McGregor's Hypothesis of ME/CFS

[gregh286]

I think it's possible to have normal levels of ATP, meaning proper mitochondrial function, but still feel tired/fatigued/exhausted because of something in the brain malfunctioning and creating a false perception. Phantom pain supposedly feels just like real pain, but doesn't arise from real tissue damage (the tissue is missing). Maybe what we're experiencing is 'phantom fatigue'.

Nothing phantom about.
Legs are.heavy with lactate.
Muscles are sore and ligaments tender.
My finger tells me so. It's real and physical.

 

[Inara]

Is the throat thing: vagus?

My sore throat is a daily issue. The other nite it was so bad I was sure I was getting a cold. Next morning gone, returns at: run down PM.

No, I don't think a sore throat means this is the Vagus - I mean, I didn't read it's a typical symptom. But if there are other typical Vagus symptoms? In my case it seems to have been related to the immune system because it resolved with IGG.

 

[Wishful]

Nothing phantom about.

Well, we do have individual responses, so it's certainly possible that some people are experiencing real physical fatigue from ME, or might have a comorbid disease causing real fatigue. Without a standard clinical test for physical fatigue, it's hard to know.

Maybe some of us are experiencing 'phantom fatigue'.

 

[boolybooly]

I think phantom pain is not a credible explanation for what I have experienced but given the historical sophistry of psychologists trying to hoodwink healthcare decision makers into funding more psychology and thereby their own careers, I can see there is a risk some people might hypothesise something like that, based on the idea of afferent nerve inflammation hypersensitising patients, without bothering to check their assumptions and find out what is really going on. So I feel its a scenario I want to discuss in order to show why it is not a useful assumption in the kind of CFIDS I have experienced.

Firstly, reliable diagnosis and subtyping are the primary obstacles to progress in acquiring useful scientific understanding about ME / CFS. We may be talking across purposes regarding our own subjective experiences, about different conditions causing different kinds of CFS. Regarding the argument at hand, it is not appropriate for anyone to project onto anyone else based on hypothese about phantom pain or their own experiences, but rather it is appropriate to proceed with caution and respect for the limits of our understanding.

Secondly assuming there are others out there like me with my kind of CFIDS, while neuroinflammation and hypersensitivity are a distinct and very difficult aspect of my condition, that is not even half the story, there is much more to it than the neurological phenomena.

Thirdly phantom sensation as an explanation is not sufficient to explain the character of PEM, being delayed for a day and causing a 3 day crash which appears to be some kind of an inflammatory reaction in itself, not simply a magnified sensory phenomenon. There is no question too much activity makes the condition worse in a way which cannot be explained by a phantom sensation.

Fourthly phantom sensation is not a helpful assumption for treatment and management. As a one time rower who trained to pass through the pain barrier during racing, the first thing I did with ME CFIDS was to ignore the pain and try pushing through as if it was a phantom and the result was more extreme relapses with neurological dysfunction like rigors, severe lucid perceptual paranoia, complete referential meltdown along with heart arrhythmias and diarrhea. Which all improved when I followed pacing advice from an ME counselling service called Westcare which treated the condition as real but unknown.

Fifthly even if discomfort is magnified by hypersensitivity it is a sensation of something real. The deathly feeling of my brain caving in due to severe lack of energy during bouts of more severe ME was corroborated by cell free DNA tests with Dr Myhill, which showed this feeling-like-death sensation was associated with apoptosis rates off the chart, not a phantom sensation of feeling like death, but cells really dying in droves.

Sixthly, there is something causing the inflammation which causes hypersensitivity and other pathology which cannot be phantom either and is probably an immune challenge and response. I have very clear evidence of immune system dysfunction in my own case as I have a recurrent virus which acts like a canary as it were in a coal mine, demonstrating my CFIDS visibly. It has been diagnosed by PCR multiple times and photographed as it produces visible lesions, so I have been able to document a year which produced thirteen virus episodes of this virus alone and there are others which produce no visible sign but still make me feel very unwell. So there is evidence something is really going wrong with the immune system in my own case, setting me up for recurrent virus, deathly bouts, inflammation, PEM etc and neurological hypersensitivity.

