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

Thanks for this info @Kitty.

It sounds like I’ve been taking them differently to you.

I started out on a daily dose as per the bottle, which was 2 tablets. Weirdly I felt too wired and I reduced the dosage to half. I was taking this as well as a vegan protein shake and I really felt it made me feel more ‘normal’ and able to get through the daily tasks without too much trouble.

In fact I was feeling so ‘normal’ I went to a wedding, drank a bucket full of rum punch and danced all night. Then I went home, vomited, had a dreadful hangover and I haven’t felt alright since! That was 5 weeks ago.

I think I’m just in a bad crash but I haven’t actually had one for a long time.

All the best and thanks again

 

There were a few threads re BCAAs at the other place.
Many used them for "PEM busting ability"

 

https://twitter.com/user/status/1154286233025175552



thread covering the basics

 

Lordy, I don't even understand the basics presented in that thread. I'm glad they took the time to do this, though.

What does this bit mean? In the 3rd tweet in the thread:

Is this referring to the patient's activity (i.e. pacing), or is it referring to activity in bodily systems that we don't really have any control over?

 

It is attempting to stay below the anaerobic threshold as advised by Workwell by keeping any exertion short in duration.

 

Thank you!

 

I'd like to reopen the discussion on this study because it shows more significance than usual CFS studies thanks to their PEM differentiation.

As a first note, there might be a measurement bias regarding the measured purine metabolites in the urine. Here are two quotes from their original study that has been published in 2015 (10.1007/s11306-015-0816-5). The new study used the same collection methods.

They should have switched to 24h urine since this is the only other way of normalization that allows a total quantification with blood levels. I don't think that hyperfiltration is untypical for CFS, so this is a general issue when CFS studies try to analyze single urine samples. The only value of the result is the concentration relative to each other.

 

This is an interesting paper and thread!

This seems to have been a retrospective analysis of data they had gathered over previous years.

This is the talk Neil McGregor gave in 2019 at the Australian ME/CFS Conference. Worth listening to if you have not already. The paper was published shortly after.
https://mecfsconference.org.au/videos/neil-mcgregor/

 

@mat You might also like to revisit Lipkins 2018 metabolite paper.
Thread : https://www.s4me.info/threads/insig...tabolomics-2018-lipkin-et-al.4873/#post-87496

In that paper Lipkin and co found increased mannitol in plasma. In the paper of this thread McGregor found increased mannitol in urine. Perhaps there might be other correlations you find......

 

I mistakenly assumed that the second study referred to an extended sample set and that the first one was on data from 2010 only by how they mentioned "second urine sample" and "first specimens".

I'll eventually read these papers and come back with some more information and references. Especially the comments here drew my attention and I'd like to elaborate on some of them. At least some of the open questions I could explain by data that has recently been published and would fit into my COMT hypothesis. Where I'm still not sure how the altered lipid metabolism fits into this.

For mannitol in particular, I can think of three possibilities at the moment. It interacts with the fructose metabolism. One possibility would hence by an aldolase defect, which also affects glycolysis, ATP recycling, and phosphorylation severely, as well as it fits into the emerging Diabetes 3 hypothesis, which basically classifies diseases of glycolysis-dependant neuropathy (in my words). If this was the case, and the aldolase defect was hereditary, the DecodeME study could identify it. If this was the case, it's probably not a critical hereditary disease like HFI but rather like hereditary lactose intolerance - a silent condition that requires certain triggers like an infection and if untreated will still become more and more severe. Unknown compound heterozygote mutations are difficult to filter and identify, though. It could be overlooked in a study because not every patient will have the same mutations.

A second explanation would be that it is the overburdening of glycolysis that also overburdens the fructose metabolism indirectly by their shared metabolic pathways. I have to look into this one first to confirm the possibility.

The third explanation fits into my COMT/methylation hypothesis where NADPH-cycle-dysbalance is induced in multiple ways. Previous research has already linked this with xanthine oxidase as well, which was one point previously mentioned here (10.1096/fasebj.26.1_supplement.678.10). But I still have to look into this one. Specific immunological signals can affect xanthine oxidase to create ROS, which normally is a physiological reaction (10.1155/2016/3527579). Overall, the sample size of NADs in CFS patients is quite limited unlike the data around the methionine metabolism.

 

The following study will be measuring HDAC in PEM

Epigenetics of Post-exertional Malaise in Patients With ME/CFS: Oct 2020
https://www.s4me.info/threads/epige...t-yet-open-for-recruitment.15047/#post-258995

 

And this is McGregors Hypothesis slide showing "Glycolytic Activity determines histone deacetylation (HDAC1, HDAC2)"



Source (~28-32mins) : https://mecfsconference.org.au/videos/neil-mcgregor/