Substrate utilisation of cultured skeletal muscle cells in patients with CFS

sometexan84

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First off, it must be noted that Frank Comhaire holds the patent for the use of sodium dichloroacetate for the treatment of ME/CFS. So, a bit of a conflict of interest...

And he did the 2018 (not 2016, I'd put the wrong year) study Treating patients suffering from myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) with sodium dichloroacetate: An open-label, proof-of-principle pilot trial.

As well as the other two I'm going to mention.

In his late 2018 follow-up, (Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not?) he mentions possible co-morbidities and auto-immunity as potential reasons for non-responders.

In 2019, his update News and views in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): The role of co-morbidity and novel treatments, he talks about potential treatment w/ the following combo, which I found interesting....

"Metformin, or possibly Momordica charantia extract, which will correct insulin resistance, with Meldonium improving the transportation of glucose into the mitochondria, with sodium dichloroacetate activating pyruvate dehydrogenase, and with nutraceutical support reducing oxidative and inflammatory impairment"

I've been looking into this a bit lately.

Dietrich Klinghardt did a Feb 2020 conference in London, "A Future without ME/CFS", in his slides he mentions Meldonium combined w/ DCA (sodium dichloroacetate).

He says "I combine DCA (20 mg/kg) with Meldonium for rapid and excellent improvement of many ME symptoms"

...and that Meldonium "is a game changer in ME"

That said, @ljimbo423 is correct, it doesn't address the whole problem. The above solutions do not seem to address EBV infected cells, or cells affected by HHV-6, both of which seem to cause a different kind of mito dysfunction. Nor does it address other infections, or auto-immune issues, or the deregulated immune system by EBV (epigenetic miRNA deregulation and DNA methylation dysregulation).
 

raghav

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Thanks @andyguitar I am a type II diabetic and the first drug I tried was metformin. I took a 500 mg tablet and within 30 mins felt like crap. I was completely drained of energy and this feeling lasted for 4 hrs approx. I will look into the research findings when I dont have brain fog. Now my brain is groggy so no reading possible. Thanks anyway.
 

raghav

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@andyguitar Out of the 200+ cell types in the body we dont know which ones any drug will help in terms of mito respiration and which ones it will suppress. Even if one cell type is suppressed it is going to give problems. This is the dilemma mitochondrial researchers face. They have to factor in other things like dosage for each cell type, tissue permeability of drug and many other factors and then decide whether it is worth further research on that drug. So many potential drug candidates get eliminated. This is unfortunate. For example Pioglitazone makes my heart go so weak I was bedridden for 12 hrs from just the first tablet I took. Subsequently I found out it too and many of the oral anti diabetic medications mess with mito complexes 1 to 5 in some combination or other.
 
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I will look into the research findings when I dont have brain fog. Now my brain is groggy so no reading possible. Thanks anyway.
This is what it says on page 6 of the research paper I posted (it was published 5th Nov 2019) "We found that Metformin treatment did not inhibit liver mitochondrial complex 1 activity;rather,treatment with 50mg/kg/day of metaformin significantly increased mitochondrial complex 1 activity"
 
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Thanks @andyguitar I am a type II diabetic and the first drug I tried was metformin. I took a 500 mg tablet and within 30 mins felt like crap. I was completely drained of energy and this feeling lasted for 4 hrs approx. I will look into the research findings when I dont have brain fog. Now my brain is groggy so no reading possible. Thanks anyway.
Metformin is very widely used so if it could help in me/cfs we would know. Instead we see the opposite.
 

Mithriel

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I felt fantastic on metformin. It did not last, but I had a few months where I was able to go out more and do more without payback. Beta blockers on the other hand had me pinned to the bed unable to move yet some people with ME feel they help.

I think a lot comes down to an interaction between the drug, the disease and our individual biology.

Though it may be because I do not have EBV. I was too young to have had it before I took ME and have since tested negative for antibodies a few times.
 

Inara

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You might find page 6 of this research interesting @raghav
@andyguitar, great find! Thanks for sharing. I took it as a starting point for more searches. Seems like most studies on metformin's blockage of mito complex I were performed with so-called supra-pharmaceutical concentrations (much higher concentrations that wouldn't be found in human metformin therapy)? I also understood that it is not 100% proven until now how metformin really acts. (So it cannot be said for sure that it blocks complex 1.) Edit: There seems to be growing evidence that metformin does not block (but promote) mito respiration in therapeutical dosages, e.g.
https://link.springer.com/article/1... major finding in this,0.2 mg/day) or control

https://www.sciencedirect.com/science/article/pii/S1550413115000042

https://eje.bioscientifica.com/view/journals/eje/173/5/683.xml
(small study)

(Edit end)

My other takeaway - more a speculation: Maybe there's an individual metformin concentration that works well, i.e. in some a dosage will be too high (let's say 2x500mg, just a random dosage without sense) so that e.g. complex I blockage or other side effects occur, in others the same dosage will be too low to show an effect, and yet in others it will be good (e.g. for mito function).
And: Might in some individuals low dosages of metformin already help?
 
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Inara

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So, in the paper "Substrate utilisation of cultured skeletal muscle cells in patients with CFS" they used so-called supra-pharmaceutical dosages of metformin: the concentration of the fluid in which the muscle cells were was 2mM (with a therapeutical dosage you would see sth around 19-60 micromolar (at the plasma portal vein of animals) - I would have to re-check for the exact number, I just know that it was in the lowish micromolar range.)

