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

I've given Rob Wüst a couple of reminders on Twitter/X but he's not replied. I suspect he's been inundated and may not have seen them but I don't feel it would be appropriate for me to ask/remind him again.
 
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Robert 1973 said:
I've give Rob Wüst a couple of reminders on Twitter/X but he's not replied. I suspect he's been inundated and may not have seen them but I don't feel it would be appropriate for me to ask/remind him again.
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I also suspect following the discussion might be somewhat confusion if one isn't used to S4ME, because the discussion is already 8 pages long.

SNT Gatchaman said:
I hope Rob Wüst and team might join this discussion, or at least read through this thread. @Robert 1973 maybe this question might warrant a reminder. I expect they'll be in discussion with Resia Pretorius and team.
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Indeed they are, to some extent, collaborating with Pretorius as well as Fluge/Mella (see also https://projecten.zonmw.nl/en/proje...ptoms-patients-mecfs-skeletal-muscle-exercise where this is described).

According to that website they also have 3 patients that act as patient representatives. Perhaps if the researchers don’t have time for S4ME it will be possible for one of the patients to become active here and then have a sort of indirect line of contact (which would be somewhat similar to @Andy updates on DecodeME from what I can tell).

In either case it would make sense to contact them via email about various questions I would think.
 
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SNT Gatchaman said:
To pin this down one way or the other, perhaps they could use the AmyTracker which might not cross-react this non-amyloid content. If that were still positive it would be good to control AmyTracker against AChE (and cfDNA) to be confident, if not previously established as negative. Presumably they could also look with TEM, cryo-EM and AFM to confirm fibrillar forms in the tissue sample?
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It would be easy to see whether or not the staining is nerve endings, using one of the nerve specific antibodies (or a panel). It sounds as if there are quenching agents for amyloid binding that might not block AChE binding. Immunogold with TEM would be ideal if it could be got to work but it used to be fiendishly tricky and the signal often too sparse to be really sure about
 
For what it is worth. Some people report benefit from Mestinon. Mestinon is pyridostigmine bromide.

From Wikipedia,

"Pyridostigmine bromide has been FDA approved for military use during combat situations as an agent to be given prior to exposure to the nerve agent Soman in order to increase survival. Used in particular during the first Gulf War, pyridostigmine bromide has been implicated as a causal factor in Gulf War syndrome.[7][8]"

"Pyridostigmine inhibits acetylcholinesterase in the synaptic cleft, thus slowing down the hydrolysis of acetylcholine. Like its predecessor neostigmine, it is a quaternary carbamate inhibitor of cholinesterase that does not cross the blood–brain barrier. It carbamylates about 30% of peripheral cholinesterase enzyme, and the carbamylated enzyme eventually regenerates by natural hydrolysis and excess acetylcholine (ACh) levels revert to normal."

https://en.wikipedia.org/wiki/Pyridostigmine
 
EndME said:
I also suspect following the discussion might be somewhat confusion if one isn't used to S4ME, because the discussion is already 8 pages long.
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In my opinion the discussion being on the forum means it is a lot easier to follow than anything on social media with multiple branches. You start at post 1 and skim through the thread. if the reader is a researcher who is not ill that shouldn’t be problematic.
 
NelliePledge said:
In my opinion the discussion being on the forum means it is a lot easier to follow than anything on social media with multiple branches. You start at post 1 and skim through the thread. if the reader is a researcher who is not ill that shouldn’t be problematic.
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I agree that social media is bad for discussing anything research related and shouldn't really be used for that. I was more so proprosing to contact him (or one of the patient representatives) via email.
 
Andy said:
For what it is worth. Some people report benefit from Mestinon. Mestinon is pyridostigmine bromide.
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I had a dramatic improvement on starting Mestinon. Was able to do small things like using an eraser or reaching for an object that would have caused PEM before starting Mestinon. I was sure I was on the mend but that was not to be.

Jonathan Edwards said:
Yes, although my impression is that it is unsatisfactory longer term.

But that would fit with a problem with regulation of cholinesterase that was based on an accommodative mechanism. Sort of hair of the dog situation!
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Exactly. Lasted about a week and then BAM - back in PEM. I continued taking it for some months but didn't get the improvement back.

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.
 
