Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases, 2019, McGregor et al

[Barry]

As far as I can tell, the science on food intolerances is about as chaotic as that on "chronic fatigue", the symptom™. So really impossible to say until that moves forward from the starting line of "there may or may not be such a thing as food intolerance, or something like it".

I don't think there is any doubt about the existence of food intolerances, in that certain people cannot tolerate certain foods, and they are not due to an allergic reaction but something else. Whether the "something else" is understood, definitive or woolly, only time will tell.

 

[mariovitali]

@mariovitali Can you take a look at the supplementary data to see if any of those genes pop out to you.

Supplementary data. Post Exertional Malaise, Hypoacetylation and Purine metabolism
deregulation in ME/CFS Cases
https://www.mdpi.com/2075-4418/9/3/70/s1

Thank you @wigglethemouse

cc @ScottTriGuy

Please see below an email sent to a well-known ME/CFS Researcher, February 28th 2018 the tool identified SMAD7 + BMP6 :






Very close call i would say but an expert opinion is needed. The above suggests a subset of ME/CFS patients with problematic iron metabolism. Also in the radar for some time are CPS1, G6PD (this appears on the Network Analysis as node named Glucose6-Phosphatase) and SCARF1 (see here for SCARF1, end of the post : http://algogenomics.blogspot.com/2017/09/more-genes-relevant-to-phagocytosis.html)

Of HIGH interest to the supplementary material is the entry for Glutamate in Fecal samples. CPS1 is related to Urea metabolism which is not a surprise (also exists as a node in the Network analysis).

 

[Amw66]

There was a really interesting thread on PR a couple of years ago re purinergic signalling by necessay8. May be worth another read.

 

[mariovitali]

I wanted to see more about purinergic signalling. What i am trying to do is to see how whatever we are seeing in ME/CFS is connected and -most importantly- where does all of this comes from.


Here is a network analysis of the concepts we are seeing if we are considering purinergic signalling as our core concept :





My radar is for quite some time now pointed towards glutamate metabolism. Here i selected to see how glutamate is connected to several topics of interest. Observe how we have connections of Glutamate with hypoxanthine, acetate, kynurenine, ATP and microglia.

From the supplemental material, pointed out by @wigglethemouse :



I postulate that Glutamate is a key factor of the vicious cycle we are seeing in ME/CFS.

 

[Robert 1973]

I’ve not managed to read this in detail or keep up with everything but does the suggestion that PEM is associated with hypermetabolism contradict Naviaux’s theory that ME/CFS may be associated with a hypometabolic state? (https://www.pnas.org/content/113/37/E5472) Where are we at with Naviaux’s hypometabolic state theory?

I postulate that Glutamate is a key factor of the vicious cycle we are seeing in ME/CFS.

I’ve never been convinced by the notion that ME is caused by a vicious cycle. My understanding is that, by definition, vicious cycles get worse and worse unless they are broken. If ME was caused by a vicious cycle, would it not be progressive? My understanding is that most people with ME seem to be stuck in a fairly steady state with some getting gradually worse over time and some making gradual improvements. Also, many people with ME seem to experience periods when they feel some improvement but then deterioate again, regardless of how carefully they manage their activity. If it was a vicious cycle, would one not expect an improvement to break the cycle and lead to steady improvement?

I initially only thought about this in relation to the BPS vicious cycle theories, but the same logic would apply to any biological vicious cycle model. My feeling is that it is more likely to be some sort of trap where a critical threshold is reached – leading to an unhealthy but potentially steady state – rather than a vicious cycle as such.

[edit - typo]

 

[mariovitali]

@Robert1973

The problem is that i do not understand the difference between a vicious cycle and a trap. In my case ME was progressive. All symptoms were gradually becoming more serious, new symptoms were being added and crashes kept occuring more frequently as years passed by. Again, i disucss what happened to me but i heard other patients suggesting a similar mechanism.

 

[S-VV]

In the study they talk about hypoacetylation and of upregulation of HDAC enzymes, as well ass acetate deficiency.

Also, if hypoxanthine serves as a proxy for ATP breakdown, PEM is a hypermetabolic state when compared with resting ME/CFS state.

 

[rvallee]

I’ve not managed to read this in detail or keep up with everything but does the suggestion that PEM is associated with hypermetabolism contradict Naviaux’s theory that ME/CFS may be associated with a hypometabolic state? (https://www.pnas.org/content/113/37/E5472) Where are we at with Naviaux’s hypometabolic state theory?

On balance there does not seem to be an observable energy deficit, so the total available metabolic energy seems about normal.