So in summary it is not an accurate model to consider the sensations unreal, in the way the word "phantom" implies, nor is it helpful to behave as if they are. That was in fact the hardest lesson I had to learn, through thirty+ years of unpleasant experience, the best way to manage the condition is to respond appropriately to the sensation of pain and fatigue and be very gentle with oneself because it is a sign of something very real.

 

[percyval577]

(@boolybooly, I am not sure if I have understood your post, however
I think @Wishful meant that phantom fatique would be located in the brain and would be a non-appropriate judgement by the brain regarding objective resources.

As I argumented above, I fully agree with the approach that our brain makes such misjudgments. So to say, the mechanism of judgement would be ill. It´s the most elegant way to unify the hundreds of different strange things we are reporting.
It may not be already sufficiant, but the HPA axis is commonly accepted to have influence on the immunesystem and more (for my still limited brain resources I take it as given, so I can provide only few literature).

In my opinion, this indeed should be the startpoint of investigation, given the onset (most often after impacts suddenly) and possible some difficult to grasp PEM/Pacing mechanism. Otherwise we might have to assume to be affected by thousands of different subdiseases, cheers.

Nothing phantom about.
Legs are.heavy with lactate.
Muscles are sore and ligaments tender.
My finger tells me so. It's real and physical.

Earlier in my life I cared for some time for handycaped children, including some spastics. In spasticity (wikipedia) the brain has lacked oxygen supply during the act of birth, and nerve cells have died. This lack often affects not only physical movements (spasticity) but also cognitive issues, leading to more than one handycap.

The muscles of spastics are rather healthy, it´s only that they get wrong signals from the brain (because nerve cells have died). Then it happens that the muscles are stiff, and I remember that once or twice each week a physical therapist would come to work with the children to relax the muscles as far as possible. But the muscles were rather completely healthy. You may look at a spastics when they move. You may get the false impression that their muscles are ill.

It´s also that the concrete symptoms in different spastics differ - reasonably - a very lot, depending on which nerves have died. Also the children I knew have been very different in their two handycaps.
So this is a pretty good comparison, I think. I don´t want to deny that we may well have more effects downstream which though may be influenced by different genetics and other conditions. And also - other way around - such condition may well contribute to the (difficult to grasp) core symptoms of ME/CFS, which makes it all not easier to look through.

 

[percyval577]

If there are other typical symptoms (e.g. hoarseness, coughing, clearing throat - with no other apparent causes), could this point to a vagus nerve issue? Or muscle weakness? Or...?

I am sorry for answerering late @Inara. It took a while until I have grasp your message, tough it´s completely logical what you are saying. I tried to say it - so, my opinion -in this post:

Then the question is, where could a feeling-ill mechanism be located (in higher organisms)? I think a good candiate is basal ganglia and thalamus together. I bet this would make the complete chaos of symptoms here and there understandable,
a)... it could also explain an exaggeration, including delayed PEM and pacing (conditioning is not possible)
b)... it could explain the strange diversity of symptoms that you can read about eg on this forum, and
c)... it would explain the non-specificy of concrete symptoms and the linkage to (more) normal illness-fatiques.

Also the two proceeding ones were meant to lead to a single core, so this one, I should say.

In my experiencing I don´t feel it far away to interprete hoarseness and coughing as being caused by conditions in the brain.
There is also a medical for a special kind of cough, and the medical works on NMDR´s, it´s dextrometotphan (wikipedia). It has been discussed on the forum as well. (I my case it can help for my MECFS, but I don´t use it, maybe I will try it again).

 

[Wishful]

Secondly assuming there are others out there like me with my kind of CFIDS, while neuroinflammation and hypersensitivity are a distinct and very difficult aspect of my condition, that is not even half the story, there is much more to it than the neurological phenomena.

