A few theories based on recent findings

[AdamS]

Hi all, like many of us on here I read quite a lot about ME, mainly because I want to solve it, get better and go for a pint with all of you great people when i'm well!

I decided to map out a few theories based on what i've been reading about energy metabolism over the past few weeks/months, I don't expect much of this to be new to you, but i've added my own spin on a few of the theories...hopefully it gets us talking and thinking of new ideas All comments, criticism and ideas welcome!

EDIT: I've also created a map of common serum contents, if it's the case as Davis, Fluge & Mella say that the problem is in ME/CFS patients' serum, then these are the areas we need to be searching. (These are from wikipedia, there may be some overlap).

Cheers, Adam

 

[lansbergen]

I am in favor of 4 but that does not exclude the others.

 

[arewenearlythereyet]

This looks great but you forgot the most common cause...... The BPS theory that it's all in our heads!

I'm open to any theory given where we are but anything that centers around Krebs cycle blockage seems to be more on track. Theory 4 seems the least likely for me.

 

[A.B.]

ME/CFS might be a mix of different diseases that have in common substantial impairment of energy production.

 

[Tunguska]

The Fluge & [Mella] also noted increased PPARδ.

You mentioned FoxO1. Normally a lot of this would be mediated by FoxO1 and FoxO3. They act as the stress response program for the cell and dominate in starvation + increase lipolysis reliance. It was already posted that FoxO1 will increase PDK but so will FoxO3:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354049/#bib5
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486978/#__sec2title

Thus, FOXO3a has multiple effects on mitochondrial function; it reduces mitochondrial capacity through inhibition of c-Myc and lowers the entry of pyruvate into the mitochondrial metabolism by induction of PDK4 [etc]

The problem is, almost any stress signal can set off FoxO, so it gives you no real information, and there is a little bit of conflicting info here and there w.r.t. CFS/ME. I think the repression of FoxO by Akt may be one part of why "mTor" activators seem to help but it's also possible for signal to "force" FoxO in spite of Akt.

nandixon posted more specific other ways in which PDK might get ablated and mTor might help in the Fluge & Magella thread, the sphingolipid and S1P-related ideas, etc, I don't have the post links on hand. I am just trying to paint a general picture.

 

[Jesse2233]

These posts are great @AdamS

From my own blood work I can attest something strange is happening with pyruvate and one or more Krebs cycle enzymes

Looking forward to reading more discussion

 

[AdamS]

The Fluge & Magella also noted increased PPARδ.
nandixon posted more specific other ways in which PDK might get ablated and mTor might help in the Fluge & Mella thread, the sphingolipid and S1P-related ideas, etc, I don't have the post links on hand. I am just trying to paint a general picture.

Yes, it would be cool to get @nandixon 's input.

As far as the Sphingolipid findings go, Fluge & Mella said the following:

The most prominent changes in ME/CFS patients were widespread decreases in sphingolipids, glycosphingolipids, and phospholipids. These findings were consistent with a lower ATP and GTP turnover and with decreased amounts of branched amino acid metabolic intermediates.

I'm not sure how to interpret this, are they saying that lower ATP turnover results in decreases in sphingolipids etc? It's hard to tell.

Our studies in cultured human muscle cells indicated that exposure to ME/CFS serum led to increased rates of mitochondrial respiration, driven by amino acids alone or in combination with glucose. This effect was particularly evident under conditions of energy depletion, when mitochondrial respiration works at a maximum rate (condition IV). Although lactate production tended to be low under resting conditions, it was excessively induced by energetic strain in muscle cells exposed to ME/CFS serum. These observations are compatible with a metabolic obstruction at the level of PDH

One thing that stands out to me is the above, something in ME/CFS serum is causing this, Davis said this too in his video. I've created a map of common serum contents below, i've also added it to my first post in the thread.

 

[A.B.]

The evidence seems to point towards the factor x in blood being an antibody or some undiscovered chemical signal.

 

[wastwater]

Could something cleave away or take out foxo function from the genome
Foxo has many functions

 

[AdamS]

@A.B.

Agreed, just looking at the key serum contents, one thing stands out to me: Antigens

I'm of the opinion that it is some kind of large antigen/molecule which triggers the initial insult/response and then on a very basic level the antibody/antibodies produced as a result of this antigen mean that every time we exert ourselves we trigger an immune response/cascade of reactions which leave us feeling terrible. All speculation of course, but that is my educated guess.

