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

[Andy]

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.

Open access at https://www.mdpi.com/2075-4418/9/3/70

 

[Andy]

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 graded exercise may be more detrimental than beneficial as claimed in some studies [39,40]. Until such time as these biological changes can be further investigated, the use of graded exercise as a therapy for those with severe forms of ME/CFS should be considered potentially harmful. In support of this, the use of graded exercise therapy has caused significant protest by ME/CFS sufferers as they see it as harmful [41,42].

 

[Hoopoe]

The principal biochemical change related to the 7-day severity of PEM was the fall in the purine metabolite, hypoxanthine.

What does this tell us about the illness?

 

[Trish]

From the discussion:

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 graded exercise may be more detrimental than beneficial as claimed in some studies [39,40]. Until such time as these biological changes can be further investigated, the use of graded exercise as a therapy for those with severe forms of ME/CFS should be considered potentially harmful.

 

[Keela Too]

This looks like a really interesting lead. I hope more research follows!

 

[Barry]

@Jonathan Edwards, @MEMarge

 

[Barry]

Until such time as these biological changes can be further investigated, the use of graded exercise as a therapy for those with severe forms of ME/CFS should be considered potentially harmful.

Yes, although I would suggest GET has not been proven safe for any ME severity level. There seems to be a lot of anecdotal evidence that those severely affected might not have become severe, if they had avoided GET whilst still mild or moderate.

 

[Diluted-biscuit]

Sounds really interesting

 

[rvallee]

bacteremia

So that would make it independent validation of this? I don't see Shukla on this paper.



From the wikiwikiwik:

Bacteremia (also bacteraemia) is the presence of bacteria in the blood. Blood is normally a sterile environment,[1] so the detection of bacteria in the blood (most commonly accomplished by blood cultures[2]) is always abnormal. It is distinct from sepsis, which is the host response to the bacteria.[3]

Abnormal, but how much so?

 

[Mithriel]

There now exists plenty of evidence that something is going wrong with exertion in ME even if it has not been pinned down.

 

[Barry]

So that would make it independent validation of this? I don't see Shukla on this paper.

View attachment 7726

From the wikiwikiwik:

Abnormal, but how much so?

I do get the impression there may be a correlation between food intolerances and ME. So many pwME seem to have a variety of food intolerances, including my wife; seems the prevalence could be higher in pwME than the general population? Could certain foods provoke certain bacterial gut leakages in certain people? And more so in pwME? Or could some pwME experience something that masquerades as food intolerance, but is actually different? Or is food intolerance a generic term, that can include gut leakage issues anyway?

And note I am not confusing intolerance with allergy, which I'm fully aware are very different.

 

[MeSci]

It seems to have been started in 2010!

 

[wigglethemouse]

I find this interesting. Study sample collection started 2010 - a long time ago.

This study was approved by the University of Melbourne human research ethics committee (HREC# 0723086, 2010) and the first specimens were collected on 23 September 2010.

and the results were previously published

The sample collection and processing has previously been published [2] and are provided here in summary.
.....
2. Armstrong, C.W.; McGregor, N.R.; Lewis, D.P.; Butt, H.L.; Gooley, P.R. Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients. Metabolomics 2015, 11, 1626–1639. [Google Scholar] [CrossRef]

And this paper looked at the results of the previous study to try and derive a hypothesis

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. This study with these limitations has resulted in the development of a hypothesis which now requires to be assessed by a typical hypothesis-driven process. Whilst the study size is small it reproduced the earlier findings but should be reproduced with a larger sample or multi-centers to reconfirm the findings.

That in addition to saying replication is needed, they suggest avenues to follow up on in future studies

Studies investigating acetylation and its related DNA transcription changes and the alteration in cytosol enzyme activity should allow the development of the understanding of the mechanisms of PEM development and the development of appropriate therapies based upon the underlying biochemistry.

So how did this hypothesis come about now, many years later. (from Video Link : https://mecfsconference.org.au/videos/neil-mcgregor/ )

Ron also challenged us to develop a hypothesis so we could test it. So I'm going to go out on a limb and put some data down and propose a molecular basis for what we see

The power of collaboration, sharing, discussion, challenging!

