McGregor's Hypothesis of ME/CFS

[percyval577]

@gregh286 But I think you rejoinder is not going to prevail.

My impression is that delayed PEM is not preceded by an abnormal - this is what we are talking about - feeling related to its trigger. So in your example we felt the first day nicely tired (after being exhausted as well, I guess), and then the second or (possibly strongest) third day we were not getting out of the car - in addition.

But if PEM is delayed than it comes delayed, and there is no preceding PEM, like the normal tiredness in our healthy days. This is how I have understood some reports, there might be others as well possible (i.e. not necessarily required).

I got btw a delayed reaction from mistakes in my then newly discovered diet, and it was exactly 22h later every time, and it lasted for 26-28h. This is what I would like to refind in reports of delayed PEM, and I would think that this bears the sought mechanism inside.

And can muscle aches or repair or breakdown explain the possibility of Pacing? Of course if some special muscles got damaged you might use other ones, and this would be pacing. But is this what we pacing is? I remain sceptical. My impression would be that you walk the one day to the grocer, and the second day you care a bit for your garden. Alot of the same muslces will be involved. But of note may be, I think, that the chain of movements is another one.


In addition it´s my understanding that also mental effort is subject to pacing and PEM. Recently I could play trumpet every three months for some hours. And some years earlier I needed to shift my mental activity - as far as it was possible at all - every four months.
In regard of PEM, where M stands for Malaise, the CCC (point 2) make the additional proposal of something that would be abbreviated PEF, with F for Fatique.

 

[percyval577]

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.

I had basically a same reaction, as I just said.

But PEM can also appear several days later, or even months, @Hufsamor recently told so (quite related to my four months pacing).

I admit that the immunesystem is complex enough, but it´s working every week differently, you have these little infections, that small wound and so one, and nothing of this is prone to be put into a regularity, though there might be some regularity in time inside the immunesystem.

I f you ask me, the nerves will proceed all things on a regular timely basis. And then prodeeded things may sometimes irregularily add up or cancel each other out.

 

[Learner1]

As gregh286 said, there's a delayed reaction to using muscles beyond their normal usage. There are probably several mechanism for the delayed reactions.

• Oxidative and nitrosative stress in mitochondria increase
• LPS increase after exercise
• cytokines change after exercise

The body reacts to what happens and it's resources are used in increased activity, as the body tries to recover from this increased load, using up ATP, NAD, amino acids, lipids, minerals, vitamins, etc. in the process. I have found that PEM can be AVOIDED and even REVERSED by replenishing these resources that the body is using up too quickly.

There is likely no "one size fits all" solution, so what I take may be different than what others need, but I have been able to gradually increase my activity and manage my ability to do what I want to do by preloading wtih the resources my body seems to demand when I increase activity.

The largest observation from this N=1 experiment is that my body has accelerated its demand for amino acids, antioxidants, and B vitamins - a much greater amount than pre-ME/CFS. This goes back to what McGregor is saying. It's not just the amino acids, as the amino acids are used in numerous processes, so you need the cofactors to get through those processes.

And can muscle aches or repair or breakdown explain the possibility of Pacing?

Yes, we are breaking down tissue, according to McGregor. So, we either have to ration our activity, or we have to supply the resources to properly support what we are demanding of it.

 

[sb4]

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.)

Just to clarify, you are talking about 2g/kg/day of both dietary protein and amino acid supplementation and not just amino acid supplements?

 

[Wishful]

I got btw a delayed reaction from mistakes in my then newly discovered diet, and it was exactly 22h later every time, and it lasted for 26-28h.

Type IV delayed food sensitivity is supposed to have a delay of 48-72 hrs. Mine started with a precise and consistent 48 hrs. When I tried a rotation diet, my time delay abruptly switched to a precise and consistent 17.5 hrs, which doesn't fit what I've read about type IV reactions. A small box of cherries triggered a really bad reaction, and my delay abruptly switched to 22 hrs, thirty-some minutes (didn't last long enough to refine it). Then food poisoning cured the type IV reaction.

From this experience, it seems that t-cell reactions aren't quite as simple and straightforward as the (fairly limited) information about it suggests. Maybe the 'molecular tally stick' can be changed, and that change is body-wide. My time delay for physically-induced PEM is harder to measure precisely, but it does seem fairly consistent, so I expect that it's using the same time delay mechanism. I wonder if a t-cell inhibitor would block PEM?

