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

Learner1

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And the study suggests that xenobiotic-induced and/or oxidative modification of mitochondrial autoantigens is a critical step...

Not sure if this might have any relevance to the Fluge and Mella findings. It certainly indicates that an autoimmune response can inhibit pyruvate dehydrogenase.
Likely... thanks for pointing this out!
 

justy

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PS I wonder how diagnostic we could make an NK cell function test in ME. If we test NK cells in our own serum, and isolated NK cells, and compare function, would this be diagnostic? Would that be an easy test? This would be a way to turn the inconsistencies in our NK cell tests to our advantage, presuming it works and is reliable.
a group of us appears to have high NK cell activity - and I have classic M.E.
 

nandixon

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The Fluge & Mella results tie together very well with the results from the Naviaux study using the apparent problem in the Akt/mTOR (mTORC1) pathway that the Fluge & Mella results may suggest.

Naviaux showed that sphingolipids, in particular ceramides, are low in ME/CFS. The low ceramides suggest that sphingosine 1-phosphate (S1P) is likely to be low as well, since S1P is made from ceramides (in two steps).

There are several S1P receptors (e.g., S1P1 aka S1PR1) located on different types of cells, and some of these receptors are necessary to properly activate mTOR.

So if S1P is low due to low ceramides (or if there is actually plenty of S1P being made but there are antibodies against either S1P or to its receptors) then mTOR will not be sufficiently activated.

This insufficient activation not only impairs the PDH complex, as the Fluge & Mella results may suggest, but it also reduces natural killer (NK) cell function (reference), one of the most commonly found ME/CFS defects.

So the Fluge & Mella results combined with Naviaux may be indicating impaired S1P signaling in ME/CFS, with perhaps the greatest number of symptoms being mediated by a resulting failure to activate mTOR.

It doesn't appear that Naviaux measured S1P, or that S1P has ever been measured in any ME/CFS study. Can anyone confirm this?
 

NexusOwl

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I've read in cases of congenital PDH deficency thiamine, carnitine and lipoic acid are used as supplementation and many respond to thiamine.

Do you guys think any of these would help us? I remember thiamine being one of the most recomended supplements by Ken Lassesen whose protocol some people I know are following with relative success.
 

Tunguska

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I've read in cases of congenital PDH deficency thiamine, carnitine and lipoic acid are used as supplementation and many respond to thiamine.

Do you guys think any of these would help us? I remember thiamine being one of the most recomended supplements by Ken Lassesen whose protocol some people I know are following with relative success.
Lipoic acid tends to work well acutely for what it does (I used this one a lot) but would be at best a stopgap for this because it lowers mTor which you want to target for healing things (I felt nandixon took the right direction there as far as band-aid solutions go). Carnitine is mostly for shuttling fatty acids and it's glucose oxidation you want to fix most (feel free to disagree but I'm pretty set on this). I'm sure thiamine can help some, it's worth a try, with magnesium, but gave me more sides than benefits. Cheers
 

nandixon

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I've read in cases of congenital PDH deficency thiamine, carnitine and lipoic acid are used as supplementation and many respond to thiamine.

Do you guys think any of these would help us?
When the first subunit of the PDH complex is phosphorylated by a pyruvate dehydrogenase kinase (PDK) - which Fluge & Mella found to be high - it is rendered completely inactive and no amount of thiamin (a cofactor for the first subunit) can overcome this. The complex has to be dephosphorylated (by pyruvate dehydrogenase phosphatase, PDP) to be operational again.

The situation is even worse with respect to the high SIRT4 which Fluge & Mella also found. That enzyme removes the lipoic acid "cofactor" from the second subunit of the PDH complex, essentially destroying it because humans do not have an enzyme that can reattach this. Thus supplemental lipoic acid is of no help in that regard (despite what you may read on hundreds of websites suggesting that you can supplement lipoic acid as a cofactor). (When the PDH complex is initially assembled, the lipoic acid group is built up in pieces directly onto the 2nd subunit, starting from, e.g., octanoic/caprylic acid. Lipoic acid itself is not used.)
 

Mary

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Very interesting! The study you linked to says:


So it seems important to stress that L-glutamine and EAA (essential amino acids) such as L-leucine when taken alone do not work; they only work when taken in combination. I have taken both glutamine and leucine many times in the past, but probably never together.

