Is ME a metabolic problem or a signalling problem?

Could it be both? Could the metabolic problems arise as a result of improperly cleaned away central signalling which would normally be resolved during sleep?

 

This is an interesting thread
https://forums.phoenixrising.me/threads/the-rbc-nox-hypothesis.77228/#post-2222454

Necessay8 had an interesting thread a couple of years ago re purinergic signalling. I'm ll post if I can find it.

 

Something in the blood is what I mean by a signalling problem - a signal that affects the way tissues can generate useful function.

There is still the question of why the cells cannot generate useful function. That might be shortage of ATP but there has to be a reason for that. The something in the blood might divert metabolic pathways, and a number of researchers are suggesting that, but so far I am unclear how that would work without there being something fairly easily measurable wrong with tissue biochemistry that does not seem to have been found yet.

 

Paul Fisher thinks he's found something.

 

The something in the blood could be a hormone?

 

You'd think they'd have found it by now

 

What do we know about what causes flu-like symptoms (respiratory aside)? The weird headaches, achiness, general malaise, heaviness, pain and throbbing in the head, dizziness, brain fogginess, general wobbliness and rapid fatigability that makes tiny efforts lead to outsized exertion and every minute of existence feel downright awful?

Are those metabolic or signalling? Any explanation for ME should also feature some explanation of those symptoms. Likely a common root.

 

(Only able to skim this and related threads and now just slightly amended an older draft which might fit into this thread -- if not, please feel free to move.)

Again, I think in order to assess symptoms and build hypotheses on underlying processes, it's important to distinguish between different categories of symptoms.

It seems to me that in mild to moderate ME 4 categories of symptoms could be distinguished:

1) Permanent symptoms, e.g. sore throat, mild dizziness, mild flu-like symptoms, difficulties with sleep

2) Exertion-induced symptoms that limit the ability to exert immediately or after an extremely short period of time, (ETA: = rapid, exertion-specific fatiguability?)

e.g. muscle weakness or stiffness in the limbs used for the exertion (having to stop typing, walking, sitting etc.), vertigo, severe coordination problems, cognitive impairments like severe concentration difficulties, difficulties finding words or disorientation (not finding the way to a well-known destination, taking the wrong bus/ train etc.), (pain)

3) Early PEM symptoms building up slowly during activities which pre-illness weren't perceived as exertion (reading a short story, chatting with friends, sitting in a café, watching a movie) --> more general symptoms e.g. flu-like symptoms, dizziness, general, more vague muscle stiffness, (general muscle pain), noise and light sensitivity
(ETA = slower but still abnormal, general fatiguability?)

4) Delayed PEM symptoms, similar to 3) but mostly all symptoms together, more severe and lasting longer.

I just realized that in my case category 1) disappeared some years ago, maybe due to getting repeatedly high doses of cortisone, a further reason why I tend to describe my illness as only "ME-like".

I associate [edit: sometimes] (2) but mostly 3) with the feeling of loss of energy, while I experience 4) rather like having the flu without the runny nose and cough.

The feeling of loss of energy doesn't mean that it actually has to have anything to do with energy, though.

(Apologies for multiple editing)

 

The definition of hormone is a bit vague at the edges and there may be more to be discovered but on the whole yes.

 

I quite like the hypothesis that 'mental fatigue' may be due to impaired ability (possibly genetic) of atrocytes to clear (uptake) glutamate leading to impaired information processing and increased extracellular glutamate. This could explain sensory sensitivites, reduced ability to distinguish signal to noise and of course easy mental fatiguability.

While this hypothetical schema may be proposed primarily in respect of mental fatigue I don't see why the same mechanism may not also apply to physical.

Pretty simplistic I know but impairment in transport for some neurotransmitter could easily interfere with signalling/

On the potential role of glutamate transport in mental fatigue

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC533886/

 

That could potentially explain the anecdotal reports of certain meds and supplements being helpful.

Magnesium reduces the effects of glutamate by blocking NMDA receptors.

LDN may increase glutamate transport. (https://www.ncbi.nlm.nih.gov/pubmed/15694688)

Alpha lipoic acid increases glutamate uptake.