 

[Learner1]

I wonder if a t-cell inhibitor would block PEM?

Have you tried glutathione?

Just to clarify, you are talking about 2g/kg/day of both dietary protein and amino acid supplementation and not just amino acid supplements?

Sorry for the confusion. It's total protein/aminos, so 95g of food protein plus 35g of custom aminos a day (commercial powders are heavy in arginine and light in all the aminos I'm short of).

 

[percyval577]

The / an article related to the hypothesis is out now. LINK --- the whole article is open access (thanksfully).

Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases
Neil R. McGregor 1,*,Christopher W. Armstrong 2,Donald P. Lewis 3 andPaul R. Gooley 2

1
Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville VIC 3010, Australia
2
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biochemistry Institute, 30 Flemington Road, Parkville VIC 3010, Australia
3
CFS Discovery, Donvale Medical Centre, Donvale VIC 3111, Australia
*
Author to whom correspondence should be addressed.
Diagnostics 2019, 9(3), 70; https://doi.org/10.3390/diagnostics9030070 (registering DOI)
Received: 17 June 2019 / Revised: 30 June 2019 / Accepted: 2 July 2019 / Published: 4 July 2019
(This article belongs to the Special Issue Biomedical Insights that Inform the Diagnosis of ME/CFS)

Abstract (my paragraphing)

Post-exertional malaise (PEM) is a cardinal predictive symptom in the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). If the cases overexert themselves they have what is termed “payback” resulting in a worsening of symptoms or relapse which can last for days, weeks or even months.

The aim was to assess the changes in biochemistry associated with the cases self-reported PEM scores over a 7-day period and the frequency of reporting over a 12-month period. Forty-seven ME/CFS cases and age/sex-matched controls had a clinical examination, completed questionnaires; were subjected to standard serum biochemistry; had their serum and urine metabolomes analyzed in an observational study. Thirty-five of the 46 ME/CFS cases reported PEM in the last 7-days and these were allocated to the PEM group.

The principal biochemical change related to the 7-day severity of PEM was the fall in the purine metabolite, hypoxanthine. This decrease correlated with alterations in the glucose:lactate ratio highly suggestive of a glycolytic anomaly. Increased excretion of urine metabolites within the 7-day response period indicated a hypermetabolic event was occurring. Increases in urine excretion of methylhistidine (muscle protein degradation), mannitol (intestinal barrier deregulation) and acetate were noted with the hypermetabolic event.

These data indicate hypoacetylation was occurring, which may also be related to deregulation of multiple cytoplasmic enzymes and DNA histone regulation. These findings suggest the primary events associated with PEM were due to hypoacetylation and metabolite loss during the acute PEM response

 

[percyval577]

p.9

This study was designed to investigate metabolic changes in ME/CFS subjects using a discovery hypothesis and not a specific hypothesis-driven method to assess specific biochemical events.

p.8

The findings that the PEM is associated with a loss of metabolites, reduction in acetylation, deregulation of purine metabolism, increased contractile protein breakdown and bacteremia associated with exercise suggest that treatments such as graduated exercise therapy may be more detrimental than beneficial as claimed in some studies.

 

[Wishful]

Have you tried glutathione?

No, that seems to be an antioxidant, and I've only had bad results from the ones I've tried. I was thinking more along the lines of immunosuppressants. Nasty things to experiment with, but if someone was desperate for a PEM blocker, it might be something to try. Cumin is a very effective PEM blocker for me, so I don't have to risk bad side effects from other things. I don't know how cuminaldehyde works; maybe it's an unrecognized immunosuppressant. It seems to work in a non-dose-dependent manner: it seems to trigger something that is protective for three days. Larger doses don't work better, and last only a couple of days longer. I'm sure that would help in figuring out how it works, but it's not enough information on its own.

 

[Inara]

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.

Is there an assumption about "what normally triggers fatigue"? I thought there are many, many causes for tiredness or exhaustion. I never had the feeling any researcher wasn't aware of that? Also, my impression wasn't that McGregor assumed there exists THE "fatigue". Did he?

Still, tiredness is not a core part of ME, and in my view exhaustion isn't the central player either. I'm always a bit frustrated if researchers focus on "fatigue" when they look at ME. I find McGregor a positive example because he looks at muscle issues in ME. Whether is hypothesis will be correct only research and time can tell. At this point of time, it's still a hypothesis.

