• Phoenix Rising needs funds to operate: please consider donating to support PR

Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS

Wishful

Senior Member
Messages
2,124
Likes
3,608
I was browsing old threads, followed some 'what does that do?' questions, and found that sphingolipids are produced on palmitoyl-CoA, which is part of the carnitine shuttle system. I've wondered why my symptoms get worse after consuming animal fats, unless I take an adequate amount of carnitine with them. While it's hardly proof of a link, I think my observations support the involvement of sphingolipids, and thus the PDH function.

I also find a benefit from T2, but if it's from increasing fat burning, the effect is by triggering some other changes, because T2 only helps me with one dose every 21 days. It seems to trigger some change with a fairly precise and consistent 21 day lifespan.

Just thought it was interesting enough to mention.
 
Messages
124
Likes
281
Some amino acids break down into keto acids. Some will enter the cycle above pyruvate and therefore still 'pass through' Acetyl CoA. Others enter the cycle at oxaloacetate, further on in the cycle; and others enter at alpha-ketoglutarate, even further down.

I wouldn't say that Acetyl CoA isn't involved because they're all part of a cycle, which means every part of the process 'leans' on every other part. But there are places for amino acids to enter the cycle that are after (or depending on your point of view, before) Acetyl CoA.



I find that to be a weird statement in general. Note there's nothing about proteins, our other macronutrient. Proteins would not be a macronutrient if they didn't play a part in cellular respiration someplace. ;)

This is from an explanation I made regarding (I think) C Armstrong's paper before last. You can see that amino acids enter the cycle at various points, though:

View attachment 19075



"Not used up" BUT "converted from one form into another".

Since Acetyl CoA is a molecule, the only way you can use it up is to convert it from one form to another. Since matter is never created or destroyed, this is the only way in which a molecule can be used up.



Arguably the case, PROVIDED that all of the enzymes that help catalyze those reactions are present and accounted for, and not blocked by inhibitors; which F & M say is not the case.



Pyruvate to oxaloacetate requires that there first be pyruvate, which would be lower without Acetyl CoA.

Ditto for pyruvate to alpha-ketoglutarate.

You can feed amino acids straight to alpha-ketoglutarate in the cycle. But since, in a healthy person, you'd also be getting additional alpha-ketoglutarate as the result of glucose metabolism, without proper glucose metabolism (and without increased amino acid uptake) you'd have lower alpha-ketoglutarate.

As you say, if you increase alpha-ketoglutarate you increase everything in the CAC (without errors in enzymes) -- but you have to have some way of increasing it! Women, at least, are feeding it allll their protein, according to F & M.

Note: all of this is upper-level-high-school knowledge and may be incomplete. Take with a grain of salt!

-J
nice explanation and insight @Hip !
 
Messages
124
Likes
281
So side effects of treating ME thru boosting Akt/mTOR might be accelerated aging and an increased chance of cancer.
The PI3K pathway, sometimes referred to as the PI3K/Akt/mTOR pathway, is recognized as being the most 'widely mutated pathway' in cancer. That is, more cancer-causing mutations (also known as oncogenic mutations) have been identified in components of the PI3K pathway (which includes Akt and mTOR) than any other known signalling pathway inside cells. Drugs that boost the long-term activity of PI3K, Akt or mTOR activity would be expected to increase the likelihood of cancer. Thus, it would be potentially very dangerous to try and pharmacologically boost Akt/mTOR as it might increase the chance of cancer as suggested by @adreno.

