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

[NexusOwl]

You've increased protein intake and amino acids but not decreased any other food intake and you're very, very hungry? That's baffling!

I'm REALLY hungry... I've had to increase meals and I go to bed hungry. It's a real pain, but I've survived the new year's eve so I think it's helping.

 

[alex3619]

I'm REALLY hungry... I've had to increase meals and I go to bed hungry. It's a real pain, but I've survived the new year's eve so I think it's helping.

All I can think of is something has changed in the way your brain is perceiving either the increased aminos or other things that might include secondary effects. That will most likely stabilize but without knowing for sure this is mostly guessing. Is the hungry all the time, or at some specific time after eating, or seemingly random?

 

[NexusOwl]

All I can think of is something has changed in the way your brain is perceiving either the increased aminos or other things that might include secondary effects. That will most likely stabilize but without knowing for sure this is mostly guessing. Is the hungry all the time, or at some specific time after eating, or seemingly random?

When I wake up I'm not too hungry but if I don't eat I feel really bad. Once I start eating I get hungry again in less than half an hour.

I suspect I might have anemia tho, so maybe the hunger can be explained by it.

 

[JaimeS]

When I wake up I'm not too hungry but if I don't eat I feel really bad. Once I start eating I get hungry again in less than half an hour.

I suspect I might have anemia tho, so maybe the hunger can be explained by it.

Or hypoglycemia?

Hmm. Let us know how this develops, @NexusOwl !

 

[kangaSue]

I'm REALLY hungry... I've had to increase meals and I go to bed hungry. It's a real pain, but I've survived the new year's eve so I think it's helping.

Leptin resistance? Leptin is your satiety hormone so a leptin-resistant person always feels hungry and can be prone to overeat.

Seen more in obesity but you can develop this from constantly going on diets too, something which can be mimicked by gut dysmotility problems where you constantly alter your normal food intake to reduce symptoms so you might eat a little for a few days then try to eat a bit more to compensate for the lost calories or even just return to your normal intake.

 

[AndyPR]

Norwegian TV clip about ME and this study

 

[nandixon]

I wrote on another thread here that I believe that this Fluge & Mella study is showing that the PI3K/Akt/mTOR signaling pathway is being inhibited (or not properly activated). I'm not able to find any other way that SIRT4 expression can be significantly increased, as found in the study, and mTORC1 not be inhibited and everything still make sense. (mTORC1 is one of two mTOR enzyme complexes and is downstream in the signaling pathway.)

A properly activated (unihibited) mTORC1 represses SIRT4. Too much SIRT4 inhibits the pyruvate dehydrogenase (PDH) complex (reference); it inhibits fatty acid oxidation (reference); and it inhibits glutamate dehydrogenase (GDH) which converts glutamate to alpha-ketoglutarate (reference). These inhibitions could contribute to exertion intolerance, exhaustion, PEM, hypoglycemia, and/or glutamate excitotoxicity.

There is also a direct correlation between aldosterone levels, which can be inexplicably low in ME/CFS, and the degree of activation of the Akt/mTOR pathway. (Reference)

Also, fludrocortisone (Florinef), which is sometimes useful in ME/CFS - even in the absence of low aldosterone levels, can help activate the Akt/mTOR pathway. (Reference) So this fits as well.

Interestingly, an inhibited (or unactivated) mTORC1 can cause an impaired ability to concentrate urine. (Reference) So we may finally have an explanation for that common secondary ME/CFS symptom.

Note also that inhibition of the PI3K/Akt/mTOR pathway leads to an upregulation of the pyruvate dehydrogenase kinases (PDKs) (reference), which was also found in the Fluge & Mella study.

So it seems to me that in ME/CFS there may be a dysregulation in the pathway involving mTORC1 that is essentially opposite to that found in most cancers, where mTORC1 is over-activated.

[There's also an additional signaling pathway that leads to mTORC1, the ERK pathway, that is apparently parallel and additive with the Akt pathway. (Reference) I haven't looked at this pathway yet.]

What might help if mTORC1 is in fact inhibited? See my next post.

