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

[deleder2k]

@Snow Leopard, I don't know what they do and not do, but they have always been very careful in saying "too much". I think at no point did the say that they had applied for a patent for nitric oxide treatment, and that they've been engaged in a few small pilots. It also took them a long time to say anything about the cyclophosphamide discovery. As I said; I don't have any clue, but I wouldn't rule out that they know more than they say. Another example could be the fact that they probably know whether their rituximab trial is positive or not now. They are of course blinded, but when they look at the data and look at the total response rate, and then study those patients that have improved, they will get pretty good idea of what the response rate will turn out to be. We also know that the placebo effect in the phase 2 trial was minimal. If that stays the same in this trial, they have a pretty good idea of how the study will turn out.

 

[nandixon]

Thanks I'll look into it. Haukeland is aware that some say they improve drastically after alcohol intake. As far as I know they are working on some gene analysis' with regards to this in the lab.

@deleder2k, your post reminded me that I forgot to give you a reference I'd found on how your relief of ME/CFS symptoms with acute alcohol ingestion appears to fit in with the under-activated Akt/mTORC1 pathway theory.

In this 2010 study (on mice):

We found that acute in vivo exposure of both strains of mice to alcohol significantly increased the phosphorylation level of S6K and 4E-BP proteins (Fig. 1 and Fig. S1A). These results indicate that acute alcohol treatment triggers the activation of the mTORC1 signaling pathway in the NAc [nucleus accumbens].

I haven't studied it well enough myself, since alcohol is bad for me, but I think the authors suggest in the paper that there's some sort of undesirable molecular neuroadaptation that can happen that would cause a person to have an increased mTORC1 response in this way, and thus for alcohol to appear to be "beneficial."

The authors' findings also fit with your experience of the positive effect of alcohol for you lasting well into the next day (I think @Bdeep86 also experiences this as well):

We observed that both mTORC1 substrates, S6K and 4E-BP, are phosphorylated in the NAc of rodents in response to a single exposure to alcohol, in response to voluntary alcohol consumption, and after 24 h of alcohol deprivation.

Or as the same researchers stated later in a 2014 paper:

In agreement with this hypothesis, we observed that excessive alcohol drinking ... triggers mTORC1 activation in the NAc which lasts at least 24 hours after alcohol withdrawal (Neasta et al. 2010).

 

[Asklipia]

The authors' findings also fit with your experience of the positive effect of alcohol for you lasting well into the next day (I think @Bdeep86 also experiences this as well):

Same for me.

 

[Tiger_Eyze]

STAT3 is going to be under-activated in ME/CFS. We know this for a number of reasons, including finding low VEGF-A in patients. (Reference)

Given that, the possibility of increased HIF1α seems pretty unlikely, especially since mTORC1 is under-activated. Note also that Fluge & Mella specifically looked at HIF1α in their study and didn't find an increase.

Since the Fluge & Mella study, I've found it extremely helpful in understanding ME/CFS to adopt the paradigm of an under-activated Akt/mTORC1 pathway (i.e., the opposite of most other diseases). If an idea runs counter to that then it's not likely to be correct.

I'm not disagreeing with you on the mTorc downregulation; hence my specification that Hif1a can be expressed via a pathway that doesn't require AKT/mTorc activation.

My mom and I have high VEGF. I know a few others who do as well. So by your logic, our STAT3 is up-regulated, right?

The cluster of markers in that paper was only 43-46% sensitive for CFS, so less than half of patients with CFS have low VEGFA, low IL7 & low IL16. In their scatter plots, VEGF had a huge range among healthy and CFS, with the highest outliers actually among the CFS cohort. They tried to attribute most of the higher numbers to patients with comorbid PSC, but only a few of the highest VEGFA people came from that group.

So isn't it possible lower median VEGF is one subpopulation and there is another with higher VEGF? Maybe the high VEGF people have autonomic/endothelial dysfunction bad enough to cause a degree of ischemia, or maybe we have too much STAT3 and/or too much NFKB due to cytokine signaling or other factors.

Additionally, in Fluge's paper, they detected and compared mRNA levels of HIF1a, etc., not the actual protein levels.

I was under the impression Hif1a is constitutively expressed at some level, but its effects in the cell are primarily determined by post translational modifications that affect its stability and degradation. If thats true, mRNA may not reflect actual functional levels of the protein, yea?

I'm really trying to dig in and make sense of how all the info fits together in my/my mom's cases because we are deciding whether or not to pursue Rituxan vs Ampligen vs Plasmapheresis next.

