United Kingdom: Learn about ME - webinar for GPs

I'd like to ask something about research into findings like this.

Given that real-life PEM is almost never triggered by pedalling a bike and breathing into a tube, are there practical, scientifically respectable ways of measuring pre- and post-effort effects without all the resources needed for the two-day CPET? And that enables the inclusion of people who can't or daren't risk pushing to Vo2 max, which might make recruitment easier?

 

Good point about group 3. Group 2 generates acetyl CoA but group 3 don't so you would expect levels of oxaloacetate/ malate to increase and citrate levels to be low.

You would still get a lot of the electron transport chain substrates generated from the krebs cycle post alpha ketoglutarate though.

Oxaloacetate is also the alpha-keto acid version of aspartate, which means amino transferase enzymes could regenerate alpha ketoglutarate (at the cost of another molecule of glutamate). I'm not saying that's what is happening but is at least some conjecture.

 

So true! I can't imagine what would happen to me if I did a CPET. Must be dangerous for so many people. Maybe something like longitudinal sampling combined with an activity tracker? Collecting regular urine samples would be easy at least.

 

Yep.

But also, people with experience of living with ME/CFS have a very good idea of what exertion is too much—what will leave them with the post-exertion effects that people want to investigate. Guess I'm wondering whether it's possible to use that knowledge to design short term investigations of the kind that currently use the 2-day CPET, to make them more accessible to participants and less expensive for investigators.

 

Had a quick look but it also talks about multi-system dysfunction, POTS, JHS, hEDS, testing NK cytotoxicity, recommends GET and CBT and suggests trying older antihistamines for sleep. It includes some interesting observations but not sure if it is that much better than other educational material.

https://pubmed.ncbi.nlm.nih.gov/27436349/

 

I agree that there is stuff that needs trimming out but as a guide to understanding the diagnostic category and how to make a diagnosis it has a lot of good material I think. I wouldn't suggest it was used now in isolation. Maybe there needs to be an S4ME Learn About ME/CFS package!

In comparison, Kerr's rambling is irresponsible and in many places just disinformation.

 

Wow wouldnt that be amazing

 

Wouldn't that be a long discussion!

 

I haven't read up on these, but with amino acid cycles -
Is there a male / female difference ?
There's been a couple of papers suggesting that females tend to use protein as energy source more easily, and males use fats .
Would this make a difference?

 

Oh my,

 

The amino acid results in Tronstadt's 2016 paper seem to be pretty much a female only effect.

Interesting! I don't know unfortunately, maybe it'll be good to read up on that.

 

Yes, I thought that was interesting. There seems to be a clear difference between men and women and that made me think that this could not be just a chance finding (unlikely with the p values) or more likely a processing artefact. It looks real.

However it could be a real effect of some dietary difference I guess and women may modify their diets in the face of il health differently from men.

It would interesting to know what was found if you know where they might be found. Both men and women must presumably eventually use all the protein and fat they eat as an energy source, if their weight is steady, but maybe they use different pathways.

 

There have been a fair few " omics" papers . The couple I can recall having this suggestion were the Fluge & Mella one ( Metabolic switch may bring on chronic fatigue syndrome | New Scientist) and Hanson's ( 2016/ 2018).
Hanson's are female only, so could perhaps be useful in eliciting differences.
I'll have a delve over the next few days as there was a plethora of different " omics" research 2014 onwards with Naviaux, Lipkin, McGregor & Armstrong as well.

Sadly Fukada is often used for selection.
I'll post back some references once I've had a delve

 

The muscle metabolomics done by Rob Wust's team in long covid would fit fairly well with that:


If glutamate and alpha-ketoglutarate are feeding the TCA then their levels will be low, it'll travel around the remaining 3/4s of the TCA cycle (where most of the energy generating steps are), but get stuck at oxaloacetate due to the lack of acetyl-CoA, which would lead to a lack of citric acid just like they see.

The more conjecturey part: Oxaloacetate could regenerate an alphaketoglutarate by using another glutamate, and producing an aspartate in the process - which could hypothetically diffuse into the blood and make it's way to the liver for disposal or be used for other things. Wust report a (not significant) increase in aspartate in the blood (but not muscle) after exertion.