The study says the maximal effects occur with blood concentrations 1 mM L-glutamine. By my calculation, to get such a concentration of glutamine, you would need to take an oral glutamine dose of 5.8 grams, assuming 100% oral bioavailability, and assuming 40 liters of fluids in the human body. (The method of calculation explained at the bottom of this post).

And looking at Figure 1B in the study, it looks like if you go higher than the maximal effect concentration of glutamine, the effects become less. So you to get optimum effects, you have to hit the maximal effect concentration of glutamine spot on, no less, no more (and the dose that achieves this will vary with body size, but will be around the 5.8 grams mark for a normal weight body).

Looking at Figure 1B, it seems that the concentration of leucine that achieves maximal effects is also around 1 mM (though it is a bit hard to tell on that 3D diagram).

By my calculation, to get a 1 mM concentration of leucine in the blood, you would need to take an oral leucine dose of 5.2 grams.


I happen to have both glutamine and leucine in stock, so I am going to start on the glutamine + leucine protocol immediately!



It says in the Wikipedia article on mTORC1 that insulin-like growth factors can activate mTORC1. I also have some velvet deer antler tincture lying around, which contains 139 ng of IGF-1 per sublingual drop, so I will also take some of that sublingual IGF-1.
@Hip - I've gone back to my original BCAA dose of 2+ years ago and am also taking 1000 mg. glutamine (had cut that to 500 mg). I've been taking this for about 3 days now I think, and much to my surprise,. my energy has noticeably increased. I don't remember this happening 2+ years ago. I remember very clearly my PEM recovery time was cut in half but I don't recall an increase in energy (and I recall anything that increases my energy!)

So this is a very nice surprise. Of course time will tell - I've had other things increase my energy quite a bit (NADH, l-carnitine e.g.) but it was short-lived, 7 - 10 days.

I do feel a little edgier which may be from the glutamine so I'm not going to increase that for awhile but will stay at this dose and see what happens.

FWIW, the products I'm currently taking are https://www.amazon.com/Optimum-Nutr...076575&sr=8-2&keywords=optimum+nutrition+bcaa (8 capsules a day - in 2 divided doses, equaling 2000 mg leucine, 1000 mg isoleucine and 1000 mg valine) plus http://www.swansonvitamins.com/swanson-ultra-ajipure-l-glutamine-pharmaceutical-grade-500-mg-60-caps (2 per day, divided doses)
 

Hip

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I do feel a little edgier which may be from the glutamine so I'm not going to increase that for awhile but will stay at this dose and see what happens.
The edginess might perhaps be due to increased glutamate in the brain, as glutamine and glutamate freely interconvert (although I not aware of any way that glutamine can raise brain glutamate).

To counter this edginess or anxiety, you might try some of the supplements that I found have good anti-anxiety effects, such N-acetyl-glucosamine, flaxseed oil or turmeric (see this thread). I suspect these reduce anxiety by reducing brain inflammation (brain inflammation releases glutamate).



I have been taking the leucine + glutamine protocol for the last 5 days, to try to induce mTORC1, and boost energy. I have been taking:

Leucine 5.2 grams
Glutamine 5.8 grams

Both taken together on an empty stomach once or twice a day.

Actually, in the last two days I substituted the leucine for the same dose of essential amino acids (EAAs), but I found EAAs give me vivid and slightly strange dreams, so I think I will go back to the leucine.

The first day I took the leucine + glutamine, a few hours later I noticed some mild exuberance in my mood, and the next day when I visited some friends that I see regularly once a week, I noticed that I was in a more good-humored mood than normal.

However, generally so far, I have not really felt much in the way of improvements in my ME/CFS symptoms.
 
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Tunguska

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When the first subunit of the PDH complex is phosphorylated by a pyruvate dehydrogenase kinase (PDK) - which Fluge & Mella found to be high - it is rendered completely inactive and no amount of thiamin (a cofactor for the first subunit) can overcome this. The complex has to be dephosphorylated (by pyruvate dehydrogenase phosphatase, PDP) to be operational again.
Great info. So it warrants (even) less enthusiasm. But what does it mean when people do get benefit from thiamine? (aside, most of what I got from it - 4 or 5 different forms - felt like acetylcholine https://www.ncbi.nlm.nih.gov/pubmed/8239567 - no overwhelming support for that, but it fit)

About SIRT4: given that SSRI can increase it, is there support for gut serotonin in general increasing it? (IIRC in a previous forum episode you were interested in serotonin) Or is it SSRI-specific effect? (devil in the details with those things)