So the energy has to be used somewhere, as it's not expelled as waste either. The hypermetabolism may be localized and upstream, depriving the available energy for less critical stuff (from a survival perspective) like thinking and moving around. On balance it adds up to similar total available energy but if one part of the process uses too much then some other part will have less available.

This is roughly what we see with any viral infection like the flu, there is a hypermetabolic state with the immune system hogging it up to do its thing, depriving voluntary systems like muscles but on balance still achieving some equilibrium that can't be distinguished if we can only look at total output.

So it'd be dependent on how precise we can get with observation. If all we have is input-output with everything in-between a black box, we don't even notice any difference. If we can reduce the systems that satisfy all other things being equal and pinpoint where the energy gets diverted, we'd likely see where the imbalance occurs, which system overuses energy to deprive other systems of metabolic energy they would otherwise have access to.

 

[wigglethemouse]

I’ve not managed to read this in detail or keep up with everything but does the suggestion that PEM is associated with hypermetabolism contradict Naviaux’s theory that ME/CFS may be associated with a hypometabolic state?

I wondered the same thing. Then I thought McGregor is probably referring to hypermetabolism that uses up more than usual amounts of raw materials and leaves us in a hypometabolic state with a lack of raw materials as per Naviaux?

 

[wigglethemouse]

My radar is for quite some time now pointed towards glutamate metabolism.

Yes @mariovitali ! Karl Morten NZ presentation slide 59 showed a 6 fold difference in glutamate between patients and controls with reduced Glutamine. Hope that team can get some funding to continue!

I wish I knew what PC was? Have a guess - Pyruvate Carboxylase, probably way off.............? Maybe have to watch the presentation again to see if he says..........

EDIT2. PC seems to be metabolites containing phosphocholine according to google

EDIT. Had a quick watch. I don't think he says what PC is. Here is slide 60



Uggggh. Funding could help identify the "unidentified" metabolites that also show a huge difference.

 

[mariovitali]

@wigglethemouse nice catch !


I haven't gone through the presentation but PC usually means PhosphatidylCholine and in this case it appears that it was found to be low

 

[mariovitali]

The following paper was retrieved with the Information Extraction system i've been using lately and i am inclined to contact Dr Jonas Berquist :

Cerebrospinal fluid hypoxanthine, xanthine and uric acid levels may reflect glutamate-mediated excitotoxicity in different neurological diseases.
Stover JF1, Lowitzsch K, Kempski OS.
Author information

Abstract
Glutamate-mediated excitotoxicity is associated with adenosine triphosphate (ATP) degradation and generation of oxygen radicals. Hypoxanthine and lactate depict energetic impairment, while xanthine and uric acid reflect activity of radical producing xanthine oxidase. Cerebrospinal fluid (CSF) glutamate, hypoxanthine, lactate, xanthine, and uric acid were investigated in neurological patients. In multiple sclerosis, myelopathy, stroke, epilepsy and viral meningitis glutamate, hypoxanthine, xanthine, and uric acid are increased 2-3-fold compared to controls. Lactate is only elevated in meningitis. Normal lactate dehydrogenase (LDH) levels and absent correlation between the albumin ratio and neurochemical parameters exclude an artificial increase due to cell lysis and barrier damage. Absent correlation between neurochemical parameters within each patient group is most likely related to preserved glial and neuronal uptake mechanisms. CSF hypoxanthine, xanthine, and uric acid levels appear superior to lactate in reflecting glutamate-mediated excitotoxicity in neurological patients.

@wigglethemouse what do you think? Recall the connection of Glutamate with Adenosine-Triphosphate (ATP) shown on Network Analysis i posted above

 

[wigglethemouse]

@wigglethemouse what do you think? Recall the connection of Glutamate with Adenosine-Triphosphate (ATP) shown on Network Analysis i posted above

Interesting. First, are there any other papers that reproduced these findings? The paper is 20 years old and mass spec techniques have improved a lot. From talking to Scientists I'm left with the impression that only 5-10% of published Scientific papers are truly meaningful and many others cannot be replicated.

I can't remember the details of Jonas Berquists presentations on CSF analysis. I don't think he has published his results has he? I don't know if the raw data is posted for sharing amongst researchers via the Stanford portal they set up - that seems to be their intention long term esp for OMF funded work. Chris Armstrongs role is Science liaison for OMF, so it might be worth you touching base with him especially as this relates to his and McGregors paper.