If auto-antibodies are driving everything - which F&M seem to think based on the response lag time in Rituxan responders, plasmapheresis should technically work similarly by removing the antibodies, without the potential side effects, right?

But if it's cytokines Rituxan is reducing, plasmapheresis won't help much from what I understand.

If it's an infection, Ampligen would help.

I really appreciate all of your help and insight on this. Your level of knowledge is incredible!

 

[nandixon]

@Tiger_Eyze, How long have you and your mother had ME/CFS for?

 

[nandixon]

So isn't it possible lower median VEGF is one subpopulation and there is another with higher VEGF? Maybe the high VEGF people have autonomic/endothelial dysfunction bad enough to cause a degree of ischemia, or maybe we have too much STAT3 and/or too much NFKB due to cytokine signaling or other factors.

That's a good point about excessive NFkB being a possible cause for your increased VEGF.

 

[Tiger_Eyze]

@Tiger_Eyze, How long have you and your mother had ME/CFS for?

I think my mom & I had symptoms of undiagnosed Hashis (and myself of antibody subclass deficiency) for years, but we could exercise fine and had no cognitive issues. The downward spiral really kicked off after a weird 'flu' -ascending numbness and weakness for me, and malaise/low fevers for her - in fall of 2004. So just past 12 years for us.

 

[Bdeep86]

@deleder2k, your post reminded me that I forgot to give you a reference I'd found on how your relief of ME/CFS symptoms with acute alcohol ingestion appears to fit in with the under-activated Akt/mTORC1 pathway theory.

In this 2010 study (on mice):



I haven't studied it well enough myself, since alcohol is bad for me, but I think the authors suggest in the paper that there's some sort of undesirable molecular neuroadaptation that can happen that would cause a person to have an increased mTORC1 response in this way, and thus for alcohol to appear to be "beneficial."

The authors' findings also fit with your experience of the positive effect of alcohol for you lasting well into the next day (I think @Bdeep86 also experiences this as well):



Or as the same researchers stated later in a 2014 paper:

Again my guess is the acute alcohol stimulating bile synthesis and flow (which it does to a major extent), is influencing the bile acid sensors (particularly FXR). I haven't studied the FXR-Akt-Mtor axis in great depth but I can look into it more this week.

 

[deleder2k]

Thank you so much for your answer, @nandixon. I told my doctor about my experiences with alcohol, and he gave me a script for Verapamil - a calcium channel blocker. 60 mg three times a day. I've only tried it for three days, so I can't conclude. I read about calcium channel blockers and alcohol on wikipedia. Not sure if my doc is on the right track or not: https://en.wikipedia.org/wiki/Calcium_channel_blocker#Ethanol

Ethanol[edit]

Ethanol blocks voltage-gated calcium channel
Research indicates ethanol is involved in the inhibition of L-type calcium channels. One study showed the nature of ethanol binding to L-type calcium channels is according to first-order kinetics with a Hill coefficient around 1. This indicates ethanol binds independently to the channel, expressing noncooperative binding[12] Early studies showed a link between calcium and the release of vasopressin by the secondary messenger system.[13] Vasopressin levels are reduced after the ingestion of alcohol.[14] The lower levels of vasopressin from the consumption of alcohol have been linked to ethanol acting as an antagonist to voltage-gated calcium channels (VGCCs). Studies conducted by Treistman et al. in the aplysia confirm inhibition of VGCC by ethanol. Voltage clamp recordings have been done on the aplysia neuron. VGCCs were isolated and calcium current was recorded using patch clamp technique having ethanol as a treatment. Recordings were replicated at varying concentrations (0, 10, 25, 50, and 100 mM) at a voltage clamp of +30 mV. Results showed calcium current decreased as concentration of ethanol increased.[15] Similar results have shown to be true in single-channel recordings from isolated nerve terminal of rats that ethanol does in fact block VGCCs.[16]

Studies done by Katsura et al. in 2006 on mouse cerebral cortical neurons, show the effects of prolonged ethanol exposure. Neurons were exposed to sustained ethanol concentrations of 50 mM for 3 days in vitro. Western blot and protein analysis were conducted to determine the relative amounts of VGCC subunit expression. α1C, α1D, and α2/δ1 subunits showed an increase of expression after sustained ethanol exposure. However, the β4 subunit showed a decrease. Furthermore, α1A, α1B, and α1F subunits did not alter in their relative expression. Thus, sustained ethanol exposure may participate in the development of ethanol dependence in neurons.[17]

Other experiments done by Malysz et al. have looked into ethanol effects on voltage-gated calcium channels on detrusor smooth muscle cells in guinea pigs. Perforated patch clamp technique was used having intracellular fluid inside the pipette and extracellular fluid in the bath with added 0.3% vol/vol (about 50-mM) ethanol. Ethanol decreased the Ca2+ current in DSM cells and induced muscle relaxation. Ethanol inhibits VGCCs and is involved in alcohol-induced relaxation of the urinary bladder.[18]

 

[gregh286]

Same for me.