Wust also report a trend decrease in muscle amino acids (but not blood) following exertion.

 

Tronstadt's group do another metabolomics study in a 2021 paper, and don't really replicate their 2016 result in their whole ME cohort but do argue that they see some branched chain amino acid derivates indicative of amino acid's being used for energy.

They cluster the ME patients into three groups M1,M2,M3 and their M1 group does reflect the 2016 amino acid results pretty well.

 

What I am unsure about is why amino acid levels that feed into TCA should be low if PD is blocked. Doesn't this require a compensatory up regulation of the steps that feed the AA's into the cycle? It is fair enough to suggest that an illness is mediated by an abnormal block in PD but is there a good reason to think that the system is designed to compensate for such a block? It might be, but do we have data from selective feeding studies to show that when one substrate is down others get metabolised more in this way? Might we not expect a general compensatory mechanism that increased usage of type 1 AA's as well?

 

I'm not sure, but isn't the question of regulation of amino acid use also linked to the question of why pyruvate dehydrogenase is inhibited in the first place. The whole regulatory situation is a mystery isn't it?

In general it seems perfectly plausible that the cell would compensate for a lack of other energy substrates by using amino acids. That's what happens in a starved metabolic state. Sorry i might be missing your point.

Nevertheless heres some speculation. It's interesting that they see higher transcript levels of the transcription factor PPAR delta. This family of transcription factors appear (from a brief google) to regulate glucose uptake and fatty acid beta oxidation. If memory serves the group 2 amino acids use the beta oxidation machinery to produce acetyl coA so that would be a plausible explanation I think.

Glutamate I think would use probably either alanine or aspartate aminotransferase to convert to alpha ketoglutarate. So I suppose you'd either expect to see higher transcripts of these enzymes or I wonder if it could be possible it's just driven thermodynamically. The lack of the enzymatic product alphaketoglutarate driving the reaction forward entropically.

I don't know about selective feeding studies. You could probably just do this in cell culture though couldn't you? without the influence of the liver converting amino acids to glucose and so on.

 

You may be right but I think their hypothesis needs to be thought through carefully and as the paper is written there seem to be quite a lot of assumptions about what one would expect that I am not sure are necessarily as self evident as they might suggest.

 

Granted the language is…

However on a practical level I could actually do with some of this help.

I have only ever experienced symptom relief from experimental interventions. This is not surprising since non-experimental interventions don’t exist.


I don’t think it’s fair that patients can only get any pharmacological or physical interventions if they can afford to see someone privately and find someone willing to experiment.

Still my argument would be that it’s ethically okay to provide medications off label, physical stuff like compression garments, on account of patients symptoms if you are direct that is what you’re doing.

Where as it is not okay to go about presenting your own or others speculations, and budding hypotheses as backed by solid scientific research. Because they’re not. So you’re either lacking comprehension on the matter and have yourself become confused or you’re lying. To patients and other doctors.

Since all medication and interventions on any human body carries some risks of harm, along side the fact that sick people are and will be so desperate to ‘do something anything’ and to be proactive, while sadly being too sick to be proactive in other ways than attending a doctors surgery, and that when a patient does attend their cognitive function is likely impaired making decision making very difficult, also patients will likely at least to begin with have high trust in their doctors, it really is beyond manipulation to over sell your offer like this training does and on into exploitation.


Edit: the wording wasn’t quite as intended.

 

For me the shakiest part of their argument is suggesting that PDH inhibition is the cause and that the increased respiratory capacity they see in their seahorse data (the part Audrey and I are attempting to replicate) represents an adaptation. It's not clear that the seahorse data represents the same biology as what they are inferring from the metabolomics, but even if it does that argument feels tenuous to me.

Ultimately they don't work out anything mechanistically in the paper, it's simply observations of differences in levels of molecules - it's hypothesis generating data as the authors say.

I've been wondering whether our blood factor - if it exists - could be lipid based, maybe in multiple forms (VLDL/ TAG/ FA acid carrier proteins). Fat changes are the most consistent metabolomic finding and again seen in beentjes/ponting biomarkers paper. Proteins such as FABP and PPARdelta sense broad classes of lipids and signal to increase fatty acid beta oxidation and inhibit PDH.