Edit: Here is a review on metformin concentrations:
https://www.sciencedirect.com/science/article/pii/S1550413115000042


One has to account for that. So other publications show that supra-pharmaceutical concentrations of metformin inhibit mitochondrial complex I and increase AMPK production in TD2 cells.

ME/CFS cells seemed to behave like normal/TD2 cells when put into a metformin solution with a 2mM concentration, i.e. they behaved like cells in supra-pharmaceutical metformin concentrations. Re. metformin that is everything I can deduce from the paper. We don't know what would happen if therapeutical concentrations were used. So one cannot conclude that metformin is or is not a possible treatment in ME. One can evaluate if ME muscle cells behave like they should.
 
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pattismith

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Some acquired PDH inhibition are known to occur with:

-Thiamine deficiency
-sepsis (endotoxines)
-cytokines (TNF alpha, IL-1alpha)
-fungal toxines, pesticides
-arsenic


PDH is also inhibited by the products of its activity by negative feedback (acetyl coA, NADH, ATP)
If PDH is inhibited, then lactatemia will rise.

But Lactatemia will rise as well if mitochondria complexes are inhibited.

Metformin is a known trigger for hyperlactatemia @raghav @andyguitar @Murph

Lactatemia should tell us if we have a problem with our muscle PDH or mitochondria.
 

roller

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https://www.nature.com/articles/s41598-020-75406-w

...ability of CFS skeletal muscle cells to utilise glucose as a substrate is diminished compared to healthy control cells...
whatever the cause - trimetazidine may be a (quick) solution?

Trimetazidine inhibits beta-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase, which enhances glucose oxidation.[8] In an ischaemic cell, energy obtained during glucose oxidation requires less oxygen consumption than in the beta-oxidation process. Potentiation of glucose oxidation optimizes cellular energy processes, thereby maintaining proper energy metabolism during ischaemia. By preserving energy metabolism in cells exposed to hypoxia or ischaemia, trimetazidine prevents a decrease in intracellular ATP levels, thereby ensuring the proper functioning of ionic pumps and transmembrane sodium-potassium flow whilst maintaining cellular homeostasi
the med blocks something, so that glucose oxidation is increased.
the advantage of glucose oxidation is, that it needs less oxygene.
so, making the max energy of the reduced "substrate" that is there...
 

Pyrrhus

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If PDH is inhibited, then lactatemia will rise.

But Lactatemia will rise as well if mitochondria complexes are inhibited
Lactatemia should tell us if we have a problem with our muscle PDH or mitochondria.
And yet, there does not appear to be any chronic lactic acidosis in ME patients.

To me, this means that:
  • There is no major PDH or mitochondrial inhibition in every cell of the body. (Although there may be minor inhibition, or major inhibition in just a few cells.)
 

ljimbo423

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And yet, there does not appear to be any chronic lactic acidosis in ME patients.

To me, this means that:
  • There is no major PDH or mitochondrial inhibition in every cell of the body. (Although there may be minor inhibition, or major inhibition in just a few cells.)
Didn't Fluge and Mella find an increase in lactate when cells were activated but not while at rest? But then I don't remember any studies showing higher levels of lactic acid after exertion, at least most didn't, iirc.

Very confusing stuff. I often get major burning in my thighs after I walk up the 2 flights of stairs to my apartment. Although it fades very fast, usually within seconds. Wouldn't that suggest lactic acid buildup?

So many contradictions!
 

Pyrrhus

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Didn't Fluge and Mella find an increase in lactate when cells were activated but not while at rest?
Good question. That was an in vitro study concerning only specific types of cells in a specific environment.

It is quite another thing to measure significant, constant accumulation of lactic acid in a human being, which is what lactic acidosis (AKA lactatemia) represents. Such a finding is likely to represent a significant mitochondrial defect in most cells of the body.

Very confusing stuff. I often get major burning in my thighs after I walk up the 2 flights of stairs to my apartment. Although it fades very fast, usually within seconds. Wouldn't that suggest lactic acid buildup?
Muscle burning upon exertion is likely due to acid buildup in the muscles, but not lactic acid as is commonly thought. It is more likely that the acid buildup is due to hydrogen ions released by overstressed mitochondria. There may also be a significant contribution from extracellular ATP released by damaged muscle cells.

Hope this helps.
 

pattismith

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Good question. That was an in vitro study concerning only specific types of cells in a specific environment.

It is quite another thing to measure significant, constant accumulation of lactic acid in a human being, which is what lactic acidosis (AKA lactatemia) represents. Such a finding is likely to represent a significant mitochondrial defect in most cells of the body.



Muscle burning upon exertion is likely due to acid buildup in the muscles, but not lactic acid as is commonly thought. It is more likely that the acid buildup is due to hydrogen ions released by overstressed mitochondria. There may also be a significant contribution from extracellular ATP released by damaged muscle cells.

Hope this helps.
thank you to clear up this common false idea.

Another false idea is hyperlactatemia = lactic acidosis. The two things are separate and lactic acidosis usually occur only with severe hyperlactatemia.

I do have chronic mild hyperlactatemia but I have chronic metabolic alkalosis with high blood bicarbonates.