 

[nandixon]

If mTORC1 is inhibited, then even though it may be well downstream of the primary problem (although an mTORC1 component could actually be the direct target of autoantibodies itself, for example), we might still be able to get some symptom relief by attempting to activate it through a simple technique.

It turns out that mTORC1 is activated via a bidirectional transporter (SLC7A5/SLC3A2). (Reference) And this activation does not use the Akt (or ERK) pathway.

The transporter requires two amino acids to operate. One must be an essential amino acid, of which leucine is best, the other must be glutamine.

The transporter pumps glutamine out of a cell in order to transport leucine into the cell. This counter process activates mTORC1.

So taking leucine and glutamine simultaneously may work to ameliorate at least some ME/CFS symptoms if mTORC1 is indeed inhibited.

Interestingly, when I searched on "leucine" in this forum I found that there was already one member who was essentially using this combination and having some relief:

I started taking BCAAs and glutamine last November and within a week my recovery time from PEM decreased by more than half.

I haven't been able to try this idea yet myself. I ordered both leucine and glutamine powders and have only received the leucine so far. I'll probably try something on the order of taking 2 or 3 grams of each AA twice a day, on an empty stomach first thing in the morning or at least 2 hours after and at least 30 minutes before eating.

Note that if a person is sensitive to glutamine/glutamate they may need to start with only leucine, and gradually add the glutamine over some days or weeks. If the glutamine sensitivity is due to mTORCH1 being inhibited (which impairs the conversion of glutamate to alpha-ketoglutarate), then activation of mTORC1 via leucine and the bidirectional transporter may relieve this and supplemental glutamine will then be needed to prime that transporter.

Also, I doubt that a broad-based AA supplement is likely to deliver as good a result as just the two AAs mentioned, because there's going to be some degree of unintentional inhibition by non-transportable AAs in both transporter directions.

Lastly, leucine is being used here as a signaling agent, not for its ketogenic ability but that might be a secondary benefit.

 

[anciendaze]

We have at least one patient here who has shown a zero level of alpha-ketoglutarate (AKG) on tests, even though glutamates are unusually high. This almost pinpoints the problem.

I have to express caution about even dietary supplements normally considered harmless. (We just saw a patient with very unusual responses to bananas, about as natural and wholesome a food as you can get.) Responses to changes in biochemicals are non-linear, more often than not, and there is a great deal of feedback involved. Raising one level may provoke the opposite response to the one you want.

Whether you are taking medication blessed by a doctor or not, you should always start with low doses, and proceed cautiously to raise them. Do not assume "if a little is good, then more is better."

 

[MeSci]

Whether you are taking medication blessed by a doctor or not, you should always start with low doses, and proceed cautiously to raise them. Do not assume "if a little is good, then more is better."

How many people here (in the UK at least) have their doctors prescribe too-high doses of things and put them off? I certainly have. I have to try to remember (harder since March when my brain went strange) to ask doctors to keep doses low.

 

[anciendaze]

How many people here (in the UK at least) have their doctors prescribe too-high doses of things and put them off? I certainly have. I have to try to remember (harder since March when my brain went strange) to ask doctors to keep doses low.

I have a pill cutter, so should you. You can start low even when doctors don't think this necessary.

 

[Hip]

The transporter requires two amino acids to operate. One must be an essential amino acid, of which leucine is best, the other must be glutamine.

Very interesting! The study you linked to says:

Importantly, L-glutamine and EAA alone have little effect but together they synergize to activate mTOR (Figure 1B). Maximal effects occur with 1 mM L-glutamine, comparable to circulating levels which range from 0.5 to 0.7 mM

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.

 

[Murph]

The ideas @nandixon describes here are exciting (if somewhat beyond my ability to assess in detail).

But the PDH kinases found by Fluge and Mella seem to me important. It firms in my mind for the first time the idea that at least part of the mechanism in CFS is the body shutting things down (in response to ... something), rather than an invader or antibody directly shutting things down without any intervening steps. A deliberate hypometabolism, although probably a mistaken one.

This fits in with the Armstrong/McGregor hypothesis that CFS is like starvation or sepsis, and is almost certainly what Ron Davis is talking about when he keeps talking about "a switch."

