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

[antherder]

Looks like the following page may be a more relevant:

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

That's a much better link. Thanks for tracking it down.

 

[nandixon]

It seems there is a major departure in the findings between ME/CFS and SIRS/sepsis. Naviaux found that ceramides are low, whereas in sepsis they are actually high (e.g., 2016 reference, 2003 reference).

Researching this further, studies have shown an inverse correlation between sphingosine kinase 1 (SK1 or SPHK1) activity and ceramide levels. (SK1 is the enzyme that makes S1P from sphingosine which in turn is made from different ceramides.)

In particular:

S1P inhibits CerS2 [ceramide synthase 2] activity in vitro by interacting with two residues that are part of an S1PR-like motif found only in CerS2 and not in other CerS (5). However, CerS2 does not efficiently utilize C16-ceramide as a substrate, and it is predominantly this ceramide species that is most reduced when SphK1 is overexpressed (4). [Reference]

It looks a bit suspicious that the C16-ceramide (d18:1/16:0 aka N-palmitoyl-D-erythro-sphingosine) was the one most significantly reduced in males in the Naviaux study. (See supplementary material, Table S1.)

Based on the above, of the two options I previously mentioned, the second option - that S1P may be high in ME/CFS - seems more likely to me now:

If S1P is low, then presumably it's because of the low ceramides (or because there are autoantibodies directed against S1P)...

If S1P is high (or normal), then perhaps it's because there are autoantibodies directed against one or more S1P receptors (e.g., S1PR1 aka S1P1), causing S1P production from ceramides to be upregulated in a effort to overcome this (and making ceramides low in the process).

So a possible reason why Montoya apparently found such a high ("100%") correlation in mRNA gene expression between ME/CFS and SIRS is perhaps that in both diseases there is impaired S1P signaling, but in SIRS this is due to low levels of S1P (reference) while in ME/CFS this is due to autoantibodies against a S1P receptor(s) (or associated components).

It could really be helpful now if S1P levels were measured in ME/CFS as this could help focus an autoantibody search.

 

[eljefe19]

@nandixon I'm going to the OMI on Wednesday for my first appointment, I will be sure to pass your post on to the doctors and hopefully Prof Davis.

 

[AndyPR]

@nandixon I'm going to the OMI on Wednesday for my first appointment, I will be sure to pass your post on to the doctors and hopefully Prof Davis.

FYI, the OMI is a different organization to the OMF (Open Medicine Foundation) which Ron Davis is part of. Common confusion due to the similarities in name.

 

[Sidereal]

It seems there is a major departure in the findings between ME/CFS and SIRS/sepsis. Naviaux found that ceramides are low, whereas in sepsis they are actually high (e.g., 2016 reference, 2003 reference).

Yes, ME/CFS is not a 100% match to sepsis or SIRS or starvation or any of those loose analogies researchers have used, otherwise it would be one of those conditions. As Naviaux points out in his paper and Q&As, the closest match to a known metabolic signature seems to be dauer where the body seems to perceive an inability to overcome the stressor and just hunkers down basically and sequesters key energy metabolites to limit their availability to the pathogen. Hence the "everything low"/hypometabolic pattern in ME/CFS.

 

[Snow Leopard]

More confirmation bias.

Human Cytomegalovirus Regulates Bioactive Sphingolipids
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533798/

Finally, we present evidence that de novo sphingolipid synthesis and sphingosine kinase activity directly impact virus gene expression and virus growth. Together, these findings demonstrate that host cell sphingolipids are dynamically regulated upon infection with a herpes virus in a manner that impacts virus replication.

Also of note, Fingolimod can lead to reactivation of herpes viruses and has led to several deaths as a result...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446999/

 

[eljefe19]

Similar to how citrulline is able to restore muscle protein synthesis rates[59][60]and muscular function[61] during aging and malnourishment in rats via mTORc1 dependent means,[62][63] citrulline itself is a weak agonist (enough that it could be false positive from sensitizing mTORc1[59]). Conversely, Leucine itself is a potent activator of mTORc1 activity.

Citrulline may positively mediate leucine's signalling through mTOR, which theoretically suggests that they are synergistic.

Examine

 

[eljefe19]

@nandixon
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746808/

Siponimod is a true agonist of both S1P1 and S1P5. It's currently in Phase iii trials. Appears to have opposite action to Fingolimod.

