I want to say that i think
@mariovitali's core idea here is very good.
I'm starting to think that PEM being related to (or just being) the unfolded protein response is a really plausible theory. Let me explain why.
The biggest single attraction here is that it's a crisis system that is triggered by exercise, even in normal people. That just *feels* right to me. and it has 2 phases, one of which comes after a delay. That's exactly what we need for PEM.
1. The UPR is triggered by exercise in healthy people. If the UPR doesn't resolve the unfolded protein excess, the body moves to cell apoptosis.
This potentially provides a cause for PEM. After exercise perhaps the body tries the UPR for a while but it doesn't work and at the end of that you get a new phase, which in us manifests as PEM? This could explain delayed PEM neatly.
2. Skeletal muscle UPR makes people sleepy. Could this be one reason why some people with mecfs sleep so much?
3. Both viruses and toxic exposures can create endoplasmic reticulum stress. This could explain why some people have toxic exposure at the start of their MECFS.
4. viruses love to hijack the endoplasmic reticulum. Could they even still be in there? and maybe not in all cells, just in some.
5. Hwang found problems with the ER in his patient that was making excess WASF3.
6. Every so often you hear about a patient who rests their way back to health, or paces their way back to a higher level of halth. Maybe the endoplasmic reticulum can heal, or heal in some cells, if you reduce ER stress enough?
7. Endoplasmic reticulums are membranes. really foldy little structures. If we have membrane issues (and scientist have found consistent issues with sphingolipids etc) they might be especially prpblematic in such a folded structure.
8. Hanson's recent paper finds that in patients, the normal response to exercise simply doesn't happen. There's two ways to think about that. Either we can't do it, or we were already doing it so there's no room to do it
more. Whether the UPR doesn't work or we were already in UPR, both fit with this theory.
9. There's no apparent research on the UPR and MECFS yet. see pic:
This is uncharted territory. But the UPR is not a fringe idea. Nor is it a new system in the body. it's extremely well-established. we don't need weird open-minded doctors for this to be plausible. (this is also the big reason to think UPR might not be relevant to mecfs: upr is well-known enough that if it was being suggested by the data ,someone would have looked into it? you'd hope?).
In summary my really simple hypothesis is that we have rolling ER stress due to faulty membranes or persistent viral infection. The only thing that stops it ticking over into full UPR is pacing/resting.
But when we overdo it the body tries UPR and it doesn't work well.
e.g. when we exercise our endoplasmic reticulums call on the UPR, and PEM comes perhaps during UPR or perhaps at the end of that UPR period when the body is like, welp, that should have worked but it didn't, time to kill these cells off.
The advantage of this theory is it doesn't need a new body system to be discovered. it's a falsifiable idea. We can measure the expression of the genes that cause UPR. They are called PERK, ATF6 and IRE1.
It could even be the case that there's existing data out there that can falsify it (or help confirm it) that just needs to be re-examined from this perspective.
