The itaconate shunt hypothesis

Very good to hear there are more studies in the pipeline.

Am I right in thinking that other metabolomics studies (Lipkin, Hansen, maybe Unutmaz, Naviaux) didn't find increased use of glutamine/ate?
Though I note this:

 

Is this the sort of hypothesis that the DecodeME GWAS study could rule in or out?

 

I don't get the impression that the hypothesis is well enough formulated as yet to be testable by anything much. If it was I suspect it would be most easily testable by simple MRI spectroscopy of tissues before and after exercise. If the problem is really a shortage of energy supply from a diverted metabolic pathway then different levels of metabolites would show up in a very predictable way.

DecodeME would only be relevant if the hypothesis stated what possible genetic predisposing factors might occur such that an immune response might lead to an unusual diversion.

 

Would this be likely to hold, no matter what type of metabolic diversion were in place?

(I suspect life's not that simple, but it sounds so much like what we need that I thought I'd wonder about it aloud anyway...)

 

I cannot answer that for sure. However, in the 1980s I worked in the next lab to people who did MR spectroscopy and they showed plots with peaks for pretty much any metabolite you might be interested in as far as I remember.

If cells are really running out of ATP or pyruvate or whatever it ought to be possible to show some shifts in at least some of these peaks. And of course if you have different proportional shifts in a range of metabolites you should be able to work out roughly where the blockage is.

I suspect the reason why it is not used more in ME is that it has been tried and nothing found. Some recent stuff looked at lactate in brain ventricles, so you can do lactate. Even that did not seem to be followed up.

 

I've been going swimming almost every day lately and there is a trend of finding it increasingly difficult over time. I keep having to reduce the time and intensity and have to spend more time horizontally during the rest of the day. This is similar to other periods in my life so it's probably not due to confounders like say the heat wave. There has to be some way to measure what is changing in my body that is causing this. My heart rate doesn't seem to have increased, if anything it's slightly lower. This seems consistent with some degree of cardiovascular training occurring but for whatever reason I'm getting weaker.

PS: regular swimming was an attempt to see if I could recreate my substantial improvement that occurred last summer but this year it's just not happening it seems.

 

would this be a typical "wasting disease"?

my blood-creatinine values (these values paralyzed ppl usually have):
2009 = 0.68 mg/dL (Range 0.60 - 1.10)
2022 = 0.64 mg/dL (Range 0.67-1.17) DOWN!!

I have been on a (at least once) weekly extraordinary strengeous exercise since october 2021.
The very minimum is 9 hours in a row with heavy equipment.
i think i got (slooooowlly...) some "muscles" which are still invisible.

could this "wasting theory" explain, that the additional exercise-creatinine is used for more energy-production?
i do have strikingly more energy.

but it took months und it would be of course still from the "wrong cycle".

and the liver values are still as bad as they were.
there is potassium above the range (Hyperkalemia), which indicates cardiac issues, ie. not sufficient muscle to keep heart rate up

 

Thank you, that's interesting. I suppose it partly comes down to money—it doesn't sound like a particularly cheap technique, and it might be more difficult than it looks at first sight to get the timing right.

No, but perhaps if you could show something odd was going on, it might provide enough of an evidence base to get more research funded. And you'd be able to discuss it with people who're finding oddnesses in other conditions, which might help you direct your investigation. It's the sort of thing that needs to happen to move us forward.

 

Well, when I was shown these peaks each one was clearly identified as lactate or glutamate or pyruvate or whatever. There was lots of them. As far as I know each molecule has a particular signature that is known beforehand.

 

I doubt it has much to do with money. These are machines that have been available since maybe the 1960s, at least since 1980. They do not require the complicated set up of MR imaging although they need a powerful magnet. My guess would be that once you have a machine studies cost rather little.It may be that to get results relating to effects of exercise you need to make use of glucose labelled with a carbon isotope to follow the metabolism through. I forget. But I don't think cost is an issue.

I just think that it must be that when people with ME were studied nothing showed up - which makes it hard to sustain any theory that puts symptoms down to failure of metabolic pathways I think.

 

A study by Morten and his Polish collaborators found a decrease in central energy metabolism in patients with ME/CFS when comparing pre and post exercise program timepoints. There was no control group so this was not published.

This study of exercise for long covid also seems to be reporting something similar: "a decrease of oxidative metabolism index of 6.89 standard units."

https://www.s4me.info/threads/can-a...-long-covid-outcomes-2022-lobanov-et-al.28618

 

I was talking about magnetic resonance spectroscopy rather than mass spectroscopy.

 

Sure, but if the claim is that symptoms are due to failure of major respiratory pathways preventing energy usage then surely some easily identified molecules would show shifts. You might not be able to track exactly why but if there isn't even a shift in the some common pathway elements it is hard to sustain a theory based on energy blockade. I am not familiar with the detail but I am sceptical of fancy 'trap' theories that do not seem to take into account the need to show something pretty simple at the end of the day - not enough of some common energy pathway product.

 

Yes, but if you do NMR on a whole leg you have plenty of metabolite! You can do NMR on arms and legs without disturbing the patient at all - other than asking them to put a leg in a ring magnet.

 

For MR spectroscopy in clinical imaging, we typically target a voxel. For metabolic diseases this is usually standardised to the left lentiform nucleus, but looks like right thalamus in the example below. Lactate, NAA, creatine and choline are the typical metabolites of interest in the brain. In the normal example below there's no lactate peak (at 1.3 ppm).

Glutamine/glutamate and GABA are both 2.2-2.4 ppm so may not be discriminated.

Usual peaks

• lipids: 1.3 ppm
• lactate: 1.33 ppm
• alanine: 1.48 ppm
• N-acetylaspartate (NAA): 2.0 ppm
• glutamine/glutamate: 2.2-2.4 ppm
• GABA: 2.2-2.4 ppm
• 2-hydroxyglutarate: 2.25 ppm 6
• citrate: resonates 2.6 ppm
• creatine: 3.0 ppm
• choline: 3.2 ppm
• myo-inositol: 3.5 ppm
• water: 4.7 ppm

Less common peaks

• propylene glycol: 1.14 ppm
• ethanol: 1.16 ppm
• acetate: 1.9 ppm
• acetone: 2.22 ppm
• acetoacetate: 2.29 ppm
• succinate: 2.4 ppm
• methylsulfonylmethane: 3.15 ppm
• scyllo-inositol: 3.36 ppm
• taurine: 3.4 ppm
• glucose: 3.43 ppm and 3.8 ppm
• mannitol: 3.78 ppm
• creatine (second peak): 3.95 ppm 10
• lactate quartet: 4.11 ppm