I wasn't suggesting that ME was a 'phantom disease'. It quite obviously has physical triggers and physical results. What I'm questioning is whether the fatigue PWME experience is identical (chemically) to fatigue caused by physical exertion, or is the brain perceiving similar sensations due to a different set of chemical signals. Asking questions is the basis of science. In the case of ME, I'm not sure that anyone has properly asked that question, or whether the means to answer the question exist yet. My quick search for 'how is fatigue measured' seemed to indicate that there is no clear definition of fatigue, and no way to actually measure it. Saying "I feel fatigued" doesn't necessarily mean that you are low on ATP or high in lactic acid. You could have the same feeling from some drugs, many medical conditions that might not affect ATP levels, or even hypnosis.

Thirdly phantom sensation as an explanation is not sufficient to explain the character of PEM, being delayed for a day and causing a 3 day crash which appears to be some kind of an inflammatory reaction in itself, not simply a magnified sensory phenomenon. There is no question too much activity makes the condition worse in a way which cannot be explained by a phantom sensation.

I wasn't saying that phantom sensation was a cause of anything. What I'm questioning is the pathway to the perception. Is hearing a noise proof that a physical phenomena caused pressure waves in the air? No, a person with synesthesia might be convinced that they hear the sound, but it was actually their brain misprocessing the sight of a red object, or the smell of cinnamon. I assume that our brains have a set of inputs from various sensors that trigger a set of outputs that means "I feel fatigued". I see it as possible that the output pattern can occur without the specific input pattern, due to altered neural thresholds, misconnections, or other such alterations.

In my case, I've experienced significant muscle aches, specifically in my front thigh muscles. This hampered my willingness to walk. This experience of pain wasn't affected by exercise or rest, or NSAIDs, which I would expect would affect physical muscle problems. The aches were effectively blocked by LDN and also by acupuncture (which supposedly triggers endorphin production in the brain cells processing the signals from the treated nerves). From that, it seems reasonable to assume that I had the perception of pain without actual physical problems in the muscles.

I think it's quite reasonable to question the cause of the feelings of fatigue. Simply assuming that the fatigue is due to low ATP or whatever is bad science, especially if the researchers ignore any findings that don't match that assumption. If they find that the feeling of fatigue correlates 96% with ATP levels, that would be significant. If it only correlates well with 20% of PWME, then ATP levels aren't the core cause. What if the correlation for most PWME was to the inverse of IL-17, or the diameter of capillaries leading to the hypothalamus?

Since 'fatigue' is such an important part of ME, defining and measuring it seems pretty important.

 

[Learner1]

@Wishful @percyval577 and everyone else...

This thread is to discuss Neil MCGregor's insightful talk. Can we stick to that topic please? If you'd like to debate fatigue, or PEM, or correct diagnosis of ME/CFS, there are ample threads around here to do that.

Here is the original post, to get us started again:

Last week @Cort released a great article on Neil McGregor's (Australian researcher) hypothesis on what is going in ME/CFS. This article was posted by @Rufous McKinney, but it was embedded in another thread and I think this hypothesis warrants its own thread. Simply fascinating stuff and a great write-up by Cort. If you read the article and scroll down through the comments, McGregor addresses some of the comments.

https://www.healthrising.org/blog/2...gregor-metabolism-chronic-fatigue-glycolysis/

 

[Inara]

In my case, I've experienced significant muscle aches, specifically in my front thigh muscles. This hampered my willingness to walk. [...] From that, it seems reasonable to assume that I had the perception of pain without actual physical problems in the muscles.

So why didn't you just ignore the pain and walk?