The Open Medicine Foundation has completed 95 muscle biopsies and are performing extensive analysis - Genomics, Proteomics, Metabolomics, Phospho-proteomics, Ultrastructural analysis, Mitobiogenetic markers..
https://www.omf.ngo/skeletal-muscle-dysfunction-research/

They also have another muscle biopsy study kicking off - it uses a 2 day CPET protocol.
https://www.omf.ngo/investigation-into-post-exertional-malaise-between-historical-and-recent-me-cfs/

I was wondering what @Jonathan Edwards thoughts are today after giving it a day to sink in. Does the idea still have legs? Has anyone here had contacts with Philip Atherton (University of Nottingham) who is one of the leads on the OMF study. He could be a good sounding board for the acetylcholinesterase hypothesis.
 
Jonathan Edwards said:
Well none of you have shot it down yet.
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Not yet. But I thought of an intriguing tie in idea......

At the same time acetylcholinesterase turned up I was thinking quite a bit about Schwann cells. Specifically I was wondering if Schwann cells could be affected by MBP catalytic antibodies as they express the MBP gene. They are very important for maintaining, repairing, and regenerating peripheral nerves.

Turns out they are important in the Neuro muscular junction - the area we could be looking at for possible acetylcholinesterase buildup.
Schwann Cells in Neuromuscular Junction Formation and Maintenance
https://pubmed.ncbi.nlm.nih.gov/27656017/

[I did notify the Stanford researcher about Schwann cells expressing MBP and possible effect on peripheral nerves in ME/CFS].
 
Kitty said:
I can just about say cholinesterase,
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Yes, it is even trickier if you insist on acetylcholinesterase.

But mark you, this is trivial in comparison to how things were when we hired Andy Pitsillides in the lab, an expert on uridine diphosphoglucose dehydrogenase, the key enzyme for synthesis of sticky synovial fluid. Saying uridine diphosphoglucose dehydrogenase is actually not too hard but we always referred to it as UDPGD.

Try saying UDPGD nonchalantly in the middle of a sentence - any sentence.
We could always tell the professionals from the amateurs by how well they did. It often came out as UGPGD or UDPDwhatsit.
 
Jonathan Edwards said:
Well none of you have shot it down yet.
I am very disappointed!;)
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Would you expect to see an increased need for choline to make acetylcholine and thus reduced choline availability? Or would there be excess choline due to the breakdown of acetylcholine?

This study is interesting in that it showed reduced compounds in the CDP-Choline pathway.
Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in ME/CFS
https://www.s4me.info/threads/metab...ndrome-2022-levine-hornig-lipkin-et-al.28647/

CDP-choline is also know as Cytidine-5'-diphosphocholine and citicoline. The following paper states that "Citicoline also provides choline for synthesis of neurotransmitter acetylcholine, stimulation of tyrosine hydroxylase activity and dopamine release."
https://onlinelibrary.wiley.com/doi/10.1046/j.0022-3042.2001.00697.x

Could the need for extra acetylcholine caused by the presence of excess cholinesterase be so great that choline is procured from other compounds leading to knock-on effects?
 
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For a sanity check I looked into what regulates Acetylcholinesterase in muscle specifically. Short story it seems to be muscle. Longer story :-

Acetylcholinesterase Expression in Muscle Is Specifically Controlled by a Promoter-Selective Enhancesome in the First Intron
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692871/
Expression patterns in muscle and CNS neurons establish that virtually all AChE activity at the mammalian neuromuscular junction arises from skeletal muscle rather than from biosynthesis in the motoneuron cell body and axoplasmic transport.
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The influence of intron 1 functioning only with the endogenous promoter in the intact gene (Fig. 2), the tissue-specific and dramatic differences revealed in the AChE intron regulatory region knock-out animal, and demonstration of an involvement of MEF2, MRF, and AT-rich sequences (Fig. 8) all point to intron 1 exerting dominant control of AChE gene expression in muscle.
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MEF2 is required for muscle regeneration. Perhaps the regeneration process increases MEF2???? We will need transcriptomics to answer if MEF2 is increased after exercise in muscle in ME/CFS.
 
I wonder what affect this would have on our kidney function. I came across a couple of old blood tests from 2012 this morning that had low eGFR. I will try to find more recent test results.

It must not have been low enough for concern though.
 
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