(aside, I will probably also try the glutamine again with BCAA, but it was never a noticeable effect when combined with egg white compared to glutamine alone - but gut absorption issues with egg white is a huge variable)
 

junkcrap50

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Great info. So it warrants (even) less enthusiasm. But what does it mean when people do get benefit from thiamine? (aside, most of what I got from it - 4 or 5 different forms - felt like acetylcholine https://www.ncbi.nlm.nih.gov/pubmed/8239567 - no overwhelming support for that, but it fit)
This very small study / case study really, showed that high dose thiamine does help CFS / Fibromyalgia. http://www.prohealth.com/library/showarticle.cfm?libid=18113
EDIT: Adding http://www.healthrising.org/blog/20...survey-fibromyalgia-chronic-fatigue-syndrome/

Damn, yes after some very brief review, it does look like PDK does render it completely inactive. Perhaps high doses of thiamine does do something. I'll have more thoughts on this in a later post. So, it looks like DCA will likely lead to some improvement and symptom relief.
 
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nandixon

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This very small study / case study really, showed that high dose thiamine does help CFS / Fibromyalgia. http://www.prohealth.com/library/showarticle.cfm?libid=18113

Damn, yes after some very brief review, it does look like PDK does render it completely inactive. Perhaps high doses of thiamine does do something.
Yes, very high dose thiamin was shown to inhibit PDK in the study that @JaimeS previously mentioned here. (Direct link to study here.)

So the idea would be to inhibit PDK before it has a chance to inhibit PDH.

That's great information to know that a therapeutic dose of thiamin could be as high as 1800 mg.
 

Hip

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I've ordered 25 grams of dichloroacetate (DCA) for £32, and will be trying it soon.

I am going to take benfotiamine, alpha lipoic acid and acetyl-L-carnitine with the DCA in order to try to prevent any neuropathy (as recommended by the article quoted in this post).

Other side effects of DCA can include heartburn, nausea, vomiting, indigestion, but these can be countered with a proton pump inhibitor drug (see the same post). I wonder if DCA can be administered as a suppository or transdermally to try to avoid these stomach issues.

The one forum member who tried DCA said:
it actually seemed to work well for the fibro and CFS. However, I am not sure whether or not it was the cause of some of my stomach pain and nausea.
I want to try to avoid these stomach side effects.

I read that caffeine can boost the effects of DCA, which then allows for lower doses of DCA, and thus lower side effects. However, I have also read articles advising caution when taking caffeine with DCA, perhaps because it boosts the effects of DCA too much. One article said taking caffeine with DCA is more likely to cause the fatigue and weakness side effects.

Daily DCA dose recommendations for cancer treatment that I saw here are 10 to 20 mg per kg body weight (20 mg/kg to treat cancer, and 10 mg/kg as a maintenance dosage and to help prevent cancer).

In a study of treatment of congenital lactic acidosis in children, a DCA dose of 12.5 mg per kg body weight was given every 12 hours.

In patients with severe lactic acidosis associated with septic shock, 50 mg of DCA per kg body weight was used; see here.

In a rat study, 5 mg per kg body weight of DCA was used to reduce lactate accumulation in endurance exercising. For humans, that equates to a human dose of 0.8 mg per kg body weight. So for an 80 kg person, the dose would be 64 mg of DCA.



So judging by the cancer doses, typical DCA doses for an 80 kg person would equate to around 800 to 1,600 mg daily. I may try 300 mg of DCA three times daily to start with.
 
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Cort wrote about a small Italian study on B1 "Cheap, Effective Relief From Fibromyalgia (and ME/CFS) Found? Early Reports Spark Interest in Little Used Supplements" on 5th July 2013. (don't know how to do a link)

I built up to 1750 mg a day and had less pain and more energy for a few weeks, then I crashed.

 

nandixon

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All of the studies so far (Naviaux, Hanson, Armstrong and this one) are all pointing in the same direction.
@Ben Howell, do you know if Ron Davis and Naviaux have measured sphingosine-1-phosphate (S1P) levels?

This Fluge & Mella study seems to fit with the Naviaux one to indicate impaired S1P signaling, as I mentioned here.

(I suppose it should be obvious for them to measure S1P after finding the low ceramides.)
 

Sidereal

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I'm glad that the research is catching up to my personal observations and experiences re: pyruvate dehydrogenase.