It is for this reason that pharamceutical companies are very interested in developing drugs that inhibit PI3K, Akt and mTOR because of their potential to block the growth of cancers. To date, there are many drugs that inhibit the activity of PI3K, Akt and/or mTOR that have been examined in cancer clinical trial. Some have been approved for the treatment of specific cancers (e.g. I have discussed the use of mTOR inhibitors in the treatment of cancer and CFS elsewhere).
\cheers
Rodger
 
Messages
124
Likes
281
I think my mom & I had symptoms of undiagnosed Hashis (and myself of antibody subclass deficiency) for years, but we could exercise fine and had no cognitive issues. The downward spiral really kicked off after a weird 'flu' -ascending numbness and weakness for me, and malaise/low fevers for her - in fall of 2004. So just past 12 years for us.
Note @Tiger_Eyze that mitochondrial defects are inherited maternally. Just something to consider when CFS is found in families/relatives......
 
Messages
124
Likes
281
I have not tried DCA again, only tried it once. Will try it again at some point.
Hi @Hip , I was following your thread on using DCA in early 2017. Personally, I think it is potentially dangerous to self-medicate with DCA so it is not something I would consider myself. However, I am curious.

Did you try it? What doses? Did you combine DCA with a specific diet? Did it change your capacity for either anaerobic or aerobic exercise? Did it affect your recovery time? If you exercise on day 0, did DCA change your aerobic or anaerobic exercise capacity on day 1 or 2? Did it change your blood glucose or blood ketones such as hydroxybutyrate?
Very curious,
Rodger
 

knackers323

Senior Member
Messages
1,561
Likes
580
H
See Azithromycin in Chronic Fatigue Syndrome (CFS), an analysis of clinical data





That's interesting, because when I was taking a course of erythromycin (also a macrolide) 800 mg plus ampicillin 500 mg daily, I noticed that the PEM I get from social interaction was noticeably reduced.

In my experiments with azithromycin, this also seemed to help a bit: I felt less groggy, and sleep seemed more refreshing. Nothing major though, just minor improvements.

Azithromycin is a bit expensive, but erythromycin is quite cheap, so at some point I want to try erythromycin again, to see if I can get the same results.

The macrolides roxithromycin, erythromycin, clarithromycin and azithromycin have been shown to inhibit IL-1β, TNF-α and IL-6 (the sickness behavior cytokines). Ref: 1 (full text).

And amoxicillin significantly decreases IL-6 plasma levels by the 7th day of therapy. Ref: 1
@Hip is thete anything else you know of that works like clarithromycin on these cytokines?
I felt much better on it within a day also
 
Last edited:

Hip

Senior Member
Messages
13,539
Likes
25,740
@Hip is thete anything else you know of that works like clarithromycin on these cytokines?

I felt much better on it within a day also
I have tried plenty of supplements and drugs that inhibit IL-1β, TNF-α and IL-6, but usually without much success. However, a few things have helped. The supplement vinpocetine 40 mg (must be taken with food for proper absorption) I find helps a little for the blunted emotions of ME/CFS; it's a TNF-α inhibitor.

Glucosamine is known to inhibit IL-1β, and I found N-acetyl-glucosamine (a version of glucosamine that can cross the blood-brain barrier) very effective for treating my generalized anxiety disorder, which I posit can be caused by chronic brain inflammation.

But erythromycin is the only thing I've noticed that has these anti-PEM effects.
 

JaimeS

Senior Member
Messages
3,408
Likes
12,234
Location
Silicon Valley, CA
The supplement vinpocetine 40 mg (must be taken with food for proper absorption) I find helps a little for the blunted emotions of ME/CFS; it's a TNF-α inhibitor.
'Blunted emotions' has never been a problem for me, but I took vinpo for awhile -- it significantly reduced the pain at the back of my neck. However, be aware it's a vasodilator, so those with POTS should be wary.
 

HowToEscape?

Senior Member
Messages
623
Likes
842
Is there anyone here who can write up a summary of this thread, with an outline and links to details/further reading? Even attempting 40 pages is no longer realistic for me.
 

nandixon

Senior Member
Messages
1,092
Likes
3,133
I've been meaning to provide an update for the hypothesis that I made in this thread, which was that the Fluge & Mella results were showing an under-activation of the critical enzyme mTOR/mTORC1, ever since Mark Davis’ work regarding the possibility of CD8+ T cell expansion in ME/CFS was revealed a couple months ago.

