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

[Sidereal]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2425703/pdf/postmedj00252-0008.pdf

N=5 though.

 

[paolo]

N=5 though.

More similar to impaired glycolysis than to PDH deficiency.

 

[Sidereal]

More similar to impaired glycolysis than to PDH deficiency.

Yes. Glycolysis seems to be inhibited based on other research as well (like the Australian study and some comments Ron Davis has made at conferences).

 

[paolo]

I don't understand why Fluge and Mella did not test directly for the PDH acivity in PMBC of their patients. In the mouse study I mentioned above they tested for the PDH activity, for instance.

 

[Snow Leopard]

I don't understand why Fluge and Mella did not test directly for the PDH acivity in PMBC of their patients. In the mouse study I mentioned above they tested for the PDH activity, for instance.

Did you look at the methods of the mouse study in detail? They killed the mice and took tissue samples.

@Snow Leopard https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282483/

I was searching pubmed for articles on lithium and mTor when I came across this article. It talks about lithium activating GPCR I believe, although it is over my head. Perhaps it's of value to you? I plan on using lithium when I start a mini Ketamine trial, for their synergy on mTor activation.

Lithium is far too non-specific and I cannot see how it would be directly useful without dysregulating a whole series of other pathways.

Also, there are many types of GPCR out there, even the list of Rhodopsin-like receptors is quite long (which include neurotransmitter receptors, S1PR etc), it doesn't make sense to inhibit or activate all of these receptors when only one specific pathway is being disrupted due to disease.

https://en.wikipedia.org/wiki/Rhodopsin-like_receptors

If you're looking for an metabolism-Immune-B Cell nexus that could be indicated by low ceramides, this is one. (Of course, I'm not a boichemist, maybe such nexuses are a dime a dozen.)

They are a dime a dozen, at least in the literature where every specialist thinks (from their viewpoint) that what they are an expert in is the central most important part of a complex system. Nails always look like the central feature when you're a hammer.

Mere involvement in immune cell regulation is not unique. Immune cells are complex and require many things to survive and function correctly. But if you are following the hypothesis keep in mind that, inhibiting mTOR inhibits immune cell development.

Lastly, anyone experimenting with specific drugs, eg DCA be very careful! DCA is noted to have substantial side effects in some patients.
Disclaimer: I don't condone this sort of self-experimentation

 

[paolo]

Did you look at the methods of the mouse study in detail? They killed the mice and took tissue samples.

Yes, I know. Is not possible to perform the same test on peripheral blood mononuclear cells (PBMC)?

 

[Snow Leopard]

I don't know if you have already observed in some previous post that a metabolic alteration similar to the one depicted by Fluge and colleagues in ME/CFS, has been described in mice infected with influenza A virus, during the first 7 days of infection (Yamane K et al. 2014). In that study they found a decrease in PDH activity, a depletion of ATP in tissues, and an increase in PDK4 expression.

As antibodies are not produced during the first week after an infection, this PDH disfunction is due to other factors than autoantibodies.

The PDH dysfunction in the Yamane study is obviously due to factors other than autoantibodies. But that does not eliminate the possibility that an autoantibody could disrupt endocrine/autocrine signalling that also potentially leading to the PDH dysfunction observed.

Yes, I know. Is not possible to perform the same test on peripheral blood mononuclear cells (PBMC)?

If you want to test the functioning of an enzyme (in a somewhat similar environment to how it would function in your body) you really need a tissue sample. It might be possible to do with biopsies (they say they used ~1 mg protein per well), but it isn't easy to get patients willing to donate multiple biopsies.

 

[paolo]

The PDH dysfunction in the Yamane study is obviously due to factors other than autoantibodies. But that does not eliminate the possibility that an autoantibody could disrupt endocrine/autocrine signalling that also potentially leading to the PDH dysfunction observed.



If you want to test the functioning of an enzyme (in a somewhat similar environment to how it would function in your body) you really need a tissue sample. It might be possible to do with biopsies (they say they used ~1 mg protein per well), but it isn't easy to get patients willing to donate multiple biopsies.

