthy participants had no problems after the cycling test, all post-covid participants suffered from post-exertional malaise (PEM), extreme fatigue after exercise. They still had weeks to recover from the test.
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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
Independent said:
Now, researchers have found that long Covid can cause severe muscle damage and other problems if sufferers take part in intense exercise or physical and mental exertion.

The study published in Nature Communications compared 25 patients with long Covid and 21 people who had suffered from the virus and made a full recovery.

To control for any other factors, all the participants had been fit and healthy before contracting the virus, were of working age and none had been hospitalised with the illness.

Participants were asked to take biopsies before and after cycling to assess the impact of exercise on their bodies.

The study found that those with long Covid experienced limited capacity for exercise, far more tissue damage, microclots, metabolic dysfunction and post-exertional malaise.
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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.
 
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SNT Gatchaman said:
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?
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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?
 
LarsSG said:
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?
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@Snow Leopard ?
 
dave30th said:
yes, I assume Knoop & Co. will push back soon. Maybe they'll even come up with "eight anomalies" in the paper!!
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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.
 
:thumbup: all power to you @Solstice


On peripheral O2 extraction
lower ... peripheral O2 extraction (determined via near-infrared spectroscopy)...
during exercise all indicated peripheral skeletal muscle impairments in patients
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Screen Shot 2024-01-05 at 2.39.38 pm.png

Muscle deoxygenated [heme] responses (mean ± SD) measured by near-infrared spectroscopy were lower (p = 0.023) in long COVID (n = 16), indicative of lower peripheral oxygen extraction during exercise compared to healthy controls (n = 18; excessive adipose tissue precluded data analysis in remaining participants).
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So, an interesting difference in peripheral oxygen extraction (lower in Long Covid). But the sample size is even smaller than the whole (fairly small) study sample size.

p-values for panel D, E were determined with a two-sided ANOVA test. Dashed line (D) represents the average starting point of the exercise test.
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Methods - detail on the Near Infra-red Spectroscopy said:
Participants wore a spatially-resolved, continuous-wavelength portable NIRS device (Portamon, Artinis Medical Systems, Arnhem, The Netherlands) on the surface of the vastus lateralis muscle, halfway between the head of the femur and lateral condyle. This was around the location of the muscle biopsy. Measurements for total (Δtotal[heme]), deoxygenated (Δdeoxy[heme]) and oxygenated [heme] (Δoxy[heme]) [hemoglobin + myoglobin], as well as muscle saturation (SO2, i.e., oxy[heme]/total[heme]·100) were normalized to a maximal and minimal value obtained during blood flow occlusion proximally to the NIRS device using an inflatable cuff. Briefly, a cuff was inflated between 300–500 mmHg, and remained inflated until a plateau in Δtotal[heme], Δdeoxy[heme], and Δoxy[heme] signals were reached, and then subsequently released. The maximum and minimum yielded the physiological range for each individual, and all values were normalized to this physiological range.
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All NIRS data was analyzed related to both absolute and relative work rates. Absolute work rates were analyzed at 25 W increments from 50 W until 175 W, after which most participants could not continue the test. NIRS data was averaged for the 5 W below and above each increment to reduce noise in the data set. Similarly, for relative work rates, data was analyzed at 0%, 20%, 40%, 60%, 80%, and 100% of maximal work rate. Data was averaged for the 5% above and below each increment. All data was subsequently analyzed using a linear mixed model.
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So, I think, essentially oxygenation was reported relative to values obtained at rest using an inflatable cuff to stop blood flow.

whiskers show the 1.5× interquartile range.
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I'm not clear what they did with the whiskers on those two charts (Fig 1 D and E), or why they chose that particular measure. The 1.5 interquartile range is usually applied to the Q1 and Q3 figures (e.g. Q3 + (1.5 x IQR)) to identify the range outside of which data points can be regarded as outliers. I don't think that is what they have done here. Regardless it's clear that, although there is a statistically significant difference, there is considerable overlap between the control and Long Covid data points. I'm not sure where that leaves us, when it comes to thinking about a pathological mechanism.

It is mentioned that the actual data is available - that might be worth looking at.
 
LarsSG said:
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?
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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....
 
LarsSG said:
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?
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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.
 
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