Cellular Nitrogen and Energy Metabolism in ME/CFS, 2025, Armstrong et al

[John Mac]

STUDY HYPOTHESIS AND DESCRIPTION​

ME/CFS, a condition diagnosed by symptoms like extreme tiredness after exertion (known as post-exertional malaise), ongoing fatigue, and mental cloudiness or “brain fog,” may stem from a basic problem with how energy is made and used in the body.

We hypothesize that in ME/CFS, nitrogen compounds might be mishandled in immune cells because the mitochondria (energy factories of the cell) are using amino acids (building blocks of proteins) to make energy. To explore this idea, scientists will grow immune cells from blood samples and feed them special types of sugar, fats, and amino acids that can be tracked. This will allow them to see how the metabolism of these cells in ME/CFS patients is different from people without the condition.

This study uses innovative methods to deepen our understanding of ME/CFS and possibly uncover the root causes of its symptoms.

Objectives

1. Observe how amino acids are used by cells from ME/CFS patients compared to healthy controls.
2. Observe how sugars are used by cells from ME/CFS patients compared to healthy controls.
3. Observe how fats are used by cells from ME/CFS patients compared to healthy controls.
4. Observe the usage rate of sugars, fats, and amino acids in ME/CFS and controls.
5. Test the Nitrogen Hypothesis.

Nitrogen Hypothesis - Open Medicine Foundation

This project aims to test the nitrogen hypothesis, which is that damaging, nitrogen-containing by-products of energy metabolism accumulate more readily in the cells of ME/CFS patients.

ns1.omf.ngo

 

[Amw66]

not going to make headway if PEM is described as
"extreme tiredness after exertion " - if only

eta - it would be interesting to know if there is a metabolic male / female difference in substrate preferencce

 

[Utsikt]

Is there any mention of what the hypothesise that drives this change in metabolism? Or why it might persist outside the very local environment in the body?

 

[wigglethemouse]

Some more info from the web page.

Updates and Potential​

• Lymphoblast experiments are completed.
• We have expanded to look at cells with known genetic anomalies.
• Both the lymphoblast samples and cells with mutations have been prepared and are currently producing metabolite data for analysis.
• Expecting both projects to be completed in 2025.
• There will be 3 publications for this work.

 

[MelbME]

This work has had delays on my side trying to work out some red tape.
It is expected to be completed in 2026.
The pilot work was done.

 

[MelbME]

Is there any mention of what the hypothesise that drives this change in metabolism? Or why it might persist outside the very local environment in the body?

The basis of this hypothesis is that the increased reliance on amino acids for ATP production has consequences that could explain many of the symptoms and that the increased reliance on amino acids could be driven by many factors that may be different between people.

 

[Utsikt]

and that the increased reliance on amino acids could be driven by many factors that may be different between people.

Are those factors expected to persist for the cells you’re testing in the settings you’re going to test for them?

 

[MelbME]

Are those factors expected to persist for the cells you’re testing in the settings you’re going to test for them?

That would be the expectation. The increased use of amino acids is meant to happen in a stressed state, it's more Carbon efficient than glucose/fat (which is why we use it during stress, females go to this well faster) but it produce more negative byproducts and removes amino acids from the other roles they play like neurotransmission, nucleotide synthesis, digestive enzyme production, etc.

In addition, the consideration is built around the idea that there are an array of in-born errors of metabolism in the stress metabolism pathway that aren't a problem until someone experiences a long-term stressor like a complicated acute infection event that typically takes longer to recover (weeks/months), that longer term use of the stress pathways uncovers previously existing flaws in the genetics that were never a problem prior and creates a self-perpetuating condition.

 

[mariovitali]

In addition, the consideration is built around the idea that there are an array of in-born errors of metabolism in the stress metabolism pathway that aren't a problem until someone experiences a long-term stressor like a complicated acute infection event that typically takes longer to recover (weeks/months), that longer term use of the stress pathways uncovers previously existing flaws in the genetics that were never a problem prior and creates a self-perpetuating condition.

I second that @MelbME . I recently came across an ME patient with Fibromyalgia. She was found to have a problem with gene ALDH18A1, type SPG9A. She is now on a specific diet (not too much protein) and supplements with L-Citrulline.

She is able to do more and now does not experience any spasms. I could share her details if you wish but she is not an English speaker.

My understanding is that below is a number of conditions you will be looking at ?

 

[Utsikt]

In addition, the consideration is built around the idea that there are an array of in-born errors of metabolism in the stress metabolism pathway that aren't a problem until someone experiences a long-term stressor like a complicated acute infection event that typically takes longer to recover (weeks/months), that longer term use of the stress pathways uncovers previously existing flaws in the genetics that were never a problem prior and creates a self-perpetuating condition.

Wouldn’t you expect a much stronger genetic signal then, compared to what was found in DecodeME?

 

[salin]

I find this very interesting, especially in connection with the study by Fluege/Mella 2016, which showed a specific reduction in amino acids that drive oxidative metabolism via the TCA cycle:

JCI Insight - Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome

The study was the reason why I take amino acid pills every day

 

[Amw66]

Wouldn’t you expect a much stronger genetic signal then, compared to what was found in DecodeME?

Perhaps more epigenetics at play

 

[MelbME]

I second that @MelbME . I recently came across an ME patient with Fibromyalgia. She was found to have a problem with gene ALDH18A1, type SPG9A. She is now on a specific diet (not too much protein) and supplements with L-Citrulline.

She is able to do more and now does not experience any spasms. I could share her details if you wish but she is not an English speaker.

My understanding is that below is a number of conditions you will be looking at ?

View attachment 29373

Yeah I'd say most of the research has been around mitochondrial diseases because they have quite a strong field presence for research and funding. There may be many more beyond these that may be infection-onset.

Check out POLG1 infection onset.

 

[MelbME]

Wouldn’t you expect a much stronger genetic signal then, compared to what was found in DecodeME?

No I wouldn't, this hypotheses suggests there might be hundreds of genetic variations in an ME cohort that lead to a similar phenotype. So what Ponting and co landed on is plausible, a very heterogeneous disease that is compounded by the fact that healthy controls may have the same genetic issues but never had the initiating complicated infection.

Maybe the hits they found in DECODE are the place to start.

 

[Utsikt]

No I wouldn't, this hypotheses suggests there might be hundreds of genetic variations in an ME cohort that lead to a similar phenotype.

Would you need a specific genetic trait to get ME/CFS, or are these just possible pathways to get into the ME/CFS equilibrium that certain genes make more likely to occur by chance throughout life?