Same for me. Lasts about 24 hours. So much so I could do 10km run in Monday and housebound by tuesday at start of illness...but not from PEM. My energy swings are totally wild.
I've been a pretty heavy drinker all my adult life and.prehaps my body has readapted in some way to this for the worse.
When I originally took AAKG and got complete symptom relief last year I assumed like fluge and mella it was NO synthesis.
But something didn't sit right because let's say I never needed viagra.....so I didn't think i was low.in NO.
But I think the AAKG is just another mTORC activator lie like alcohol.
I also react really favourably to carbs...and this also increases the pathway.
But MTORC has habit of finding homeostasis so now I need to rotate continuously to stay high on bell scale.

 

[MeSci]

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.

I'm trying cimetidine on your recommendation (don't worry - I won't blame you if it doesn't work!) Do you remember how long it took to work? I'm taking 50 mg twice a day like you, but my other supplements differ of course.

I've been ill for about 22 years, and have been worse for the last year. 63 years old, almost 64. Not as bad as you, but living alone, so can't afford to get any worse.

I'm vegan, and have rather high acid levels a lot of the time, despite trying to minimise them.

 

[gregh286]

One question to the biochemists here: do recent metabolic studies tell us what diet would be ideal? Should we try to increase consumption of certain nutrients? What's the story with males and amino acids? This study here says that males are breaking down proteins at increased rate in order to make energy. Should malesincrease amino acids in their diet? Whitney seemed to benefit from amino acid supplementation.

I live on aminos.
My glutamine was really low when tested.
Body using it for alternative fuel.

 

[nandixon]

Do you remember how long it took to work? I'm taking 50 mg twice a day like you, but my other supplements differ of course.

@MeSci, The cimetidine started working within a day or two after I started using the 50 mg dosing, but I think I had been experimenting with higher doses first for about a week. So I'm not sure how long it might take starting with the lower dose at the outset.

Just to mention too, another member posted about her experience on an old cimetidine thread, and she apparently found that a single dose of 200 mg every other day worked best for her. I thought it was interesting that the two different dosing methods each averaged out to 100 mg per day.

Also, I have a progressive version of ME/CFS, and even though cimetidine took me from entering into a bedridden state to a more moderate level, my illness has continued to be slowly progressive in spite of the cimetidine these last couple of years since I began taking it. I do still notice less energy when I forget to take it, though.

 

[boolybooly]

Rootling around I found this 1996 paper which suggests that in a rat model, septic challenge induces PDHkinase activity which inhibits PDH activity.

https://www.ncbi.nlm.nih.gov/pubmed/8856841

This indicates the PDH responds to the need for immune activity.

Strikes me that from an evolutionary perspective that you would expect animals to be flexible with nutrition pathways if they were fighting an immune challenge, since it enables using all their body reserves rather than digesting new food.

This might be why it looks like hibernating, similar kind of process, curl up, hide away and stop activity until you feel better while the immune system is geared up and using energy from body mass reserves.

This suggests the PDH changes in ME patients might be indicative of immune activation, which we already suspect, though its nice to have more evidence.

It struck me this might also explain the failure of anabolic responses which I noticed all the time (30y) I have been ill. i.e. muscles challenged by exercise do not appear to get stronger or fitter. Just a thought.

 

[Sing]

I wonder if Dr. Paul Cheney's comment years ago is pertinent here? He said that if only his patients didn't have to eat, they would be much better.

It sounds like what you are suggesting @boolybooly is that due to some form of immune challenge and activation, the body switches over to a backup system for energy production--i.e., using the body's reserves instead of new food. But in our case, this switch has gotten stuck. Is that it?

Also, not being scientifically trained, I do not know what you mean about the failure of anabolic responses. Does that mean just what your example means, that muscles do not get stronger with exercise?

