A map of metabolic phenotypes in patients with ME/CFS (Hoel et al., 2021)

Pyrrhus

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A map of metabolic phenotypes in patients with ME/CFS (Hoel et al., 2021)
https://insight.jci.org/articles/view/149217

A new metabolomics paper from the Norwegian team of Øystein Fluge and Olav Mella.

In addition to providing additional support for the finding that ME cells have impaired energy usage and resort to alternative sources of cellular energy, the paper describes three subsets of patients. These three subsets are defined based upon their metabolic characteristics.

Graphical abstract:

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Written abstract:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established.

We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls.

Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses.

In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.
 

junkcrap50

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Brief summary of metabolic differences of the 3 different subsets: M1, M2, M3:
In conclusion, the ME-M1 metabotype appears to reflect a lipolytic state with increased utilization of both fatty acids and amino acids as energy substrates, possibly due to ineffective carbohydrate catabolism.
...
In conclusion, the ME-M2 metabotype shows indications of disrupted control of lipid metabolism, possibly involving compromised activity of mitochondrial oxidation pathways and consequent effects on lipid trafficking and storage.
...
The ME-M3 metabotype subset (n = 13) had relatively few features that were significantly different from the HC group....The ME-M3 subset was found to reflect an intermediate state between the 2 other ME/CFS metabotypes, albeit with some more similarity with the ME-M2 phenotype.
 

wabi-sabi

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I haven't been able to sort out the metabolic subsets yet. But the underlying problem they point to is the tissues not getting enough oxygen. Mitochondria need oxygen to produce ATP, so not enough oxygen means not enough energy even if the mitos themselves are working fine.

They also mention blood vessel (endothelial cell) dysfunction or an autoimmune problem that damages blood vessel regulation as two possible reasons why tissues are not getting enough O2.

I think the metabolic subsets are different ways the body is trying to solve the not enough oxygen problem, but I will reread it more later to see what I can figure.

Important to note-breathing more oxygen probably won't solve the problem. The issue is that oxygen isn't getting from the blood into the tissues because the blood vessels themselves aren't working.
 
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Mitochondria need oxygen to produce ATP
True. And my ATP is always (tested three times) about 99%. Above average! I've seen this in many other patients too.

I have another theory: utilization. There is sufficient ATP but the body doesn't use it, for a reason I haven't figured out yet.

What mitochondria does is that if one complex is impaired it balances it with another complex. So for example respiration of complex I is impaired then complex V is “driving hot”.

There might be another mechanism involved in hypoxia than impaired ATP production?!
 

SWAlexander

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Studies have shown a tendency to hypercoagulation, or thicker blood, that has trouble getting into capillaries, starving tissues of adequate oxygen.
Yes, it is called "oxidative stress", and can damage cells, proteins, and DNA,
A precursor could be, "cystic fibrosis", or "sickle cell anemia" (inherited in an autosomal recessive pattern), or "spherocytosis" (the production of red blood cells (erythrocytes) ). In any case and in my personel experience, it can lead to thrombosis. A D-Dimer test (two blood drops) could deliver in 10 min results for thrombosis.
 

wabi-sabi

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Here's what I can gather about the subtypes:

M1:these people seem to be burning mostly fat for energy, with some protein. Probably unable to use glucose as normal. The good news is that their blood sugar levels are normal.

M2: A bit more confusing. These people also have normal blood sugars, but something is wonky about fat metabolism.

M3: Theses people are most like the healthy controls and are partway between M1 and M2. There were fewest of this type in the study, so this may or may not be an accurate picture at this time.
 

SWAlexander

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Here's what I can gather about the subtypes:

M1:these people seem to be burning mostly fat for energy, with some protein. Probably unable to use glucose as normal. The good news is that their blood sugar levels are normal.

M2: A bit more confusing. These people also have normal blood sugars, but something is wonky about fat metabolism.

M3: Theses people are most like the healthy controls and are partway between M1 and M2. There were fewest of this type in the study, so this may or may not be an accurate picture at this time.
hypercoagulability syndrome " Hypercoagulability can be defined as the tendency to have thrombosis as a result of certain inherited and/or acquired molecular defects. Clinical manifestations of hypercoagulability can be devastating and even lethal." https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/649434
There are many more issues to be considered and many white papers available.
 

wabi-sabi

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And my ATP is always (tested three times) about 99%. Above average!
Wow! How did you get this tested?

There might be another mechanism involved in hypoxia than impaired ATP production?!
This paper is looking at metabolytes to try to get insights into how our metabolism is broken. While impaired ATP production might have an impact on hypoxia (I'm just not able to look into that right now), in this paper they are looking at it the other way around-how lack of O2 will affect the tissues. We can't switch that around in the same way we can't read the syllogism backward and get a logical result, at least in the context of this data.

The metabolic subgroups they identify are understood as different ways the body is trying to compensate for the underlying problem-lack of oxygen. Notably, they didn't measure ATP levels or ATP production directly. They measured metabolytes of fat, protein, and carbs to try to see which the body is using and how. The goal here, is if we know how the metabolism is broken, we may be able to fix it directly, or if we understand how the body is trying to compensate we may be able to support the body in doing so.
 

wabi-sabi

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That was the most uplifting read for me today, thanks!
So glad you are feeling hopeful!

The other implication I take from this article is to help my body deliver oxygen efficiently by taking good care of my blood vessels with a healthy diet- don't gum them up with cholesterol and what not- and to keep up my hydration with plenty of water and salt.

Also, reduce oxygen demand on my body with good pacing. Everything always come back to pacing, doesn't it?
 

SWAlexander

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So glad you are feeling hopeful!

The other implication I take from this article is to help my body deliver oxygen efficiently by taking good care of my blood vessels with a healthy diet- don't gum them up with cholesterol and what not- and to keep up my hydration with plenty of water and salt.

Also, reduce oxygen demand on my body with good pacing. Everything always come back to pacing, doesn't it?
This was my problem, I was badly hydrated. I don´t like water but I learn it fast. Few of these papers have thought me more than a doctor.