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
 
jnmaciuch said:
And yet that would only be discounting a small fraction of possibilities that involve metabolism
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Absolutely, but my objective is to get people out the mindset that either there is something wrong with mitochondria or you are lazy. The 'something wrong with mitochondria' approach has been the dominant paradigm for a couple of decades, if not four. It hasn't come up with anything tangible - as Audrey illustrates. It isn't yet a dead horse but it looks a bit tired. I am just pointing out that there are lots of other possibilities that go nowhere near either being lazy or needing a mind-body wand-wave.
 
Jonathan Edwards said:
Absolutely, but my objective is to get people out the mindset that either there is something wrong with mitochondria or you are lazy. The 'something wrong with mitochondria' approach has been the dominant paradigm for a couple of decades, if not four. It hasn't come up with anything tangible - as Audrey illustrates. It isn't yet a dead horse but it looks a bit tired. I am just pointing out that there are lots of other possibilities that go nowhere near either being lazy or needing a mind-body wand-wave.
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Sure, I agree, some false paradigm between either laziness or structural issues in the mitochondria is a fallacy. One which I don’t think is shared by anyone on this forum, nor any of the researchers I would take seriously. I’m not even sure it accurately encapsulates most of the metabolic theories I’ve seen from the last 4 decades.

I also don’t think Audrey’s paper was addressing mitochondrial myopathy at all either—if something in the blood induces differences in maximal respiration in Fluge’s paper, it would definitionally not be a structural issue. Audrey’s paper has disproven that there is something present in the blood of pwME taken at baseline which can alter maximal respiration.

So I agree, novel perspectives are needed. I just strongly caution the conflation of mitochondrial dysfunction = constant lack of ATP = structural mitochondrial issues (and saying the answer must therefore be in the immune or nervous system on the basis of no structural mitochondrial issues). Which is unfortunately a conflation that I’ve seen a lot. That would be the equivalent of saying that we must rule out immune system involvement because we have no evidence of autoantibodies.
 
jnmaciuch said:
Which is unfortunately a conflation that I’ve seen a lot.
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Exactly. That is the sort of simplistic analysis we need to get past. And I do think there are a lot of members here who have been led to believe that its either mitochondria or your lazy, in very simple terms. That was essentially the basis of Sasha's query. I was teasing a bit with the wording but I think it is worth going through this debate.

Audrey showed that not only has nobody found anything wrong with the mitochondria but also there seems to be nothing in the blood to make all those mitochondria all over the body slow down. There are caveats but it is another negative. It might be all T cells or maybe stroll cells, although I can't see why they should go on misbehaving. But it might be synapses too.
 
Jonathan Edwards said:
but also there seems to be nothing in the blood to make all those mitochondria all over the body slow down.
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*Nothing in the blood taken from pwME at baseline. Also I believe it was increased maximal rate not decreased. Which seems like a contradiction with other mitochondrial findings, indicating that the various data is full of flukes.

Or, perhaps, one specific thing which has already been shown to induce both of the seemingly contradictory phenotypes under different conditions which match those aforementioned findings…

Jonathan Edwards said:
It might be all T cells or maybe stroll cells, although I can't see why they should go on misbehaving. But it might be synapses too.
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…or something in the tissue interfacing all of the above ;)
 
Jonathan Edwards said:
Exactly. That is the sort of simplistic analysis we need to get past. And I do think there are a lot of members here who have been led to believe that its either mitochondria or your lazy, in very simple terms. That was essentially the basis of Sasha's query. I was teasing a bit with the wording but I think it is worth going through this debate.
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My armwaving 'etc. etc.' was really meant to indicate anything that we might normally think of as the energy production aspect of the cell (but maybe that is just mitochodria - I don't know!), as opposed to signalling.

Jonathan Edwards said:
We have masses of experimental evidence for thinking that 'conscious will' is largely a narrative concocted by other bits of brain for the benefit of bits that run a narrative of 'me'. The popular simple idea that there is a 'me' that can tell the body what to do is about as wrong as it could be

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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This really confuses me. Surely I can, under normal circumstances, tell my body what to do at the macro level, even if I can't directly order my macrophages about. Are you suggesting that I can't decide (assuming I'm not exhausted) to raise my arm? Or that I haven't decided to type this message?

If we have to persuade people of this kind of thinking then I think we're in big trouble.
 
Sasha said:
Are you suggesting that I can't decide (assuming I'm not exhausted) to raise my arm? Or that I haven't decided to type this message?
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There isn't an 'I' in biomedical science, or in fact a usably definable I in any sort of science.
If we want a biomedical account of ME/CFS, 'I' doesn't come in to it, nor does it come out of it. If we are discriminating theories with evidence, we cannot invoke the involvement or non-involvment of something outside our framework. So we cannot argue around 'but can't I decide to do this if I want'.

This is not do deny that something (or things) within us has a sense of being 'I' and that it should have a place in biophysics, but we know from experiments on perception that it bears little relation to our intuitive sense of an 'I'. Its causal role is not outside the causal story of neurobiology - synapses and potentials.

Sasha said:
If we have to persuade people of this kind of thinking then I think we're in big trouble.
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No bigger trouble than now, I would say. And, as I indicated, it is the belief that there is an "I" that can control everything and that can be told to pull its socks up is at the root of BPS thinking.

In fact, I doubt that most people will ever be persuaded but if we can find a way of dealing with the signalling that doesn't involve an 'I' anyway then the problem will evaporate.
 
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