A typical symptom of neuropathies is muscle weakness. Ion channel abnormalities can lead to muscle weakness. In Myasthenia Gravis acetylcholine receptors are "damaged" and the nerve-to-muscle-signaling doesn't work which leads to muscle weakness. Any muscle signaling disturbance can lead to muscle problems, including muscle loss. In all these cases, the muscles themselves are perfectly fine. Still the result is muscle weakness. I have neuropathies, and at the beginning I found this experience "fascinating" (and annoying, to put it nicely), because as soon as the neuropathy symptom got better, the affected muscles worked (nearly) normally again. But until that point, the affected muscles didn't work properly, I couldn't use them which led to muscle loss. (I have constantly muscle problems which are not influenced by neuropathies, so these are two different things.) Signaling disturbances are not "phantom".

Although I understand your question and although I distantly seem to understand your point, I don't totally understand what you mean by "phantom" - I associate "illusionary" with it (it's there but it doesn't exist in reality). Did I misunderstand you? I personally think that bodily symptoms go back to bodily processes, so I have trouble with "phantom" in this regard. Maybe you can explain? In your thoughts, how do you explain "phantom" pain/weakness/etc in a biochemical/physical setting?

Since 'fatigue' is such an important part of ME, defining and measuring it seems pretty important

I think "fatigue" as a symptom should remain minor. Therefore, I personally think research should not focus on it. And as you said yourself, "fatigue" is so "woolly" and is used in so many different meanings (sometimes tiredness, sometimes exhaustion, sometimes...whatever).

Edit: If this post is too off-topic, I can delete it. Sorry Learner, I read your post too late.

 

[boolybooly]

Dr McGregors theory is that something is breaking glycolysis and my own perspective on that is it is probably the body itself as it may be due to an immune response which shuts down normal energy production to fight pathogens which use our metabolic energy to grow. Like running a temperature this gives our defences an edge in terms of molecular kinetics or at least takes away an advantage for pathogens. My guess is this response becomes chronically active in any subtype of ME.

If we imagine a Venn diagram I think that immune response would be the big circle labelled ME, with subtype circles all around the edge half in and half out, linked to various causes of chronic activation.

Its well known wisdom for example that athletes are told not to exercise when they have a virus because it damages their health and IMHO this is related to McGregors finding that the body can end up using protein instead of sugars etc when glycolysis is broken.

Discussing the phantom thing is important because I think McGregors findings actually do show that the fatigue is not phantom in the sense of not being a neurologically generated illusion. I am not trying to make you feel bad @Wishful I think you are right that this kind of thing needs to be discussed and its fair enough to ask the question, because if we dont discuss it then others will, like the insurers who have for decades tried to sit on ME and argue via proxies that it is a psychological affliction which can be treated cheaply with a bit of CBT for purely financial reasons. That was the real reason ME research stalled so it is what we have to deal with. When settling cases in a law court their lawyers will try any argument which reduces their liabilities and the idea that the disease is not what it appears to be will be at the top of their list to reduce treatment expense. So that is why I am taking the time and trouble to think about counter arguments. I am not trying to be argumentative at you just deserves thinking about and discussing.

Dr McGregor's findings help a lot because they show ME is what it appears to be and so there is no reason to assume it is psychological or even caused by a neurological misfire of some kind, because the measured metabolic differences show people with ME really are tired because they cannot make the energy properly in the first place.

I would also agree however, bearing in mind the legal niceties, the inflammation of the nervous system seen in some cases could exacerbate suffering for people who already have what Dr McGregor has concluded to be a genuinely metabolic illness.

 

[Wishful]

This thread is to discuss Neil MCGregor's insightful talk. Can we stick to that topic please? If you'd like to debate fatigue, or PEM, or correct diagnosis of ME/CFS, there are ample threads around here to do that.

It has ranged a bit far, but I think it is still on-topic. Is his research on the right track? What are the assumptions he's making?

From the paper: "McGregor, then, believes that problems with glucose metabolism are at the core of what is happening in ME/CFS."