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'.

Thanks for explaining, I understand it better now.

 

[ljimbo423]

Pantethine is the coenzyme of vitamin B5 and is available as a supplement. It increases the TCA or Krebs cycle, creating more ATP and therefore energy. If glycolysis is impaired as McGregor thinks, the TCA or Krebs cycle will be slow. Pantethine can help speed it up-

Pantethine inhibits cholesterol synthesis and accelerates FA metabolism in the mitochondria by inhibiting hepatic acetyl-CoA carboxylase, increases CoA in the cytoplasm, which stimulates the oxidation of acetate at the expense of FA and cholesterol synthesis, and increases Krebs cycle activity.

https://www.sciencedirect.com/topics/neuroscience/pantethine

 

[grapes]

Attached is a graphic that totally describes my PEM. I will totally have energy to do what I'm doing, then I seemingly drop like glass onto a tile floor with massive fatigue that takes days and days to recover.

And this sentence in the McGregor article is EXACTLY how I had begun to see this in me...and why when I read the article, it was light another lightbulb all over again. : "McGregor, then, believes that problems with glucose metabolism are at the core of what is happening in ME/CFS."

The reason I had already been suspecting a glucose metabolism issue as McGregor proposes? Because I had done a stool test a week before, and voila, there were carbs/sugar in my stool. I'm not breaking down carbs correctly!

Second, I once did an activity two years ago that involved long distances of walking, and I didn't crash at all. I had been snacking on peanut M&Ms' the entire time. I just didn't put two and two together at the time. And because I wasn't putting it together, I have had many other bad crashes. So my experimentation begins.

 

[percyval577]

It happened that I looked around, a new study that is thematically along with the McGregor paper
(but not looking at mecfs). LINK

ARTICLE| VOLUME 27, ISSUE 13, P3939-3955.E6, JUNE 25, 2019

Glucose Metabolism Drives Histone Acetylation Landscape Transitions that Dictate Muscle Stem Cell Function

• Nora Yucel 4
• Yu Xin Wang 4
• Thach Mai
• Sean C. Bendall
• Michael Angelo
• Helen M. Blau 5
• Show all authors
• Show footnotes

Highlights

• Histone acetylation levels change with muscle stem cell states during regeneration
• Mitochondrial glucose utilization determines overall histone acetylation levels
• PDH activity controls histone acetylation and myogenic differentiation potential
• PDK2 and PDK4 are required for skeletal muscle regeneration in vivo

Summary (my paragraphing)

The impact of glucose metabolism on muscle regeneration remains unresolved. We identify glucose metabolism as a crucial driver of histone acetylation and myogenic cell fate. We use single-cell mass cytometry (CyTOF) and flow cytometry to characterize the histone acetylation and metabolic states of quiescent, activated, and differentiating muscle stem cells (MuSCs).

We find glucose is dispensable for mitochondrial respiration in proliferating MuSCs, so that glucose becomes available for maintaining high histone acetylation via acetyl-CoA. Conversely, quiescent and differentiating MuSCs increase glucose utilization for respiration and have consequently reduced acetylation.

Pyruvate dehydrogenase (PDH) activity serves as a rheostat for histone acetylation and must be controlled for muscle regeneration.Increased PDH activity in proliferation increases histone acetylation and chromatin accessibility at genes that must be silenced for differentiation to proceed, and thus promotes self-renewal.

These results highlight metabolism as a determinant of MuSC histone acetylation, fate, and function during muscle regeneration.

https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30743-0

 

[Inara]

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.

I can just say from my own experience that ME symptoms and PEM feel totally different from the consequences of strenuous physical activity; and I was doing high performance training for a while. I had sore muscles and a (satisfying) exhaustion. Even the sore muscles I get today with ME feel different to the sore muscles I got from training without ME. At least for me, PEM is definitely not the same principle.

 

[Wishful]

Is there an assumption about "what normally triggers fatigue"?

I couldn't find one. 'Fatigue' is poorly defined, and doesn't have a clear marker. You could measure ATP and lactic acid or oxygen levels, and maybe find a correlation between those and how a specific person feels, but there doesn't seem to be a clear 'this factor is a measure of fatigue'. Thus, when you read an article about fatigue, you really have no idea what they're talking about.

