Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)

[Tiger_Eyze]

@ScottTriGuy

Great article!

Yes, the pathway in that article is the same one. Personally, I've been trying to inhibit TNF-a/NFKB/COX2, but after reading that article, perhaps MTOR is a better place to hit the pathway.

I may just give Tagamet a try if it doesn't interact with any of my day to day essentials. It has so many drug interactions.

 

[nandixon]

@nandixon

This article mentions the mTOR pathway - any relevance to your hypothesis?

I made this post about that article on another thread:

Yes, most other types of diseases (autoimmune, cancer, neurodegenerative, metabolic) often have an over-activated mTOR (mTORC1) pathway. That seems to be the case in Castleman disease as well.

In ME/CFS, the mTORC1 pathway, and particularly beginning at the level of the enzyme known as Akt (i.e., the Akt/mTORC1 pathway) appears to be under-activated. Other illnesses with an under-activated mTORC1 include SIRS/sepsis and starvation, both of which ME/CFS seems to resemble more than other diseases.

On a broader level, I think that most of the pathways and metabolic processes which involve signaling by sphingosine-1-phosphate (S1P) are under-activated in ME/CFS, including those involving endothelial function, blood pressure/volume regulation, etc.

The Akt/mTOR pathway is just one of those S1P-related pathways. But it's perhaps the most important, though, because it leads to the pyruvate dehydrogenase (PDH) complex and is therefore a critical energy-producing pathway. The recent Fluge & Mella study found the PDH complex to be impaired in ME/CFS.

Additionally, because the PDH complex produces acetyl-CoA, and since aetyl-CoA is necessary to make palmitoyl-CoA, which is the starting material (together with serine) for the de novo synthesis of ceramides in the body, this makes the PDH complex simultaneously both downstream and upstream of what appears to be impaired S1P signaling in ME/CFS (because S1P is made from ceramides).

Anyway, under the model above, using the drug rapamycin (a potent mTOR inhibitor) that the Castleman patient found effective for his disease would theoretically be one of the worst possible drugs to use in ME/CFS.

 

[gregh286]

I have posted in many thread about the importance amino shakes to us. Personally it took from level from 40 to 80+.


The Rag complexEdit
mTORC1 signaling is sensitive to amino acid levels in the cell.[9] Even if a cell has the proper energy for protein synthesis, if it does not have the amino acid building blocks for proteins, no protein synthesis will occur. Studies have shown that depriving amino acid levels inhibits mTORC1 signaling to the point where both energy abundance and amino acids are necessary for mTORC1 to function. When amino acids are introduced to a deprived cell, the presence of amino acids causes Rag GTPase heterodimers to switch to their active conformation.[10] Active Rag

 

[gregh286]

Would agree with this 100% in my experience. I think most of us get worse if we don't eat. Personally I eat high carb diet. Noticed few.years back it was for me. Paleo diets wretched me.


Based on upstream signaling of mTORC1, a clear relationship between food consumption and mTORC1 activity has been observed.[46]Most specifically, carbohydrate consumption activates mTORC1 through the insulin growth factor pathway. In addition, amino acid consumption will stimulate mTORC1 through the branched chain amino acid/Rag pathway. Thus dietary restriction inhibits mTORC1 signaling through both upstream pathways of mTORC that converge on the lysosome.[4

 

[kangaSue]

If you don't mind my asking, how was your ischemia diagnosed? Did you end up having a vessel blockage that they found on a CT or elevated lactic acid in your blood? Or was your ischemia more of an SMA Syndrome type picture that is hard to pick up with standard testing?

A Doppler Ultrasound (of the mesentery arteries) showed an elevated mid SMA flow velocity and I had a faint abdominal bruit. A CT Angiogram didn't detect any blockage but did show an acute angulation on the SMA although this wasn't mentioned in the report at the time, not until I had a review CT Angiogram done recently so an SMA Syndrome is now on the cards.

I insisted on a colonoscopy after the first CTA when things were leading nowhere. During the procedure, severe ischemic damage was seen to the bowel mucosa (which resulted in a bowel perforation by the scope).The conclusion was it was chronic microvascular intestinal ischemia of unknown etiology but related to the issue of having low b.p. There is no test specific for intestinal ischemia and even with having a severely inflamed bowel, I had no inflammatory markers in standard blood work.

I haven't had it done but have seen it suggested that an Intestinal Fatty Acid Binding Protein (I-FABP) test can be used as a guide for intestinal ischemia though not specific to it.