Thank you @Snow Leopard. It is all very interesting.

 

[deleder2k]

I am discussing this study with a biologist. If there is a casual relationship in the findings why doesn't the disease severity and the biochemistry correlate?

 

[Snow Leopard]

I am discussing this study with a biologist. If there is a casual relationship in the findings why doesn't the disease severity and the biochemistry correlate?

It means that these are not the specific/central factors in the disease, particularly the amino acid findings.

(Though there was a PDK1 association for severity P=0.020 and activity levels. p=0.024)

 

[xrayspex]

When my virus induced chronic recurrent body-wide paresthesias (pins and needles), that lasted for around 9 years (typically getting worse after exercise, and possibly a sign of some neuropathy), benfotiamine was one of the few treatments that had a (temporary) impact on this symptom.

Since 2012, though, when I started taking high dose selenium and N-acetyl-glucosamine every day (and have taken these daily ever since), I have not had any recurrence of my viral paresthesias.

did the selenium ever correlate to any dizziness for you? I have taken it randomly in small amounts along with molybdenum in liquid form per Rich V's advice in the past. This year I started taking them both daily, just a few drops, in smoothies and it coincided with lightheaded/nausaea/dizziness increasing and when I stopped taking it the symptoms decreased significantly-seems the selenium from my various trials was the culprit. Had never noticed sensitivity to it in the past until took it regularly, but things change over the years on what I can tolerate randomly too.

 

[MeSci]

I'm afraid I can't perform scientifically at the moment - since last March at least - as my brain is not right since something happened to it around then. I live in hope...

But if anyone wants my views on animal experiments and doesn't know them yet, here are three blogposts I made when my brain was still working:

http://forums.phoenixrising.me/inde...robiota-fail-to-develop-normal-immunity.1551/

http://forums.phoenixrising.me/index.php?entries/why-differences-matter-more-than-similarities.1576/

http://forums.phoenixrising.me/inde...her-slams-requirement-for-animal-models.1691/

 

[JaimeS]

I am discussing this study with a biologist. If there is a casual relationship in the findings why doesn't the disease severity and the biochemistry correlate?

Some of it does. One of the inhibitors' activity directly correlated to disease severity.

Sorry guys, I'd like to weigh in more -- @paolo 's study looks really interesting -- but I'm going to have to take a raincheck. Haven't been doing super-well yesterday or today. Nothing terrible, just a minor crash. Thanks for the A2A!

Edit: nm, I did read this, when I was looking at PDK inhibitors in the first place. I'll look at it in more detail, though

 

[Cam Newton]

Now we all know that chronic coxsackievirus B infections of the skeletal muscles are linked to ME/CFS, but it is not clear how such infections could cause the autoimmunity that Fluge and Mella found in ME/CFS, nor the energy metabolism dysfunctions that MBM, Fluge and Mella, and other research groups have found.

But that single CVB myocarditis study could be the link: it could explain how these 3 observed facets of ME/CFS — the viral infection, the autoimmunity, and the energy metabolism dysfunction — all tie together to create a Grand Unifying Theory of ME/CFS:

CVB infection ➤ triggers translocator protein autoantibodies ➤ which whack the mitochondria ➤ leading to ME/CFS

It seems unlikely, to me, that a CVB infection could be the initial trigger to everyone's me/cfs. From my understanding there are a wide variety of infections that trigger me/cfs. For me, and others, it was obviously an ebv (and resulting mono) infection that was the initial trigger.

Furthermore, a wide variety of infectious triggers points to the actual trigger of me/cfs being the response to the infection, rather than the infection proper.

Or am I misunderstanding your theory?

 

[Hip]

It seems unlikely, to me, that a CVB infection could be the initial trigger to everyone's me/cfs. From my understanding there are a wide variety of infections that trigger me/cfs. For me, and others, it was obviously an ebv (and resulting mono) infection that was the initial trigger.