Massively supraphysiologic doses of thiamine, particularly transdermally applied allithiamine (which is fat-soluble and penetrates the cells much more effectively) and sublingual thiamine pyrophosphate to a lesser extent, were effective for me in combination with low dose lipoic acid and sublingual FMN around the clock. Regular orally administered thiamine hydrochloride you'd get in most supplements did nothing whatsoever, not even at 1,500 mg/day. The effect lasted about 4 months but it was very pronounced. I went from housebound to being able to climb hills with no PEM essentially overnight.

Deconditioning plays absolutely no role in the metabolic abnormalities in ME/CFS and no graded anything was required to restore functional capacity. Within 20 minutes of first dose of allithiamine I just felt I could go for a walk despite not having done that for years.
 

Hip

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One other supplement of potential interest in terms of boosting the Krebs cycle is triheptanoin, which is a dietary oil.

This study says that triheptanoin, an odd-carbon triglyceride, is a source for both acetyl-CoA, and for propionyl-CoA (the latter provides anaplerotic replenishment of the Krebs intermediates).


The Wikipedia article says:
Triheptanoin is used clinically in humans to treat inherited metabolic diseases, such as pyruvate carboxylase deficiency and carnitine palmitoyltransferase II deficiency. It also appears to increase the efficacy of the ketogenic diet as a treatment for epilepsy.
However, I could not find this triheptanoin oil for sale anywhere online.

This document contains a lot of info on triheptanoin, and says:
At the present time, triheptanoin can only be used as a dietary supplement in the U.S. by individuals enrolled in medical research studies of metabolic disorders regulated by the U.S. Food and Drug Administration (FDA), and can only be obtained and used under the supervision of authorized researchers.
There is some info on triheptanoin here; it says that triheptanoin is added to some cosmetics, and added to butter in some European countries, but is not commercially available in the US for clinical use.

So possibly, if we can find the chemical name or brand name of the triheptanoin that is sold to the food industry or cosmetic industry, we may be able to obtain this oil.

Some chemical information about triheptanoin (including its chemical synonyms) is given here. As a chemical, its CAS number is 620-67-7.
 

Hip

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Within 20 minutes of first dose of allithiamine I just felt I could go for a walk despite not having done that for years.
Very interesting. I had not heard of allithiamine before.

Have you ever tried the supplement sulbutiamine, which is a fat-soluble derivative of vitamin B1? I find this dramatically improves mood and brain fog, and feels like a stimulant, but then the next day it leaves me feeling flat and mildly depressed, so for this reason I tend to avoid taking it.

I take an oral dose of around 300 mg of sulbutiamine, but if I snort the sulbutiamine powder into my nose, then 30 mg will get the same effect.
 

Sidereal

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Very interesting. I had not heard of allithiamine before.

Have you ever tried the supplement sulbutiamine, which is a fat-soluble derivative of vitamin B1? I find this dramatically improves mood and brain fog, and feels like a stimulant, but then the next day it leaves me feeling flat and mildly depressed, so for this reason I tend to avoid taking it.

I take an oral dose of around 300 mg of sulbutiamine, but if I snort the sulbutiamine powder into my nose, then 30 mg will get the same effect.
Allithiamine has a bit of a cult following out there, for good reason. Not many people know about this Japanese product but if you google allithiamine and dysautonomia you'll find some interesting testimonials. The Japanese are experts on this vitamin because of their white rice & beriberi situation.

Sulbutiamine, as you note, effectively crosses the BBB which allithiamine does not, at least not in my experience. Allithiamine got rid of my physical limitations but helped only marginally with my main problem which is severe loss of cognitive function, especially executive function. Even while I was doing 10k steps a day I couldn't possibly function in my former academic occupation, the brain fog and loss of intelligence and especially sustained attention was just too impairing.

Sulbutiamine is very nootropic/cholinergic for me but way too acidifying which manifests as a kind of agitated, sweaty negative emotional state. However, at 400 mg the sulbutiamine temporarily got rid of my narrow pulse pressure, POTS and elevated resting heart rate instantly, something that had plagued me every minute of every day for the past 4+ years. 200 mg did nothing. I haven't tried snorting it up but I'd imagine it would give even more of a bump. But the neuropsych sequelae made it not worth taking, plus it gave me a feeling of being on the verge of syncope. Parasympathetic/vagal overshoot IMO. Perhaps the dose could have been more fine-tuned but I was too spooked to try it again.