Mucosa damage only happens when blood flow to the bowel falls below about 50%, something more usually encountered as an emergency situation so an absence of this doesn't rule intestinal ischemia out as most people will maintain an adequate collateral bowel blood flow.

 

[Tiger_Eyze]

@kangaSue
Thank you for sharing. You poor thing! I take it they worked you up thoroughly for vasculitis? I will look into that blood test and the ultrasound!

@nandixon

So you are saying that CFS/ME is more more like a late-onset Rett syndrome without the MR?

I read they had good results giving Rett syndrome patients sphingosine & IGF-1, which would make sense as far as activating mTORC and helping bypass the ceramide deficiency to S1P.

Perhaps that would explain why a few people I met with ME/CFS had life changing results with human growth hormone shots, which no one can get anymore, since it's essentially banned from off label use. But there are secretogogues and releasing peptides. Anyone have any good experience with those?

Also, IV ozone apparently increases S1P.
https://www.ncbi.nlm.nih.gov/pubmed/25903957

I just can't help but wonder if maybe earlier stages of CFS have up regulated mTORC due to the same inflammatory signaling that triggers microgila damage, which lowers IGF-1, and then the mTORC pathway eventually tanks?

 

[Learner1]

Also, IV ozone apparently increases S1P.
https://www.ncbi.nlm.nih.gov/pubmed/25903957

Thanks for sharing this. The article comments it's not legal in the US, which is not true. There are several practitioners doing it.

My doctor is giving me a combination of HBOT, ozone IVs (along with a bunch of nutrients), and major autoheme ozone treatments. The jury's still out, but I've made some progress. I've seen it help 2 other patients before me.

How would one work on the ceramides also?

 

[gregh286]

I previously posted, about a year and a half ago, that the drug that has helped me the most with my ME/CFS symptoms is cimetidine (available OTC in the US as Tagamet). (See this search string: http://forums.phoenixrising.me/index.php?search/34758570/&q=cimetidine&o=date&c[user][0]=6966)

It's been known for many years that cimetidine, which is usually thought of as an H2 histamine "blocker," decreases regulatory T cell (Treg) activity, i.e. relieves immunosuppression and is immunostimulatory, but the exact mechanism wasn't discovered until a few months ago, and I wasn't aware of this research until yesterday.

Remarkably, cimetidine degrades Treg activity by increasing the levels of a protein called STUB1 and as part of that process it activates the Akt/mTOR (mTORC1) pathway. (Reference)

So that fits exceptionally well with the impaired S1P signaling hypothesis, since S1P activates Akt (through S1PR receptors) by increasing the phosphorylation of that enzyme, and that's what cimetidine does as well.(!)

I found that only a narrow therapeutic window works with cimetidine (too much makes me worse) and that it is best taken twice a day roughly 12 hours apart. And this is perfectly consistent with what the researchers found to be optimal for the best effect from cimetidine in vitro in the study I referenced (in the full paper). I take only 1/4 tablet (= 50 mg) about 1 hour after breakfast and at least 2 hours after dinner to avoid interference with stomach acid secretion.

This confirms, for me anyway, that the Fluge & Mella results are likely explained by:

??--> Low ceramides--> Low S1P--> Impaired S1P signaling--> Under-activated Akt--> Under-activated mTORC1--> Increased PDKs & SIRT4--> Inhibited PDH complex

(Note that I know that cimetidine's effect for me is not related to any H2 histamine receptor activity because the other major H2 blockers, ranitidine and famotidine, either had no effect or made me worse.)

Hi @nandixon
would lipid supplementation boost ceramides levels ?
or the skin boyos: https://www.amazon.com/Phytoceramid...coding=UTF8&psc=1&refRID=C0FTMFCVA77A0MMCT382

 

[eljefe19]

Hi @nandixon
would lipid supplementation boost ceramides levels ?
or the skin boyos: https://www.amazon.com/Phytoceramid...coding=UTF8&psc=1&refRID=C0FTMFCVA77A0MMCT382

I don't think he knows, I asked about that same product, which I have been taking for a few days without major benefit fwiw.

 

[gregh286]

I don't think he knows, I asked about that same product, which I have been taking for a few days without major benefit fwiw.

But ceramides decrease with age naturally, so there would have a been a pattern of higher CFS incidence in higher age groups.
Incidentally, thats total opposite of what actually happens, that CFS almost non existent in old age.

 

[gregh286]

I don't think he knows, I asked about that same product, which I have been taking for a few days without major benefit fwiw.