 

A possibility I wonder about is if something in the microbiome could be producing a molecule that gets into the blood and causes havoc. Some post-infectious change in the balance of the microbiome might favor an organism that normally produces an innocuous amount of this molecule. Subsequent expansion of this organism might lead to the production of enough of this chemical to become toxic (if it can get into the blood).

This is pretty similar to the hypothesis which was behind treating supposed candida albicans overgrowth in the GI tract in the 1980's. Diet was thought to be the promoter of candida overgrowth in the gut. Candida albicans is known to produce is acethyaldyhyde - which, when produced by the liver following alcohol consumption, contributes to hangover symptoms.

Unlike with alcohol consumption, however, under this hypothesis acethyaldyhyde produced by yeast in the gut would constantly be entering the blood stream.

There's another type of yeast (Saccharomyces cerevisiae) which can directly produce ethanol itself in the gut, resulting in auto-brewery syndrome.

I'm not singling out yeast here. There could be other organisms (i.e. bacteria) in the gut capable of producing toxic molecules that can cross the gut barrier. There may be no problem so long as the number of these organisms remains below a certain threshold.



[As always, pure speculation.]

 

I have personally found that treating (presumed) candida overgrowth has improved some of my ME symptoms. Presumed because I found that when I took a fluconazole for a vaginal yeast infection my cognition suddenly greatly improved - so I repeated that as an experiment a couple of times, same results each time - have since then experienced a consistent 'improved baseline' from taking daily 'anti-candida' supplements and once-weekly fluconazole.

But I think I've reached a point where increasing the anti-candida/antifungal stuff doesn't improve my ME any further.

 

An off the wall thought came to mind, hence this post.

Many processes have inherent process delays, between cause and effect. I'm sure this must be true for biological processes as for any other kind of process. In process control, such system delays are perfectly normal and controlled for. But if something goes wrong, and one of those system delays suddenly becomes much greater, things can go horribly wrong.

What if PEM is a process delay that already exists in healthy people, except to a much less significant degree, so minimal that nobody notices it? But then with ME something happens and that process delay becomes hugely more intrusive?

Like when you are driving your car, there is a small human response delay between observing a hazard and hitting the brakes, but typically acceptable. But if something happens and you instead take 5 seconds to react ... major implications. Same basic delay, but different magnitude. The biological reasons could of course vary from very simple to highly complex.

 

At one point, several decades back, they were discovering a new hormone every year. Its important to distinguish between endocrine, exocrine, autocrine and paracrine hormones, but I think a new category was proposed too.

That list of 50 is also deceptive, because at least some of the categories are families of hormones.

Some hormones have half lives of only seconds, particularly autocrine and paracrine hormones such as eicosanoids. They are notoriously hard to measure. Special techniques have to be used that include flash freezing of samples as soon as they are drawn. However, while I forget details, some may have stable metabolites with long half lives and are more easily measured, though I am not sure they are necessarily reliable for other reasons.

On signalling, we have multiple layers of signalling systems in the body. Hormonal, immune, genetic, metabolic and neurological systems have signalling aspects. I currently think of ME as a command and control problem, with potentially so many layers of signal failure that its baffling. This also presents nomenclature problems, especially if the issues are distributed and involve many tissue types. Brain injury and disease classification is likely to undergo many changes as technology improves, for example.

We must also recall that the size of the factor in the blood that can be filtered is quite large, suggesting its a protein, though I would not want to rule out large lipopolysaccharides or other large organic molecules just yet.

I think the evidence is growing that the root cause of ME might be the tryptophan trap, but this will be an incomplete explanation at best. How do we link that to a blood signal? How do we account for temporary or partial recoveries? What are the secondary consequences of the tryp-trap, and do these include other signalling systems? The brain is likely to be affected, what about other systems?

We have so many questions just now, some tantalising evidence, but still lack even a demonstrable big picture.

 

If it is a signalling problem, is it likely that the absolute volumes of the metabolite, or whatever factor, are normal since most everything has come back in the normal range?

In any case, I guess a metabolic signalling makes sense to me. But I guess it's only as likely and neurologic and immune signalling.