That's a pretty strong assumption. Does it hold true for most PWME? If it holds true for 90% of his test subjects, has his selection process biases the set for people who show clear muscle endurance problems? The diagnostic criteria for ME says "physical and/or mental fatigue". Does his hypothesis hold true for PWME who only show mental fatigue? Does it hold true for everyone who 'feels physically fatigued', or just those who actually do have blood markers for physical fatigue? I think it's very important to question the assumptions of a hypothesis. If all the assumptions hold up, great. If not, then the hypothesis is suspect.

For me, I haven't seen any convincing evidence that I'm having problems with glucose metabolism. If it was a glucose metabolism problem, shouldn't I see some effects from having more or less carbs or fats in my diet, or changes correlating with insulin spikes, or other such things? I noticed a clear correlation with t-cell stimulating factors, so I'm personally convinced that the t-cells are involved with my ME. I noticed a clear correlation between tryptophan levels in my brain and symptoms severity, and with factors that would increase IFN-g, so I'm convinced that kynurenines are most likely involved in some (most?) of my symptoms. Glucose? Not convinced.

 

[Wishful]

So why didn't you just ignore the pain and walk?

Actually, many times I did, because I was desperate enough for a walk outdoors, and not walking didn't make me feel all that much better. However, the pain prevented me from enjoying walking. One day I trudged painfully to the base of the hill south of my cabin, and couldn't work up the motivation to go further. A day or two later, I tried LDN for the first time. I didn't notice a huge boost in energy, but I again walked to the base of the hill. This time I realized that I wasn't feeling the usual aches, and felt like continuing. I hiked up the quite steep slope, reached a cross-trail, and still felt non-achey. I then hiked another km or so, and turned back only because I was worried about overdoing it. I felt tired by the time I reached home again, but it was a normal healthy tired, which felt really good compared to all that ME-fatigue.

As for 'why didn't I just ignore the pain and walk' on other days, I'm not a masochist. I don't enjoy pain, and I prefer to avoid it when I have the choice. I need a really good reason to do something that causes me pain.

I personally think that bodily symptoms go back to bodily processes, so I have trouble with "phantom" in this regard.

I agree that even the 'phantom fatigue' would have a real physical cause: a chemical process or a physical change. What I meant is that it might not necessarily be the same cause as standard fatigue (if there is such a thing). It might not be ATP levels or lactic acid levels in muscle tissue. It might be that whatever triggers the set of neurons that make us 'feel fatigued' has a different source. Maybe something localized to that part of the brain causes heightened sensitivity to normal levels of inputs.

I agree that "phantom' is probably a misleading term for this. I just couldn't come up with a better term for 'cause that is different from what normally triggers fatigue'.

Dr McGregor's findings help a lot because they show ME is what it appears to be and so there is no reason to assume it is psychological or even caused by a neurological misfire of some kind, because the measured metabolic differences show people with ME really are tired because they cannot make the energy properly in the first place.

That's assuming that his test subjects represent all subgroups of PWME, which I do question.

 

[gregh286]

Actually, many times I did, because I was desperate enough for a walk outdoors, and not walking didn't make me feel all that much better. However, the pain prevented me from enjoying walking. One day I trudged painfully to the base of the hill south of my cabin, and couldn't work up the motivation to go further. A day or two later, I tried LDN for the first time. I didn't notice a huge boost in energy, but I again walked to the base of the hill. This time I realized that I wasn't feeling the usual aches, and felt like continuing. I hiked up the quite steep slope, reached a cross-trail, and still felt non-achey. I then hiked another km or so, and turned back only because I was worried about overdoing it. I felt tired by the time I reached home again, but it was a normal healthy tired, which felt really good compared to all that ME-fatigue.

As for 'why didn't I just ignore the pain and walk' on other days, I'm not a masochist. I don't enjoy pain, and I prefer to avoid it when I have the choice. I need a really good reason to do something that causes me pain.



I agree that even the 'phantom fatigue' would have a real physical cause: a chemical process or a physical change. What I meant is that it might not necessarily be the same cause as standard fatigue (if there is such a thing). It might not be ATP levels or lactic acid levels in muscle tissue. It might be that whatever triggers the set of neurons that make us 'feel fatigued' has a different source. Maybe something localized to that part of the brain causes heightened sensitivity to normal levels of inputs.