@eljefe19 I'm going to smash some of these into me. I think nandixon on right tracks about the mTORc1.
These stimulate the pathway.
http://www.geneticsupplements.co.uk/PHOSPHATIDICACID

It appears leucine can help here also but my last test I was really off the scale.high in leucine. Could be a conversion issue.

 

[eljefe19]

@eljefe19 I'm going to smash some of these into me. I think nandixon on right tracks about the mTORc1.
These stimulate the pathway.
http://www.geneticsupplements.co.uk/PHOSPHATIDICACID

There are several drugs and supplements that stimulate mTOR;
Creatine, carnitine (not alcar), Sarcosine, Ketamine, agmatine, Citrulline, Leucine and Glutamine are essential as well. TBH I think the block is better treated further upstream as I've felt no great benefit from the mTOR supplements.

 

[gregh286]

There are several drugs and supplements that stimulate mTOR;
Creatine, carnitine (not alcar), Sarcosine, Ketamine, agmatine, Citrulline, Leucine and Glutamine are essential as well. TBH I think the block is better treated further upstream as I've felt no great benefit from the mTOR supplements.

How far upstream.....ceramides?
Maybe broad spectrum lipids. I think it was a Dr. Nicholson who was big on lipids....NT factor was his product.

 

[nandixon]

Hi @nandixon
would lipid supplementation boost ceramides levels ?
or the skin boyos: https://www.amazon.com/Phytoceramid...coding=UTF8&psc=1&refRID=C0FTMFCVA77A0MMCT382

I don't think humans have the necessary cellular apparatus to convert exogenous phytoceramides into the ceramides that are used to make sphingosine-1-phosphate (S1P).

There might possibly be some benefit to taking phytoceramides for incorporation into skin, for example, if that meant that endogenous ceramides would be conserved for making S1P elsewhere, but I don't know.

 

[Learner1]

How far upstream.....ceramides?
Maybe broad spectrum lipids. I think it was a Dr. Nicholson who was big on lipids....NT factor was his product.

NT Factor helps with phospholipids, not sphingolipids, right?

"NT Factor Energy™ is a proprietary blend of phospholipids and glycolipids whose mechanism of action is to repair cellular membranes by increasing cell membrane fluidity. By repairing the membranes of the mitochondria (the energy furnaces within our cells), we allow all of our cells to increase their nutrient uptake so that the mitochondria may produce more ATP — the body’s energy fuel."

 

[nandixon]

But ceramides decrease with age naturally, so there would have a been a pattern of higher CFS incidence in higher age groups.
Incidentally, thats total opposite of what actually happens, that CFS almost non existent in old age.

I thought I remember reading that blood levels of ceramides actually tend to increase with age.(?) Perhaps there's a decreased incorporation of ceramides into the skin with aging. Or perhaps it's the composition (types) of ceramides that changes in the blood and/or skin with aging. Not sure.

 

[nandixon]

How far upstream.....ceramides?

Perhaps at least at the level of the Akt enzyme. I haven't found anything so far that is helpful that stimulates mTOR directly, I don't think. That enzyme has a large number of input and feedback signals and so seems prone to returning to homeostasis.

Cimetidine is helpful for me, and perhaps TUDCA (still testing this one). Both of these activate Akt. TUDCA does this via the sphingosine-1-phosphate receptor, S1PR2. I'm not sure if cimetidine does this via a S1P receptor or not.

A person could also attempt to correct specific problems downstream of an under-activated Akt/mTOR pathway as well, such as using fludrocortisone (Florinef) for a possible resultant decrease in aldosterone levels. (Both S1P and an activated mTOR, which is itself dependent on S1P for activation via Akt, are necessary for full aldosterone production, I believe.)

 

[adreno]

Where are you guys getting your TUDCA? Seems hard to find at a competitive price.

 

[eljefe19]

@adreno Amazon, my friend

 

[kangaSue]

Thank you for sharing. You poor thing! I take it they worked you up thoroughly for vasculitis? I will look into that blood test and the ultrasound!

@Tiger_Eyze Definitely not vasculitis, The GI motility specialist say's it's Ischemic Enteritis from vasospasm at the microvascular level but CT results says not but that could be an anomaly as it's more generally associated with occlusive disease.
Either way, I'm now looking into it being a combination of vascular compression syndromes, SMA and Nutcracker Syndromes which better fits the picture of imaging findings, just not a typical presentation.
http://forums.phoenixrising.me/inde...e-–-linked-with-pots-and-childhood-cfs.48793/