Yes agreed, but I think enterovirus may well be responsible for a good 50% of ME/CFS cases.

If you look at Dr John Chia's assessment of the likely cause of ME/CFS in 200 consecutive patients, active enterovirus infection comes up in 55% of the patients. So although other pathogens (and non-infectious triggers such as vaccination) may potentially be causes of ME/CFS or ME/CFS-like symptoms, enteroviruses such as coxsackievirus B and echovirus are probably responsible for a good 50% of the cases.

It possible that different pathogens have different methods of causing ME/CFS. If we assume that ME/CFS is caused by the sort of energy metabolism blockages found in the Myhill, Booth and McLaren-Howard Studies, and in this Fluge and Mella study, then it is possible that different pathogens may cause these blockages by different mechanisms. So you would get the same sort of ME/CFS symptoms, but the mechanism of blockage may be different across the various pathogens associated with ME/CFS.

Furthermore, a wide variety of infectious triggers points to the actual trigger of me/cfs being the response to the infection, rather than the infection proper.

Not that wide really, in practice:

Let's assume that 55% of ME/CFS cases can be attributed to enterovirus. Then in this post, I calculated that 20% of ME/CFS cases can be attributed to EBV.

So as a very rough assessment, 75% of all ME/CFS cases might be attributable to enterovirus or EBV.

Then all the other pathogens linked to ME/CFS will only account for 25% of ME/CFS cases.

 

[antherder]

Lastly, anyone experimenting with specific drugs, eg DCA be very careful! DCA is noted to have substantial side effects in some patients.
Disclaimer: I don't condone this sort of self-experimentation

Re DCA and chlorine sensitivity:

Just wanted to mention this caution in case it's relevant to anyone else.

When I ran my 23andme results through Promethease, it came up with this;

https://www.snpedia.com/index.php/Gs311

I have no idea how accurate this information is, and I couldn't find hardly anything else about it, but it is very interesting to me, as I've always had problems with chlorinated water.

The link also mentions how a high protein diet can slow the metabolism of this drug.

 

[Hip]

When I ran my 23andme results through Promethease, it came up with this;

https://www.snpedia.com/index.php/Gs311

Looks like the following page may be more relevant:

https://www.snpedia.com/index.php/Gs310

In the above they talk about the gene glutathione transferase (GSTz1) and its involvement in metabolizing DCA. Though it looks quite complicated to figure out whether you are a slow or fast metabolizer of DCA, as it depends on more than one SNP within this gene.

Interesting that they say DCA is found in chlorinated swimming pools and in chlorinated water.

 

[acer2000]

Is there any literature suggesting that mycotoxins inhibit this process in the way it is being described? I ask because a lot of cfs patients report mold avoidance and or treatment has made them feel better.

 

[Hip]

Is there any literature suggesting that mycotoxins inhibit this process in the way it is being described? I ask because a lot of cfs patients report mold avoidance and or treatment has made them feel better.

Yep, a few mycotoxins have been shown to have toxic and inhibitory effects on mitochondria: see this post.

 

[Murph]

... at least in the literature where every specialist thinks (from their viewpoint) that what they are an expert in is the central most important part of a complex system. Nails always look like the central feature when you're a hammer.

Good point! I've been using the PubMed search feature a bit in the last 6 months, and over time, my familiarity with the phrasing used in papers has improved.... I am slowly getting less excited when something is described as a "a key feature". (I think I've never seen something described as simply "a feature".) It's easy to think you're onto the one ring to rule them all when in fact you're holding some orc's toenail.

Also, authors often describe what their particular enzyme activates or affects, without necessarily mentioning all the other 100 molecules that also activate or affect that target. In a plain English reading 'X causes Y' makes X seem indispensable. But our metabolisms often seem to have myriad workarounds in the absence of X.

All traps for the young player without an advanced biology education! And why I appreciate people on these forums who do have some more understanding weighing in.