Preprint A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma, 2025, Edwards, Cambridge and Cliff

Jesse said:
Do we know why that is? And where along the chain such activity is inhibited?
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I personally have no idea. Others may know more but we have been discussing this for months and nobody has come up with anything as far as I know!

There is a strong chance that it is mediated by interferons but exactly how that stops you doing things I haven't seen posted. I don't think it is a matter of reduced energy availability rate because flu stops you from doing a single strong contraction of a muscle needed to stand up. I strongly suspect it is inhibition of efferent nerves.
 
Jonathan Edwards said:
Which is why the BPS people make no sense because they assume that there is a 'mind' that can control the body. What I am saying is directly opposed to the BPS view. The irony is that if you were right about 'me' then the BPS people maybe should be right too!!
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It would be really ironic indeed. I do like the theory the more I think about it. It fits witht the symptoms and would expain why it's been so hard to find abnormalities. It would be real nice if we knew more about sickness behaviour..

There's another symptom of mine of which I wonder about:

When I'm rested and at my baseline (no PEM) there's a certain level of activitiy that I can comfortably do. Back when I was mild for example I could cycle 15 minutes, or work for 4 hours (with breaks). After this I sometimes feels like I hit a wall. It takes immense effort to push past it. It feels like my muscles are out of energy. Like my brain doesn't function anymore. I'm usually able to push it (hard as it is), which would trigger a huge stress response in my body (hr/bp going up, sweating, GI upset, frequent urination, overstimulated brain, restlessness). When trying to rest afterwards I get stuck in tired but wired state and get insomnia. Then PEM starts the next day. During PEM it's kind of the same as above, just that the threshold for hitting the wall is way lower.

But, when I'm already a bit stressed out at my baseline (short sleep, anxious, excited, or even just feeling great) the threshold for hitting the wall is higher and it's easier to do too much and trigger PEM (I get less warning signs).

Now what I find really curious is that it really feels like a sudden lack of energy (like my battery ran out), and that the only way to overcome it is through an excessive stress response (as if my body needs to tap into emergency reserves).

Do other people experience something similar? Does this seem common in ME/CFS or do others have a different experiences when overexerting?

@Jonathan Edwards how would you tie the above into your theory? I think during PEM sickness behaviour / inhibition of nerves makes a lot of sense. But how about a sudden inhibition when overexerting during baseline ? And why the stress response? My autonomous nervous system seems strongly involved although I don't have OI.
 
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Jonathan Edwards said:
There may be exceptional circumstances where this sort of involuntary inhibition is overcome but generally not through wanting to.
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When Eddie Hall deadlifted 500 kg, he had trained himself to literally imagine that he was lifting a car that was on top of his children. He caused severe damage to himself, fainted, went partially blind for some time, and struggled with amnesia for weeks after.
 
Jonathan Edwards said:
And there is nothing wrong with the mitochondria there.
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I don’t think we can say that. Infection modulates metabolism in multiple ways, both from the effects of the virus itself and the many changes induced by an immune response, both at the cellular and systemic levels. Has been known for many decades at this point. It’s one of the main reasons why diabetics need to monitor and change insulin levels so carefully during active infection. Activity being limited during flu would be either neutral or evidence in favor of the role of metabolism, not evidence against it.
 
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jnmaciuch said:
I don’t think we can say that. Infection modulates systemic metabolism in multiple ways.
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Yep, but there is nothing "wrong" with the mitochondria. They are perfectly good mitochondria doing the bidding of the signals. Some of those signals are just a few non-covalent steric interactions away. Some are behind the sort of neural software that is still better than anything a computer contains for driving a car - and still none of that is a 'me' that might be able to override.
 
Jonathan Edwards said:
Yep, but there is nothing "wrong" with the mitochondria. They are perfectly good mitochondria doing the bidding of the signals. Some of those signals are just a few non-covalent steric interactions away. Some are behind the sort of neural software that is still better than anything a computer contains for driving a car - and still none of that is a 'me' that might be able to override.
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Again, no metabolic theory of ME/CFS need to claim “dysfunctional mitochondria.” [edit: and the line for what constitutes a dysfunctional mitochondrion is not clear cut. No evidence of structural issues, yes. But anything modulating OxPhos or fatty acid oxidation would also fall in that bucket]. Some have claimed structural mitochondrial issues in the past, and have been duly disproven. And yet that would only be discounting a small fraction of possibilities that involve metabolism
 
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