If Mark Davis’ work is correct, and I have a feeling it probably is, then my hypothesis is going to be wrong, and it's going to be more likely that mTOR is actually over-activated in the type of cells that Fluge & Mella studied, i.e., PBMCs, and this would be the result of the activation/expansion (proliferation) process occurring in the T cell population of the PBMCs, namely their switch from oxidative phosphorylation to aerobic glycolysis to support that proliferative process.

Note that this also means the impairment of the PDH complex Fluge & Mella found is with respect to the activated T cells and presumably is not happening in other cells in the body (although mitochondrial function in other cell types could very well be impaired by the cytokine signaling generated by the activated T cells).

Neither under-activation nor over-activation of mTOR is a perfect fit for the Fluge & Mella results. The possibility of over-activation is made less likely by the high SIRT4 finding and by the normal HIF-1. Under-activation is made less likely by the high PDK4 finding.

I went with under-activation because I thought there was real world confirmation of this in several different ways. For example, natural killer (NK) cell function tends to be low in ME/CFS and this almost certainly means mTOR is under-activated in those NK cells. What I didn't realize is that the high TGF-beta that is also commonly found in ME/CFS can cause impairment of mTOR. (Note that neither low NK cell function nor high TGF beta are diagnostic of ME/CFS but are found in a number of different disease states.)

In other words, the activation of the T cells, which requires the activation of mTOR for the necessary switch to aerobic glycolysis in order for the T cells to expand/proliferate, also results in the production of TGF-beta which has an inhibitory downstream effect with respect to mTOR on other types of cells including NK cells. So under this scenario, mTOR is likely over-activated in at least one type of cell (i.e., the activated T cells) in the ME/CFS patient and simultaneously under-activated in other cells that are subject to TGF-beta signalling.

Anyway, the new study posted on the thread entitled T-cells and metabolomics is likely relevant to the Fluge & Mella findings because it demonstrates how the amino acid profile they found might appear to support a general bodywide PDH impairment but yet actually be the result of the specific T cell expansion process Mark Davis may have uncovered.

Also, my apologies in advance if Mark Davis’ T cell activation/expansion work turns out to be key (which, again, requires the over-activation of mTOR) to a poster whose username I can't remember, who had believed at one point in this thread that the Fluge & Mella work was likely showing this aerobic glycolysis.

Lastly, some method of reducing the T cell activation and expansion might be helpful as a treatment if that is indeed what is happening in some people with ME/CFS. An obvious anti-proliferative agent to try might be rapamycin (sirolimus) itself.

Edit: @Janet Dafoe (Rose49) would you mind showing Dr Davis (Ron) this? Thank you!
 
Last edited:
Messages
1,450
Likes
7,319
I've been meaning to provide an update for the hypothesis that I made in this thread, which was that the Fluge & Mella results were showing an under-activation of the critical enzyme mTOR/mTORC1, ever since Mark Davis’ work regarding the possibility of CD8+ T cell expansion in ME/CFS was revealed a couple months ago.

If Mark Davis’ work is correct, and I have a feeling it probably is, then my hypothesis is going to be wrong, and it's going to be more likely that mTOR is actually over-activated in the type of cells that Fluge & Mella studied, i.e., PBMCs, and this would be the result of the activation/expansion (proliferation) process occurring in the T cell population of the PBMCs, namely their switch from oxidative phosphorylation to aerobic glycolysis to support that proliferative process.

Note that this also means the impairment of the PDH complex Fluge & Mella found is with respect to the activated T cells and presumably is not happening in other cells in the body (although mitochondrial function in other cell types could very well be impaired by the cytokine signaling generated by the activated T cells).

Neither under-activation nor over-activation of mTOR is a perfect fit for the Fluge & Mella results. The possibility of over-activation is made less likely by the high SIRT4 finding and by the normal HIF-1. Under-activation is made less likely by the high PDK4 finding.