If this paper has been replicated successfully then it would probably be of interest to Jonas Berquist, Jarred Younger, & Mike Van Elzakker who are all looking for markers in the brain using different methods, are connected via the OMF working group, and so have access to all metabolic data in addition to Neil McGregor/Chris Armstrong of this threads paper.

 

[Wonko]

It interests me because I am seeing (via the data from a fitness tracker) that after activity, several hours before what I would traditionally call PEM, something that my fitness tracker seems to think is near continuous strenuous activity, which continues and increases during PEM.

It happens whilst lying on the sofa, it happens whilst asleep, it happens at a really stupid rate whilst 'shut down'.

No idea what precisely it's picking up, but it's picking up something. which given I am doing less than squat during it wold suggest some form of hyperthingy may be occuring, whilst I have very little free energy - which I choose to waste on non essential activities like getting to the toilet occasional, or eating/drinking.

Observing this state has been useful in knowing when it's a good idea to rest, as, as I say, it starts up several hours before PEM, and paying attention reduces the time I spend PEM'd, or at least speeds up recovery.

So the title caught my interest, unfortunately I can't follow the twists and turns in the unfamiliar language used in the paper.

 

[Diluted-biscuit]

It interests me because I am seeing (via the data from a fitness tracker) that after activity, several hours before what I would traditionally call PEM, something that my fitness tracker seems to think is near continuous strenuous activity, which continues and increases during PEM.

It happens whilst lying on the sofa, it happens whilst asleep, it happens at a really stupid rate whilst 'shut down'.

No idea what precisely it's picking up, but it's picking up something. which given I am doing less than squat during it wold suggest some form of hyperthingy may be occuring, whilst I have very little free energy - which I choose to waste on non essential activities like getting to the toilet occasional, or eating/drinking.

Observing this state has been useful in knowing when it's a good idea to rest, as, as I say, it starts up several hours before PEM, and paying attention reduces the time I spend PEM'd, or at least speeds up recovery.

So the title caught my interest, unfortunately I can't follow the twists and turns in the unfamiliar language used in the paper.

I’d be interested to get a fitness tracker and see this because I feel like I get similar symptoms. My OCD just wouldn’t take well to that much data about my health though.

 

[Kitty]

It interests me because I am seeing (via the data from a fitness tracker) that after activity, several hours before what I would traditionally call PEM, something that my fitness tracker seems to think is near continuous strenuous activity, which continues and increases during PEM.

Bit off-topic, but I'd be interested to know which tracker you're using, and whether it's the tracker's own app or some kind of add-on that's analysing the data.

I've got a basic Fitbit, which I chose simply because it has no external metal parts at all but still tracks heart rate. What I've discovered about PEM is that my resting heart rate is much slower (in the low 40s) than usual (around 59), which probably explains why I feel so spacey and dizzy. However, the app's pretty basic, and I'm wondering whether there's more I could learn from the data it captures.

 

[Wonko]

Bit off-topic, but I'd be interested to know which tracker you're using, and whether it's the tracker's own app or some kind of add-on that's analysing the data.

I've got a basic Fitbit, which I chose simply because it has no external metal parts at all but still tracks heart rate. What I've discovered about PEM is that my resting heart rate is much slower (in the low 40s) than usual (around 59), which probably explains why I feel so spacey and dizzy. However, the app's pretty basic, and I'm wondering whether there's more I could learn from the data it captures.

I wrote a post, decided it was just too OT for this thread, even for me, so I've sent you a PM, containing what I wrote.

 

[Kitty]

I've sent you a PM, containing what I wrote.

Thanks!

 

[JemPD]

I wrote a post, decided it was just too OT for this thread, even for me, so I've sent you a PM, containing what I wrote.

I was going to ask the same thing @Wonko .... would you mind sending the answer to me too please if it's not a hassle

 

[dreampop]

I really think McGregor is keyed into something. I don't know what that something is, but I resonate with virtually every thing he's writing and his understanding of symptoms and the corresponding lack of typical biologic causes seems to my layman eyes to be very on point. He even throws away the very insignificant minor cytokine differences that are found.

Whilst the renal changes are very similar to the renal changes seen in central diabetes insipidus, protein-calorie restriction and infection/inflammatory mediated events, no subjects had diabetes insipidus or were protein calorie restricted, and all had average BMI’s. These renal changes provide additional support for either an inflammatory origin or a possibly an energy/acetylation or even a transcription factor problem. Importantly, multiple studies have found that the level of serum cytokines are not significantly different between ME/CFS and controls and do not correlate with symptom expression [31]. Therefore, studies to assess the activities of HDAC and BMP transcription factors in MEC/CFS cases are warranted