Is ME a metabolic problem or a signalling problem?

Trish

Trish

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I am trying to get my head around the question of whether ME could be a metabolic problem, as suggested by the 'something in the blood' findings by several different researchers, and by the problems with pyruvate dehydrogenase possibly blocking or reducing complete breakdown of glucose, and by the seahorse oxygen uptake studies.
Or, as @Jonathan Edwards suggests here, a signalling problem involving some sort switching off coming from the brain that might better explain PEM.

This discussion has cropped up on several threads recently, and rather than derail them further, I've decided to gather the information and ideas here.

Relevant thread discussions:
Blog: 'Summary so far of "Something in the blood"' by Simon McGrath

US NIH: Responses to NANDS Request for Information: How to advance ME/CFS Research
The other idea is something that came from a 'citizen scientist' patient. The key clinical problem in ME/CFS is exertion intolerance. I think we need to be able to measure that objectively. I think there is an analogy with the inability to move rapidly and smoothly in Parkinsonism. The neurologists have made progress in documenting this with actimetry - including describing on-off phenomena. Actimetry in ME/CFS has mostly looked at just quantity of activity but I think it needs to be used to look at PATTERNS of impaired activity so that these can be tracked objectively over long periods. The technical term for this is apparently 'motor fatigue'. That is to say not a sense of fatigue but a behavioural pattern that can be studied objectively. Only when we understand these patterns will we know what we are trying to explain. I think it very likely that if we really knew what the activity deficit was we would know we are not looking for a metabolic defect, for instance.
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Discussed further here, here and here and onward.

There is also the question of how much activity a person with ME can sustain day after day compared with a healthy person, as discussed here:
Andy's attempt to create a reasonable descriptive model of ME
which again raises the question of whether there is a problem metabolically in creating enough energy for activity above basal metabolic level, and how much we can exceed our sustainable level before PEM, and whether PEM is about lack of energy for basal functions, leading to a wide range of horrible body wide symptoms, or whether it is signals from the brain that are setting off PEM symptoms, or something else.
 
I wonder whether the delay between activity beyond our sustainable threshold and PEM happening is related to some sort of build up of the 'something in the blood' during that over exertion, and takes a days or longer to clear.

Energy and ME:

We all need to produce energy as ATP all the time to stay alive (basal energy requirement). Most people with ME have symptoms all the time which can vary from day to day and from person to person - 'fatigue', OI, pain, gut symptoms, malaise etc.

The immediate effect of activity above basal survival is experienced as rapid fatiguability (cognitive and/or muscle) that limits how much we can do at a time without needing to stop and rest. For some of us that is accompanied immediately by increase in other symptoms such as muscle pain.

If we exceed our sustainable exertion limit (SEL - thanks @Andy for the term), we not only suffer the immediate effects described above, but we also have a delayed larger increase in symptoms, often with additional symptoms such as headache, nausea, dizziness, sore throat etc. that enforces a period of days or weeks of reduced activity.
..........

Here's a hypothesis:

The 'something in the blood' is present all the time, and impacts cells' ability to produce and/or use energy. This affects all body cells, but is most noticeable when there is a high energy demand in particular cells, such as brain and muscle, leading to the immediate effect of fatiguability.

When we 'overdo it' the 'something in the blood' builds up to a higher level with a prolonged effect (perhaps a positive feedback mechanism that the more is present, the more is made, leading to a delayed increase in symptoms, or a metabolic trap) and takes days of weeks to clear down to a lower level, so PEM occurs. When there is too much 'something in the blood' all body systems, not just muscles and brain, are affected as basal activities happen more slowly - so temperature regulation, nerve signalling, digestion etc are also affected in PEM.
...........

I would be delighted if someone with more idea what they are talking about would deconstruct this, and/or explain how it could be a 'signalling' problem.
 
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Trish said:
I would be delighted if someone with more idea what they are talking about would deconstruct this, and/or explain how it could be a 'signalling' problem.
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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.
 
Jonathan Edwards said:
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.
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Ah, OK, thank you. I misunderstood signalling to mean coming from the brain via nerve signals or possibly hormones.
 
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.
 
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(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)
 
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Jonathan Edwards said:
The something in the blood could be a hormone?
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I kind of assume that would have already been tested and eliminated at some stage in ME research, but maybe not. My source of information, Wikipedia, gives me a list of about 50 human hormones.

I would have thought that the effects of an over or under supply of any of them would be well researched and conditions resulting from such divergence from normal levels well defined, but maybe not.
 
rvallee said:
What do we know about what causes flu-like symptoms (respiratory aside)? The weird headaches, achiness, general malade, 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.
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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/
 
Marco said:
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/
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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.]
 
Forbin said:
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.]
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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.
 
Jonathan Edwards said:
The definition of hormone is a bit vague at the edges and there may be more to be discovered but on the whole yes.
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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.
 
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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.
 
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