I agree that "phantom' is probably a misleading term for this. I just couldn't come up with a better term for 'cause that is different from what normally triggers fatigue'.



That's assuming that his test subjects represent all subgroups of PWME, which I do question.

I notice massive correlation with glucose metabolism. Racing heart rate....neuropathy with too much carb....lactate spikes....list is endless.

 

[Wishful]

I notice massive correlation with glucose metabolism. Racing heart rate....neuropathy with too much carb....lactate spikes....list is endless.

We're all different, but we do have some things in common. I just think that the common elements should have the highest priority for limited research resources. I think that the research community should try to find victims in the less common subgroups and see what they have in common with the more common subgroups. Then they could avoid wasting misprioritizing resources on downstream symptoms. Would you rather have a treatment for a symptom you personally don't have, or would you rather have a treatment for ME, which removes all the downstream symptoms?

 

[Learner1]

@Wishful All the researchers think there are subgroups, even McGregor:

...he’s able to separate infectious from gradual onset patients using metabolites. To be able to show, years after onset, that some fundamental differences persist in these two groups would be a significant breakthrough. Not only would it suggest that gradual and infectious onset patients are different, but the metabolites should, of course, tell us how these two symptomatically very similar presentations of ME/CFS are different biologically....

There definitely seem to be more subgroups, but I'd venture to say there are actuslly an infinite number of subgroups and what we really need is personalized medicine.

I say this not to be difficult, but because, even if these major subgroups did have the limited research dollars applied, it wouldn't be useful to me, because my subgroup is unique - there are no other patients like me.

I have post-hysterectomy/chemotherapy for ovarian/uterine cancer, significant car accident affecting my spine, Epstein Barr and other viral induced immunity, heriditary hemochromatosis, Hashimotos, Celiac, MCAS, lousy genes onset ME/CFS.

The best a patient like me can do is not sit around waitung for the researchers to get around to RCTs of treatments on patients exactly like me, cause it just ain't gonna happen. It's reading the research out there, comparing my diagnostics to what's found By the researchers and to take actions to push me toward normal.

So, I appreciate experienced researchers like McGregor theorizing as it helps inform my doctors' and my decision-making process in developing treatment.

As for McGregor's theory, it is much more than just glucose. Aminos seem to be a key, as others have found many of us are burning aminos for fuel, taken grom our muscles. This jives with Fluge and Mella's findings on amino acid depletion. (And my labs have agreed - unless I get my amino acid intake up to 1.8-2g/kg/day, I get depleted which has led to numerous problems that reverse with adequate supplementation.)

Our cells want to use glucose to produce energy; if they can’t get glucose they’ll turn to fats – not such a bad substitute, but if the fats aren’t working, they’re forced to turn to their last and least favorite option – breaking down proteins....

...High levels of muscle metabolites suggested that whatever muscles the people with ME/CFS had left were being broken down faster than normal....

...This dumping/amino acid depletion is, McGregor believes, a key issue in ME/CFS. It can help explain why ATP production is low and why the disease is so darn difficult to get out of...

But then he discussed HDAC problems in concert with low pyruvate and low lactate, again something that my labs have shown.

Bringing us back to square one, he proposed that the HDAC problems in ME/CFS result from the problems with glycolysis.

Glycolytic inhibition, it turns out, increases HDAC activity. Low lactate and pyruvate levels – because they are HDAC inhibitors – allow HDAC levels to rise. HDAC then causes deacetylation and silences the transcription of many genes.

2 years ago, my fasting glucose was high even though I was on a low carb diet. But, as I've treated infections, learned about the amino acid problems and replenished them, I've improved. I remain on a low carb, high protein diet, so perhaps I'm not seeing the insulin resistance and glycolysis problems McGregor sees due to the interventions I've made.