 

[mariovitali]

cc : @wigglethemouse @ScottTriGuy @Perrier


Another close call by Network Analysis in 2017. Observe the node named "Xanthine Oxidase", next to Urea Cycle :

Xanthine oxidase (XO, sometimes 'XAO') is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species.[2] These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. These enzymes play an important role in the catabolism of purines in some species, including humans.[3]

Xanthine oxidase is defined as an enzyme activity (EC 1.17.3.2).[4] The same protein, which in humans has the HGNC approved gene symbol XDH, can also have xanthine dehydrogenase activity (EC 1.17.1.4).[5] Most of the protein in the liver exists in a form with xanthine dehydrogenase activity, but it can be converted to xanthine oxidase by reversible sulfhydryl oxidation or by irreversible proteolytic modification.[6][7]

Below, snapshot from one page from a document i sent to several ME/CFS researchers, March 2018 :

 

[adambeyoncelowe]

From Wikipedia:

Hypoxanthine is a naturally occurring purine derivative. It is occasionally found as a constituent of nucleic acids, where it is present in the anticodon of tRNA in the form of its nucleoside inosine.

Inosine pranobex = Imunovir. This and the supplement inosine have have both been used anecdotally by patients and clinicians. (This isn't a recommendation, by the way.)

If this adds up, it could be interesting and might suggest treatments.

Of course, it's a tiny sample, so we shouldn't get our hopes up. But it is interesting.

 

[Hoopoe]

I think they are suggesting that the energy metabolism problems might be a downstream effect of a problem affecting the purine metabolism.

 

[wigglethemouse]

Tweet from Dr. John Whiting who I believe is closely connected with the researchers of this paper

This is the real deal ! It not only demonstrates that adenosine recovery by cells is inadequate, and gets metabolised to depletion, but purine signalling throughout the body AND the brain are going through issues. Adenosine and normal sleep are intertwined.

The adenosine salvage system will need this speculation to be studied carefully to make it real.

There is likely to be an cell membrane adenosine salvage transporter system failure here. The loss of body adenosine means it has to be re-synthesised to novo, an energy dependent system. Without sufficient adenosine, then less available to make ATP. I’m not sure if ribose helps.

If I search for this, I find papers that say trypanosomes salvage purines from their host. That might explain the reported similarity between sleeping sickness and this illness.

 

[wigglethemouse]

@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

 

[rvallee]

I do get the impression there may be a correlation between food intolerances and ME. So many pwME seem to have a variety of food intolerances, including my wife; seems the prevalence could be higher in pwME than the general population? Could certain foods provoke certain bacterial gut leakages in certain people? And more so in pwME? Or could some pwME experience something that masquerades as food intolerance, but is actually different? Or is food intolerance a generic term, that can include gut leakage issues anyway?

And note I am not confusing intolerance with allergy, which I'm fully aware are very different.

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".

It's quite likely that the thinking about food, rather than specific compounds and their interaction with gut microbes, may be the issue here. Food is made up a crapton of smaller stuff and the science is just far too immature to help guide us.

Kinda similar to the exosome and microbiome hypotheses, the science of ME is opening all sorts of possible avenues but they're all freaking unexplored and need to do some maturing all on their own before they are of use to us.

 

[ME/CFS Science Blog]

There are some things I don't quite understand in this paper. For example, it reads that "hypoxanthine was the prime predictive variable for alterations in the PEM scores". But if you look at the data, the ME/CFS group with no PEM after 7 days had larger differences for hypoxanthine compared to controls, than the ME/CFS group with PEM.

Also not sure what this means (my bolding):

In the whole group analysis, the 7-day severity PEM score and 12-month frequency PEM scores were positively correlated with serum glucose and negatively correlated with hypoxanthine, phenylalanine, lactate and threonine. No significant correlates were noted within the ME/CFS group.

So these markers did not correlate with PEM in the ME/CSF group? What do they mean with the whole group analysis- the analysis that includes healthy controls?

Even if these abnormalities compared to healthy controls (it isn't that difficult to find differences between ME/CFS patients and healthy controls) are robust, I don't see how they would have to be associated with PEM. If I wanted to figure out the biological correlates of PEM, I would test patients and controls in rest and then after exertion. If a marker is normal in all states except for ME/CFS patients after exertion, that would suggest that it might have something to do with PEM. As far as I can see, the abnormalities found here could be unrelated to exertion. Or did I miss something?