Maybe we should replace 'fatigue' with 'feeling unable to do things the way we could when we were healthy'. That's just as poorly defined, but at least it doesn't make the reader think that they actually know what it means.

I find McGregor a positive example because he looks at muscle issues in ME.

I'm not disputing that there's potential value in studying ME-induced muscle issues. I'm arguing that it seems to be a secondary symptom, since not all PWME display it, and thus is a less useful research area for the goal of treating ME.

Attached is a graphic that totally describes my PEM. I will totally have energy to do what I'm doing, then I seemingly drop like glass onto a tile floor with massive fatigue that takes days and days to recover.

Here's another example of what is probably a secondary symptom. Grape's description doesn't fit my PEM. I seem to have no reduction in physical energy. It's more like a drug (neurotoxin?) that interferes with my ability to think clearly and usually adds the perception of muscle pain, and my motivation to try to do things. I can't say for sure that glucose metabolism isn't involved in some way, but I see no evidence that it is.

 

[Wishful]

I can just say from my own experience that ME symptoms and PEM feel totally different from the consequences of strenuous physical activity;

I agree that the symptoms of PEM are totally different from the effects of healthy muscle usage. I think what gregh286 meant was that there are a number of effects that show up after a significant delay, which are due to various biological activities that follow a process. Activity damages some cells, which after a delay, release certain chemicals. Those chemicals trigger other cells, which after another delay, do something else. Eventually, this series of processes causes a symptom you feel, hours or days after the event. In PWME, one of those processes triggers another set of processes which result in PEM symptoms. So, while the symptoms feel (and are) different, the principle of what causes the delay (series of biological processes) is the same.


While looking back for who asked for an explanation of delays, I found:

I admit that the immunesystem is complex enough, but it´s working every week differently, you have these little infections, that small wound and so one, and nothing of this is prone to be put into a regularity, though there might be some regularity in time inside the immunesystem.

Yes the immune system is working on different triggers all the time. However, it does contain mechanisms for delayed responses, with impressive consistency of timing. When I had my type IV sensitivity, I asked one immunologist: 'Does the body have other responses capable of a consistent 48 hr +/- a few minutes delay?' and she said 'No, it's pretty clearly a type IV reaction.' While she probably can't be certain that there are no other possibilities, she seemed quite certain of the t-cells having this precise, consistent delay mechanism. I'll point out that it's an abrupt change: 48 hrs with no noticeable effect, then an abrupt rise in symptoms (and body temperature by several tenths) over the space of minutes. It's like one t-cell tallying ticks of a clock for 48 hrs, and then blowing a horn to mobilize an army. I have no problem seeing a similar mechanism working for delayed PEM.

 

[Learner1]

Still, tiredness is not a core part of ME, and in my view exhaustion isn't the central player either. I'm always a bit frustrated if researchers focus on "fatigue" when they look at ME.

From the ICC:

A. Postexertional neuroimmune exhaustion (PENE pen’-e): Compulsory

This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions. Characteristics are as follows:

1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.
2. Postexertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms.
3. Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.
4. Recovery period is prolonged, usually taking 24 h or longer. A relapse can last days, weeks or longer.
5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level

 

[Inara]

Thanks @Learner1 for quoting the ICC re. "tiredness" and "exhaustion". PENE comprises more than just exhaustion (tiredness is not mentioned). For me, fatigabilty and "fatigue" are different concepts.

I personally agree with @Wishful (or others) that "fatigue" is ill-defined and can mean anything. My impression is it is often defined as tiredness, and tiredness really is not ME. There is no question that a part of pwME have tiredness and/or exhaustion as symptoms, as do pwMS, cancer, HIV/AIDS (please correct me), the flu etc., but this doesn't mirror or represent the disease I think.

@percyval577, thanks for the link to the paper! Is there an extra thread discussing it?

 

[Wishful]

Well, they aren't omniscient. They may have mistaken 'inability to produce sufficient energy' with 'feels like insufficient energy'. I don't think the experts actually measured energy availability, especially for 'mental fatigue'.

 

[Learner1]

There is no question that a part of pwME have tiredness and/or exhaustion as symptoms, as do pwMS, cancer, HIV/AIDS (please correct me), the flu etc., but this doesn't mirror or represent the disease I think.

I hear what you're saying, but I'm not so sure about that statement - the mechanisns here sound mighty familiar.