The more I learn about metabolism and hypometabolism, the more I understand there may be many such switches. (And none of them are as binary as the term implies!) I'm pleased to learn that such switches are relevant to cancer, because god knows a lot of money is floating round in that field, and it's a way we can hitch a ride on the general progress of science, without necessarily having to have all the progress come from within the field.

Whether mTorc1 is the switch in question, I'm not sure. https://en.wikipedia.org/wiki/MTORC1

There are clues but also countervailing evidence. For example wikipedia says it can be activated by carbs and inhibited by curcumin, which many of us take. (Lastly it says inhibiting mTorc1 can extend lifespan. If this is the switch in question it may explain why so many very sick seeming people just keep on going - but also raises questions of what may happen if we activate it prematurely...)

 

[Mary]

Interestingly, when I searched on "leucine" in this forum I found that there was already one member who was essentially using this combination and having some relief:

I started taking BCAAs (which consist of leucine, isoleucine and valine) and glutamine a little over 2 years ago, at which time they cut my PEM recovery time in half, after taking them for about a week. I still take them and my recovery time is still almost half of what it was before.

I originally took this product: http://www.iherb.com/mrm-bcaa-g-6000-150-capsules/12581 - it was just happenstance that it contained glutamine as well as BCAAs. But I subsequently learned about some of the benefits of glutamine and so continue to take it, as well as BCAAs, though not in the original combo form.

I have cut my dose by maybe 1/4, and realize my recovery time is not quite as good as originally, so after seeing your posts @nandixon and @Hip, I think I will up my dose back to what it originally was (though still not close to what Hip is proposing). It'll be interesting to see how he does! But I do recommend not taking a huge amount all at once until you see how you react. I took the recommended dose on the bottle, 6 caps a day on an empty stomach (empty stomach of course is very important for amino acids), in 2 divided doses - this equaled 2500 mg. leucine, 1500 valine, 1000 mg. isoleucine and 1000 mg glutamine.

 

[Hip]

I took the recommended dose on the bottle, 6 caps a day on an empty stomach (empty stomach of course is very important for amino acids), in 2 divided doses - this equaled 2500 mg. leucine, 1500 valine, 1000 mg. isoleucine and 1000 mg glutamine.

Since BCAA are all essential amino acids (EAA), the 5 grams total of BCAAs you are taking daily equates to 5 grams of EAAs. This is close to the optimum 5.2 gram dose of EAA/leucine that I calculated above. (If I understood the study correctly, you can use either leucine or EAAs for the purpose of mTORC1 activation; leucine of course is just one of the EAAs).

So your 5 grams of BCAAs are already near the 5.2 gram optimum dose, for the purpose of mTORC1 activation.

Thus what you might consider is raising your glutamine dose a bit higher, towards the optimum 5.8 grams daily of glutamine. That might provide a further energy boost, assuming nandixon's mTORC1 activation treatment idea is going to work.

 

[Mary]

Since BCAA are all essential amino acids (EAA), the 5 grams total of BCAAs you are taking daily equates to 5 grams of EAAs. This is close to the optimum 5.2 gram dose of EAA/leucine that I calculated above. (If I understood the study correctly, you can use either leucine or EAAs for the purpose of mTORC1 activation; leucine of course is just one of the EAAs).

So your 5 grams of BCAAs are already near the 5.2 gram optimum dose, for the purpose of mTORC1 activation.

Thus what you might consider is raising your glutamine dose a bit higher, towards the optimum 5.8 grams daily of glutamine. That might provide a further energy boost, assuming nandixon's mTORC1 activation treatment idea is going to work.

Thanks, @Hip. You had mentioned taking 5 grams of leucine alone, which seemed like a high dose of that one amino acid. I will try increasing my glutamine. Actually I just checked my daily dose of BCAAs and glutamine and it's only half of what I originally, took so I'll go back to my original BCAA dose, and will increase my glutamine (in steps) and see what happens -- keep us posted how you do --

 

[MeSci]

I have a pill cutter, so should you. You can start low even when doctors don't think this necessary.

I have - and my current doctor knows it - in fact I use it (have two or three in fact) with his permission for my blood pressure drug. But previous, and stand-in, doctors, don't know, and my memory is currently terrible.