I went with under-activation because I thought there was real world confirmation of this in several different ways. For example, natural killer (NK) cell function tends to be low in ME/CFS and this almost certainly means mTOR is under-activated in those NK cells. What I didn't realize is that the high TGF-beta that is also commonly found in ME/CFS can cause impairment of mTOR. (Note that neither low NK cell function nor high TGF beta are diagnostic of ME/CFS but are found in a number of different disease states.)

In other words, the activation of the T cells, which requires the activation of mTOR for the necessary switch to aerobic glycolysis in order for the T cells to expand/proliferate, also results in the production of TGF-beta which has an inhibitory downstream effect with respect to mTOR on other types of cells including NK cells. So under this scenario, mTOR is likely over-activated in at least one type of cell (i.e., the activated T cells) in the ME/CFS patient and simultaneously under-activated in other cells that are subject to TGF-beta signalling.

Anyway, the new study posted on the thread entitled T-cells and metabolomics is likely relevant to the Fluge & Mella findings because it demonstrates how the amino acid profile they found might appear to support a general bodywide PDH impairment but yet actually be the result of the specific T cell expansion process Mark Davis may have uncovered.

Also, my apologies in advance if Mark Davis’ T cell activation/expansion work turns out to be key (which, again, requires the over-activation of mTOR) to a poster whose username I can't remember, who had believed at one point in this thread that the Fluge & Mella work was likely showing this aerobic glycolysis.

Lastly, some method of reducing the T cell activation and expansion might be helpful as a treatment if that is indeed what is happening in some people with ME/CFS. An obvious anti-proliferative agent to try might be rapamycin (sirolimus) itself.

Edit: @Janet Dafoe (Rose49) would you mind showing Dr Davis (Ron) this? Thank you!
Nothing more intellectually satisfying than seeing someone change their mind when new evidence comes out. Good one @nandixon. Does the paper out today from Tomas, Newton and Manning on metabolism in pbmcs shed any more light on these hypitheses, in your opinion?
 

nandixon

Senior Member
Messages
1,092
Likes
3,133
Does the paper out today from Tomas, Newton and Manning on metabolism in pbmcs shed any more light on these hypitheses, in your opinion?
If Mark Davis’ work is correct, then that study is seemingly again just showing the signature of the T cell activation/expansion process. To verify this, the next study that could be done is what Tomas et al actually propose at the end of their paper:

Stratification of PBMCs using fluorescence activated cell sorting (FACS) is a technique that could be utilised to further sub-divide cell types that fall within of the category of PBMCs to identify which specific cell populations are responsible for the observed differences in OXPHOS.

They should find (assuming Mark Davis is on to something) that the “specific cell populations” are the same T cells involved in the expansion process that Mark Davis found - or so I would think.
 

A.B.

Senior Member
Messages
3,780
Likes
23,070
Lastly, some method of reducing the T cell activation and expansion might be helpful as a treatment if that is indeed what is happening in some people with ME/CFS. An obvious anti-proliferative agent to try might be rapamycin (sirolimus) itself.
Do antivirals reduce proliferation?

Many antiviral drugs inhibit the key metabolic enzyme SAdenosylhomocysteine Hydrolase (SAHH). Inhibition of SAHH causes an increase in intracellular SAH levels. SAH is a potent inhibitor of DNA, RNA, protein, and small molecule methylation. This affects both viral and host cell epigenetics, gene expression, mRNA translation, and protein stability. The inhibition of methylation reactions in the cell also affects neurotransmitter (dopamine, norepinephrine, and serotonin) and phosphatidylcholine membrane lipid synthesis, folate and B12 metabolism, and many other reactions. So by giving antivirals, doctors are not just inhibiting viruses, they are also inhibiting many host cell metabolic functions.
https://www.omf.ngo/2016/09/09/upda...-fatigue-syndrome-q-a-with-robert-naviaux-md/