It seems we are experiencing and now scientifically finding many metabolic processes which are changed or impaired--such as the gut and liver interactions too. As a 20y patient, I am deeply interested in understanding more but would ask those of you with scientific expertise to follow your contributions with a translation!

 

[nandixon]

Rootling around I found this 1996 paper which suggests that in a rat model, septic challenge induces PDHkinase activity which inhibits PDH activity.

https://www.ncbi.nlm.nih.gov/pubmed/8856841

This indicates the PDH responds to the need for immune activity.

Strikes me that from an evolutionary perspective that you would expect animals to be flexible with nutrition pathways if they were fighting an immune challenge, since it enables using all their body reserves rather than digesting new food.

Sepsis is not part of a desirable immune response. Sepsis is an aberrant pathological inflammatory state that the body has mistakenly gotten itself into. The same state can happen without the presence of any triggering pathogen. This is called Systemic Inflammatory Response Syndrome (SIRS).

The decrease in the PDH complex (as a result of increased PDK activity) in sepsis is not a helpful adaptation. As mentioned, it's indicative of a mistake or defect. The lower PDH goes in sepsis patients, the higher their mortality.rate.

Clinicians have tried, for example, to prevent PDH from decreasing in sepsis patients by administering dichloroacetate (DCA), but without success. In the most recent (2015) followup study to the 1996 paper cited, the authors are suggesting that thiamine be tried instead in order to increase PDH. (It's rather mind-boggling that it only took 20 years for the medical establishment to think of that, whether it works or not)

This might be why it looks like hibernating, similar kind of process, curl up, hide away and stop activity until you feel better while the immune system is geared up and using energy from body mass reserves.

This suggests the PDH changes in ME patients might be indicative of immune activation, which we already suspect, though its nice to have more evidence.

In ME/CFS, multiple studies have found increased numbers of Tregs in patients (and no studies with decreased Tregs, I believe), indicating that we are more likely immunosupressed rather than immunoactivated.

The success with rituximab, for example, gives the appearance that we're not immunosuppressed, but that's only because the pathways that are affected in ME/CFS are probably the same ones that lead to immunosuppression when under-activated..

To further explain this, using as a model an under-activated Akt/mTORC1 pathway (which is just a theory I have, but I think the best one right now), let's say for the sake of argument that rituximab works in ME/CFS patients by reducing autoantibodies. (It may or may not be working that way.) If those autoantibodies are antagonistically directed against some component related to the Akt/mTORC1 pathway, then the result would be a tendency for an increase in Tregs (i.e., immunosuppression) to occur, because the Akt/mTORC1 pathway plays a role in controlling the activation and de-activation of Tregs. (Conversely, increasing Akt/mTORC1 activity causes a decrease in Tregs and hence immune stimulation.)

Thus, there's the very interesting possibility of the use of an immunosuppressant (rituximab) actually resulting in immunostimulation in ME/CFS.

It struck me this might also explain the failure of anabolic responses which I noticed all the time (30y) I have been ill. i.e. muscles challenged by exercise do not appear to get stronger or fitter. Just a thought.

That was my experience too, when I was still able to do a little exercise.

 

[adreno]

@nandixon

Since exercise activates the Akt/mTOR pathway, why doesn't GET work, according to your theory?

 

[Sidereal]

It struck me this might also explain the failure of anabolic responses which I noticed all the time (30y) I have been ill. i.e. muscles challenged by exercise do not appear to get stronger or fitter. Just a thought.

Same here, never saw any improvement in strength or fitness during the years when I could still exercise. For a while I went to the gym religiously and did not experience any benefit. Looking back, I've always had an activity "ceiling" regardless of how much or how little I exercised. Which is why I've always found the GET/deconditioning theories utterly perplexing and running contrary to my life experience.

 

[Sidereal]

Clinicians have tried, for example, to prevent PDH from decreasing in sepsis patients by administering dichloroacetate (DCA), but without success. In the most recent (2015) followup study to the 1996 paper cited, the authors are suggesting that thiamine be tried instead in order to increase PDH. (It's rather mind-boggling that it only took 20 years for the medical establishment to think of that, whether it works or not)

Typical medical establishment, go for some random toxic drug instead of a harmless vitamin. I bet when they finally trial thiamine they'll use ineffective forms.

Btw, I know people here freak out when I bring up lipoic acid but there is a bit of evidence from the animal models of SIRS/sepsis that it improves outcomes.

 

[deleder2k]

I am not certain, but I think I have been feeling better the few times I have fasted.