The antigens/molecules which can trigger immune responses and activate lymphocytes are called immunogens apparently.

>> EDIT: On reflection my comment about antigens is probably way off. I'm gunna leave it on here but it could be complete nonsense so i'd probably ignore it. As many have already said, best to leave it to the experts

 

[Tunguska]

Our studies in cultured human muscle cells indicated that exposure to ME/CFS serum led to increased rates of mitochondrial respiration, driven by amino acids alone or in combination with glucose. This effect was particularly evident under conditions of energy depletion, when mitochondrial respiration works at a maximum rate (condition IV). Although lactate production tended to be low under resting conditions, it was excessively induced by energetic strain in muscle cells exposed to ME/CFS serum. These observations are compatible with a metabolic obstruction at the level of PDH

I think the bold part is just increased beta-oxidation as compensation.

The blood factor is discussed in the Ron Davis thread I think, they said it had to be [large] ([use search function]).

nandixon is in best position to comment about the sphingolipids.

Could something cleave away or take out foxo function from the genome

Practically-speaking it's essential to survival to acute stressors via temporary activation [and controlling growth], so that's not a good idea. It's chronic overactivation that causes issues.

 

[aquariusgirl]

I really wonder abut a role for copper & iron dysregulation ? Also if accumulation of copper II is inhibiting sulfation?

 

[Alvin2]

I used to be like you OP, but 30 years later i have learned with difficulty that sometimes i need to step back and let the pros do their jobs. Not to say we should not put our talents to work, i have weeded out many doctors and diagnoses that are nonsense but right now we have Dr Davis working in areas we can't even touch, so its my opinion that we should let them get the disease mechanism then put our talents to work on treating it.
For example if they find a molecule is causing the hypometabolic state and its from the immune system we can put our energy to work on it, but if its caused by something from intestinal microbiota that would lead in a very different direction we need to attack. So right now they are making huge leaps and bounds (according to videos and recent posts from Mrs Dafoe) so i think we should save our energy for when we have their results then we can work on attacking it.
If we use energy chasing a cause then we are repeating the work being done at a slower pace with fewer resources while burning ourselves doing it.

 

[AdamS]

Dr Davis working in areas we can't even touch, so its my opinion that we should let them get the disease mechanism then put our talents to work on treating it.

You're absolutely right, they are working on areas we can't even touch and i'm extremely grateful for their efforts.

If we use energy chasing a cause then we are repeating the work being done at a slower pace with fewer resources while burning ourselves doing it.

I agree with your logic about repeating work but to be honest the biggest threat to me currently is not ME but the isolation/depression it brings. Even if i'm moving at a slower pace than the researchers, there's something about trying to figure this illness out that gives me hope and pushes me through the day.

 

[Alvin2]

You're absolutely right, they are working on areas we can't even touch and i'm extremely grateful for their efforts.

indeed, we owe them a great thanks

I agree with your logic about repeating work but to be honest the biggest threat to me currently is not ME but the isolation/depression it brings. Even if i'm moving at a slower pace than the researchers, there's something about trying to figure this illness out that gives me hope and pushes me through the day.

I understand, and the isolation/depression is very hard

 

[AdamS]

@Alvin2 Yeah it's tough...we're all in the same boat though...huge respect to you for managing for 30 years. I hope the great work being done by Davis etc allows you to get some of those lost years back!

 

[Alvin2]

@Alvin2 Yeah it's tough...we're all in the same boat though...huge respect to you for managing for 30 years. I hope the great work being done by Davis etc allows you to get some of those lost years back!

Thank, for sure, i've become rather cynical with modern medicine, but i can navigate it like a champ

 

[alicec]

say that the problem is in ME/CFS patients' serum, then these are the areas we need to be searching.

The blood factor is discussed in the Ron Davis thread I think, they said it had to be tiny.

Davis said that, based on filtration studies, the serum factor(s) is large - probably a protein. This would rule out a number of @AdamS's categories.

 

[alicec]

I'm of the opinion that it is some kind of large antigen/molecule which triggers the initial insult/response

You think that everyone with the disease has been exposed to this same mysterious antigen?

 

[Tunguska]

Davis said that, based on filtration studies, the serum factor(s) is large - probably a protein. This would rule out a number of @AdamS's categories.

Shit I guess I misremembered, sorry. I'll edit my post [you can tell I'm not looking for it lol]