 

[nandixon]

More confirmation bias.

Human Cytomegalovirus Regulates Bioactive Sphingolipids
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533798/

That's actually funny because the testing I've had shows that the only herpes class virus I've ever been infected with is CMV. (I'm completely negative for EBV, for example.)

 

[nandixon]

@nandixon
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746808/

Siponimod is a true agonist of both S1P1 and S1P5. It's currently in Phase iii trials. Appears to have opposite action to Fingolimod.

It actually does the same:

These data suggest that BAF312 [siponimod] may likely induce transient S1P1R stimulation followed by long-term functional antagonism similar to pFTY720 [fingolimod].

You can tell that if something affects the S1P receptors in a way that's beneficial for MS (or other autoimmune diseases like SLE, psoriasis) or cancer or neurodegenerative diseases (like AD, PD) or metabolic diseases (like type 2 diabetes, obesity), then it's not likely to be useful for ME/CFS under the hypothesis in my signature.

In those other diseases, the Akt/mTORC1 pathway is over-activated while in ME/CFS (and sepsis, starvation, cachexia, etc) it appears to be under-activated, based on the Fluge & Mella study and other work.

 

[eljefe19]

@nandixon Ahh rats. Well, at least we can target mTorC1. I do think my regimen doing just that has had beneficial effect on PEM and energy levels in the last two weeks.

 

[Bdeep86]

Sorry I may have missed but does the Fluge study show low ceramides? I think I missed that if it did. Is this from another study?

 

[nandixon]

Sorry I may have missed but does the Fluge study show low ceramides? I think I missed that if it did. Is this from another study?

It's the Naviaux study that shows that. (See this post for a link.)

 

[Bdeep86]

@Hip Did you try the DCA at a lower dose?

 

[junkcrap50]

More confirmation bias.

Human Cytomegalovirus Regulates Bioactive Sphingolipids
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533798/



Also of note, Fingolimod can lead to reactivation of herpes viruses and has led to several deaths as a result...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446999/

Actually, several viruses regulate sphingolipids, and in particularlly S1P. I found and bookmarked several papers on it, including a couple review papers. I'll try posting this evening. I basically just googled "S1P and [virus/influenza/EBV/CMV/HHV6/B-cells]"

 

[eljefe19]

Acute injections of THC induce rapid and transient stimulation of mTORC1 activity in the hippocampus, striatum, cerebellum, frontal cortex and amygdala91,92, whereas repeated administration of THC leads to more sustained activation of mTORC1, lasting for several days after the cessation of treatment92

Ladies and gentlemen, may I present, THC injections given chronically produce long lasting activation of mTorC1.

 

[MeSci]

Ladies and gentlemen, may I present, THC injections given chronically produce long lasting activation of mTorC1.

In a particular breed of mouse, I believe. It may be the same in humans, it may not.

 

[eljefe19]

In a particular breed of mouse, I believe. It may be the same in humans, it may not.

It was somewhat of a joke. I've used medicinal pot for years with no improvement in my illness. Just palliative care.

 

[nandixon]

Ladies and gentlemen, may I present, THC injections given chronically produce long lasting activation of mTorC1.

It looks like there may be a dichotomy between what the cannabanoid receptors do in the brain versus elsewhere in the body.

In reference #92 given in the article you quoted, they are showing mTORC1 to be upregulated in the (mouse) brain by THC acting as an agonist of the cannabanoid 1 receptor (CB1 receptor aka CB1R).

However, other studies are showing the opposite:

Treatment of the CB1R by the antagonist drug rimonabant upregulates mTORC1 in (mouse) pancreas. (Reference)

Treatment of CB1R by an antagonist drug called AM251 does the same in (human) skeletal muscle - and also reduces pyruvate dehydrogenase kinase 4 (PDK4), which helps increase PDH complex activity. (Reference)

Antagonism with AM251 also upregulates mTORC1 in (rat) abdominal muscle and again increases PDH activity (apparently by increasing expression of the E3 subunit). (Reference)

So THC would not seem to be so good from the physical energy point of view since it may down-regulate mTORC1 outside of the brain and make matters worse for the PDH complex.

 

[eljefe19]

@nandixon Is any of that permenant or will it revert upon abstinence?

Come to think about it, THC definitely improves my mental energy but probably does make me more physically sluggish. Oh well I'd rather be comfortable.