 

[junkcrap50]

Great post @nandixon . Funny you mention alpha-ketoglutarate. I was meaning to ask a question to everyone on this threat.

Does Fluge & Mella's study mention anything about alpha-ketoglutarate dehydrogenase complex (alpha-KDC) aka oxoglutarate dehydrogenase complex (OGDC) and its enzymes?

I ask this because the OGDC is almost identical to the pyruvate dehydrogenase complex (PDC) (as well as the branched-chain α-ketoacid dehydrogenase complex (BCKDC)). Each of these complexes uses the same subunit structure and same cofactors as PDC. The OGDC is also implicated in primary biliary cirrhosis. 2-Oxo-glutarate dehydrogrenase is an [URL='https://en.wikipedia.org/wiki/Autoantigen']autoantigen in the disease.[/URL]

The OGDC is later in the citric acid cycle than PDC, so maybe there aren't as many indicators that may point to a problem in its biochemistry too.

What prompted me to ask this question was reading this paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153090/pdf/biochemj00286-0103.pdf

 

[Hip]

Does Fluge & Mella's study mention anything about alpha-ketoglutarate dehydrogenase complex (alpha-KDC) aka oxoglutarate dehydrogenase complex (OGDC) and its enzymes?

I was looking at this a few days ago. I learnt that pyruvate in fact has three anaplerotic pathways, which provide three Krebs cycle intermediates (the word anaplerotic means to replenish the Krebs cycle intermediates). The creation of acetyl-CoA from pyruvate, via pyruvate dehydrogenase enzyme, is just one of these three pathways.

At timecode 4:24 in this video, it details the 3 anaplerotic pathways of pyruvate, which are the following:

Pyruvate converts to acetyl-CoA (via pyruvate dehydrogenase enzyme).
Pyruvate converts to oxaloacetate (via pyruvate carboxylase enzyme; cofactors include biotin; ref: 1).
Pyruvate converts to alpha-ketoglutarate (via alanine transaminase enzyme; also requires glutamate).

So pyruvate injects Krebs cycle intermediates (substrates) at three points in the Krebs cycle.

As far as I understand from the Fluge and Mella study, it is only the pyruvate dehydrogenase enzyme which is inhibited in ME/CFS; but the enzymes in the other two anaplerotic pathways of pyruvate (the pyruvate carboxylase and alanine transaminase enzymes) are not inhibited. So these other two anaplerotic pathways of pyruvate should continue to work as normal.

However, if have understood this correctly, then it is only the acetyl-CoA anaplerotic pathway of pyruvate which provides energy to drive the Krebs cycle; the other two anaplerotic pathway of pyruvate, oxaloacetate and alpha-ketoglutarate, only serve to replenish these Krebs cycle intermediates, but do not supply energy to the Krebs cycle. That's my understanding, but this is all new stuff for me, so I may be wrong.

Krebs cycle intermediates get used up, because as well as their role in energy production, they are also used as the basis for synthesis of various compounds needed in the body. That's why the Krebs cycle constantly needs these anaplerotic processes to replenish the Krebs cycle intermediates as they get used up.

 

[JaimeS]

However, if have understood this correctly, then it is only the acetyl-CoA anaplerotic pathway of pyruvate which provides energy to drive the Krebs cycle; the other two anaplerotic pathway of pyruvate, oxaloacetate and alpha-ketoglutarate, only serve to replenish these Krebs cycle intermediates, but do not supply energy to the Krebs cycle. That's my understanding, but this is all new stuff for me, so I may be wrong.

Ditto @Hip but...

Just logically speaking and not having read anything additionally. And being very tired and brain foggy as I write this (seriously, I was sitting here for 2 minutes trying to remember the word... the word... $*(#983 dammit. Controversial! I was trying to remember that word.

(On a total side-note, does anyone else notice if they have an aphasia moment that it repeats for the same word? That happens to me a lot.)

....sigh.

Anyway, given all that. If oxaloacetate feeds into the Krebs cycle, by definition wouldn't it be aiding in the process of generating high-energy molecules? Without that feed, the cycle would slow, and the cycle produces these high-energy molecules.

-J