Microvascular Dysfunction and Basal Membrane Thickening in Skeletal Muscle in ME/CFS and Post-COVID, 2025, Slaghekke et al
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ScoutB
Established Member (Voting Rights)
It certainly doesn't sound ideal. Am I right in thinking it would be hard to tell? Considering we are only able to find this in muscle by taking biopsies (rather than imagining).
Slowly collecting my thoughts and writing a response to your reply in the other thread @SNT Gatchaman. In the meantime, I was so foggy when I first read this post I did not realize we now have two studies finding somewhat thickened basement membranes. Is it possible for someone to add the "capillary basement thickness" tag to this thread too? I assume I can't? idk how tagging works
Done, although I changed the tag to "capillary thickness" to be a little more generic and save a bit of screen space. It's the term used in Rob Wüst's follow-up opinion paper Skeletal muscle adaptations and post-exertional malaise in long COVID (2024)
Actually four, with two from another team in 2022 and 2023.
Myopathy as a cause of fatigue in long-term post-COVID-19 symptoms: Evidence of skeletal muscle histopathology (2022)
Myopathy as a cause of Long COVID fatigue: Evidence from quantitative and single fiber EMG and muscle histopathology (2023)
See links to summary images in those papers here and here.
I would take any bet that this is 1. a real and disease relevant phenomenon and 2. occurring in the ME/CFS brain.
ScoutB
Established Member (Voting Rights)
Thanks for collecting all that together @SNT Gatchaman. Is it worth having a thread on this topic (on "capillary thickness" or more generally on the weird results showing up in these biopsies)? Has this been studied much in other diseases?
I might try to answer these questions myself when I'm less foggy. For now all I have is that wikipedia says
I might try to answer these questions myself when I'm less foggy. For now all I have is that wikipedia says
Btw be warned the lichen sclerosus wiki page is probably not safe for work unless you are like a gynecologist maybe.
For (1) I would like to see the correlation tested between such muscle biopsy findings and eg 1H and 31P MR Spectroscopy to Assess Muscle Mitochondrial Dysfunction in Long COVID (2024) with at rest and exercise challenge.
For (2) Maybe, but the brain microvasculature is very different, particularly in regard to the blood-brain barrier. It might be that the brain microcirculation is affected but in a different manner, possibly including via circulating factors generated from the muscle distress and the related immune response.
I think we've only had very limited post-mortems for (very) severe ME cases and I'm not aware of capillary thickness being reported — in muscle or brain.
Awaiting RECOVER results from Researching COVID to enhance recovery RECOVER tissue pathology study protocol: Rationale, objectives, and design (2024)
Re 1, sounds interesting, I am quite confident I could get funding for such a project. So, if you had a team in mind, please reach out.
Re 2, I understand this (and other evidence, hamster models eg are very intersting) is very indirect, but it's good enough for me to make that bet.
The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells - Nature Neuroscience
A novel study led by scientists in Lübeck, Germany, shows that SARS-CoV-2-infected brain endothelial cells undergo cell death due to the cleavage of NEMO by the viral protease Mpro, potentially causing cerebral COVID-19 and ‘long COVID’ symptoms.
www.nature.com
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For a team, I'd start with the Wüst, van Vugt et al team in Amsterdam and see if they have collaborations available with local MR researchers. There may already be someone relevant involved in that team. I'd envisage an extension of their pre- / post- single CPET biopsy paradigm, augmented with pre- / post- MR spectroscopy (± NIRS).
Spit-balling. You'd probably want to do each MRI before each biopsy, 10 days apart as before. The MRI uses an exertion paradigm but is looking at calf muscles using an exercise band, whereas the biopsy is in thigh muscle (but you don't want a sore leg in the magnet, even if you biopsied the other side).
You can't exert the thigh muscles in the MRI because that would move the thigh out of the coil position (and there isn't space anyway). The CPET uses an upright cycle ergometer, which I expect works the thigh muscles much more than calf muscles. Perhaps you could also do MRI spectroscopy on resting thigh muscle to sample it as well, but that would add time on magnet. Apart from the CPET, doing 2 rounds of MRI and biopsy would be demanding on the participants though there would be time for rest between each component.
In addition, as that would only be looking at patients capable of CPET, I think it would be informative to at least biopsy a couple of moderate+ pwME at rest. That could potentially even be in their own home though of course an MRI can't travel to them and it's likely a more severe person wouldn't be able to tolerate an in-hospital MRI. Maybe passive NIRS could show something.
Alternatively, the radiology team that did the MR spectroscopy study (Oxford/Radcliffe team) might collaborate with local exercise physiologists, interventional radiology and pathology people for the biopsies. Depending on funding options, the Oxford and Amsterdam teams might even collaborate to make this multi-centre, though equally it could start with a single-centre pilot. With a collab potentially the patients could even be scanned and biopsied in the UK and the Amsterdam team could do their established tissue analysis. That would benefit from the established skills and techniques on the imaging and tissue assessment sides with each.
Just some ideas, but there are probably practical aspects I'm failing to consider. But to my mind muscle findings are worth pursuing at length, not least because, while we're working things out, the gold standard of direct tissue analysis following exertional trigger is available for muscle, where it isn't for brain. Advanced neuroimaging techniques are helpfully closing the gap though, eg DTI-ALPS, white matter microstructure diffusion imaging and myelin water fraction.
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Thank you very much for your thoughtful suggestions. I would like to provide a brief but clearer overview of the current situation (here in Vienna).
The WE&ME Foundation is presently undergoing a restructuring process for the 'Johadamis Grant', which is valued at €100,000. The intention is to relaunch the grant next year with an updated framework.
Although the Foundation has not yet established direct contact with the Science4ME Committee, this is expected to occur, as the Foundation plans to include at least 50 percent patient representation in the jury responsible for evaluating proposals.
(The final funding decision will remain with the Foundation’s Board of Directors, but many procedural and structural details are still in development.)
For more context: I am a very severe ME patient and serve on the Foundation’s advisory board, but I am not in a position to handle all these organisational matters myself anymore (I was involved in allocating funding before).
Long story short, if you believe there is a clear ME/CFS-specific application for these funds (like you are outlining here), or if you have concrete ideas regarding how they could be effectively deployed, the Johadamis Grant module might be a good opportunity to push in that direction next year.
One of the bigger bottlenecks (apart from the lack of fundraising/funds - by far the biggest issue still) currently is actually bringing together applicants and charities - patients scouting for potentially worthy projects is currently underemployed and undervalued.
Thank you again for your engagement.
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Just because you mentioned it, re 'practical aspects you might have missed': I believe most of the actual workup of muscle tissue (including the tissue samples of the Wüst project) happens in Salzburg, Austria. I am not 100% certain, though.
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