It would be interesting to learn more about the dynamics of all of this, what tests could be used by clinicians, what treatments might effective, and how one would measure progress.

 

[percyval577]

If I have understood rightly MyGregor´s hypothesis is:

• that there is - generel (or somewhere particular?) - a problem with turning glucose or fat into energy
• that neverhteless the body tries to and tries to, and is therefore in a hyper-metabiloc state (not in a hypo-metabolic state)
• that as a consequence proteins from the muscles are broken down for making energy

 

[percyval577]

Cord then writes also, with a comparision to burns, post surgery state and sepsis:

Both burn and ME/CFS patients show loss of amino acids, insulin resistance, connective tissue degradation (an interesting finding given the EDS and craniocervical instability problems), altered triglycerides, cortisol, a switch from ATP production to “thermogenic” response, and gut-barrier issues. (Ron Davis, by the way, is finding high levels of connective tissue metabolites in the severely ill patient group he’s studying. Those metabolites could suggest that increased connective tissue degradation is occurring.)

 

[percyval577]

I think the hypothesis might give an interesting hint, but I doubt that this will explain even muscle pain in particular. (As far as I remember, muscles are getting broken down in normal live on a regular basis too, given the circumstances.)

But even if it is true that in mecfs some tissue degradation takes place (I think so), it leads obviously not to severe degeneration (my gum though on four patches). So that we feel like dead doesn´t seem to be mirrored here.

I though hope that he will find some interesting relationship, but the most findings he is referring to haven`t been strong enough to serve as a biomarker so far. So, maybe a tendency?

And I think to say >> muscle pain - some muscle degradation - problem with glycolysis - core of mecfs << is a bit short cutting.

I would suggest to ask: "How on earth is it possible that PwME can sidestep some PEM by pacing? How on earth is it possible that PEM can appear delayed. A delayed problem with glycolysis?? Delayed muscle breakdown?

The hypothesis may be interesting really enough, but it will not be core, as far as we aren´t suffering from different diseases, I would say.

 

[gregh286]

I think the hypothesis might give an interesting hint, but I doubt that this will explain even muscle pain in particular. (As far as I remember, muscles are getting broken down in normal live on a regular basis too, given the circumstances.)

But even if it is true that in mecfs some tissue degradation takes place (I think so), it leads obviously not to severe degeneration (my gum though on four patches). So that we feel like dead doesn´t seem to be mirrored here.

I though hope that he will find some interesting relationship, but the most findings he is referring to haven`t been strong enough to serve as a biomarker so far. So, maybe a tendency?

And I think to say >> muscle pain - some muscle degradation - problem with glycolysis - core of mecfs << is a bit short cutting.

I would suggest to ask: "How on earth is it possible that PwME can sidestep some PEM by pacing? How on earth is it possible that PEM can appear delayed. A delayed problem with glycolysis?? Delayed muscle breakdown?

The hypothesis may be interesting really enough, but it will not be core, as far as we aren´t suffering from different diseases, I dare to say.

How is PEM delayed?
Ever dig in a garden for a day or goto the gym once every 6 months before having cFS?
2 days later you can barely get out of the car. Same principle. Sore and aching muscle delayed in normal people as you use muscles never used in long.long time.

 

[Wishful]

How on earth is it possible that PEM can appear delayed.

As gregh286 said, there's a delayed reaction to using muscles beyond their normal usage. There are probably several mechanism for the delayed reactions. The immune system is known to have delayed responses with precise, consistent times. I don't know the mechanism involved, but I know there are biological clocks that are quite accurate. I think they use a chemical reaction with a consistent timing, and have some sort of molecular 'tally stick' that counts the reactions, and when it reaches a certain tally, it triggers some other biochemical reaction. I experienced food triggering an abrupt rise in symptoms a precise and consistent 48 hrs +/- a few minutes later, so a consistent 24 hr delay for PEM after activity seems totally reasonable. A t-cell response seems a good guess for delayed PEM.