Mitochondrial and Energy Metabolism Dysfunction in ME/CFS — Myhill, Booth and McLaren-Howard Papers

[arewenearlythereyet]

To try to equate ME/CFS with vitamin B12 deficiency is just nonsense.

Not sure which bit is nonsense?.?

 

[Hip]

Not sure which bit is nonsense?.?

I am saying the idea that ME/CFS is a simple vitamin deficiency is nonsense. Various vitamins, minerals and supplements may help improve the symptoms to some extent, but to then jump to the conclusion that ME/CFS is caused by a simple deficiency of these supplements does not have any scientific merit. ME/CFS is a serious disease, just as MS or Parkinson's disease are, and these diseases are not primarily caused by simple vitamin deficiencies.

 

[arewenearlythereyet]

I'm not sure I actually said that or jumped to the conclusion you suggest......that would be nonsense. I have CFS and like many people with the condition have problems with vitamins and minerals and methylation. I have also discovered recently that my b 12 b6 and biotin levels had almost certainly been gradually compromised over 10 years or more before I got ill (I was unaware of it at the time as this is a long term effect of the carbamazepine prescription I have had as a child). I think reading the myhill web pages, b12 has a role in mopping up nitrous oxide etc and as I understood it if B12 gets too low then you get mitochondrial damage? (I'm simplifying but that was the gist of her theory from memory). My thoughts were that since I was unaware that I was low in b12 b6 etc until I got ill, there must be some sort of event or series of events that triggers a move from just a deficiency in b vitamins to full blown CFS. I Do not think CFS and vitamin deficiency is the same thing. My Oat test shows I have a Kreb cycle block and like many I get benefits from taking methylation supplements and mitochondrial support supplements creatine d ribose magnesium etc. To improve some of the symptoms (Cognitive stamina mainly). I still lead a restricted life so I also don't think supplements are the cure to CFS.

This suggest to me that the condition itself is a metabolic disorder and I was postulating that low or slightly dysfunctional methylation is an early stage precursor and perhaps gives a vulnerability to getting sudden onset CFS from various triggers that suddenly drop the levels and tips the balance. I think the mitochondria are directly linked in some way. There is clearly more than one way you can get compromised mitos so just putting my experience out there for constructive views. Of course this is all theorising since there is much that is unknown.

 

[Hip]

@arewenearlythereyet
I think you have to examine ME/CFS using a wider scope that just your own particular circumstances of development of this disease. In some people, full blown ME/CFS can develop literally overnight, or within two or three days, of contracting a viral infection, or more rarely, within days of getting a vaccination. That is far too fast to be due to any dietary deficiencies. Whatever the mechanism for ME/CFS, it is clear this mechanism can switch from fully off to fully on within a matter of days. So what sort of mechanism can act that fast, you might ask?

It just so happens that new antibodies (and thus new autoantibodies) can be created by the immune system in a timescale of a few days (when you catch a cold, it takes the immune system a few days to devise and then large-scale manufacture antibodies which target your cold virus — and once that happens, you start to get over your cold).

An autoantibody is just an antibody made in error which unfortunately targets a part of the body, rather than targeting the infection.

If a viral infection like coxsackievirus B triggers the creation of an autoantibody that disable mitochondria, this could explain why full blown ME/CFS can appear in a timescale of days, in someone that was previously very healthy. That's why an autoimmune etiology to ME/CFS seems very plausible; that and the fact that rituximab, which destroys the autoantibody-creating B cells in the blood, appears to cure ME/CFS.

 

[eljefe19]

@Hip just one thing to point out, though I agree with you, Rituximab appears to cure SOME with CFS. The fact that it is a cure for about 1/3 of people, has given me a lot to think about in terms of having my loved ones shelling out 50,000 dollars , on the chance that for whatever reason, Rituximab doesn't work or work well enough.

 

[Hip]

There is a lot more that needs to be discovered about rituximab treatment of ME/CFS. One of the most important things is trying to find biomarkers for a successful response to rituximab, so that rituximab is only give to patients it will likely work for. I believe the UK rituximab research, which has not yet commenced, is going to look for such biomarkers. The Norwegian phase III clinical trial is just looking at the efficacy of rituximab as an ME/CFS treatment, but is not researching into why rituximab works for some patients, and not for others.

We also do not know whether the non-responses to rituximab are a result of rituximab failing to curb the autoimmune response, or whether there might be some subsets of ME/CFS which are non-autoimmune in nature, and are driven by a different disease mechanism, so that rituximab is useless for these patients.

 

[eljefe19]

@Hip I only have a couple clues as to whether Rituximab will be helpful or not. I've had anti dopamine antibodies tested (which I was exactly on the upper limit of normal for both D1 and D2, and also some very low positive titers for CVB1 and 5 (1:10). 1:640 I believe though for Coxsackie A. I may get more antibody testing done before Rituximab is considered. I will know more after my appointment at OMI the 19th of this month.

 

[arewenearlythereyet]

@arewenearlythereyet
I think you have to examine ME/CFS using a wider scope that just your own particular circumstances of development of this disease. In some people, full blown ME/CFS can develop literally overnight, or within two or three days, of contracting a viral infection, or more rarely, within days of getting a vaccination. That is far too fast to be due to any dietary deficiencies. Whatever the mechanism for ME/CFS, it is clear this mechanism can switch from fully off to fully on within a matter of days. So what sort of mechanism can act that fast, you might ask?

It just so happens that new antibodies (and thus new autoantibodies) can be created by the immune system in a timescale of a few days (when you catch a cold, it takes the immune system a few days to devise and then large-scale manufacture antibodies which target your cold virus — and once that happens, you start to get over your cold).

An autoantibody is just an antibody made in error which unfortunately targets a part of the body, rather than targeting the infection.

If a viral infection like coxsackievirus B triggers the creation of an autoantibody that disable mitochondria, this could explain why full blown ME/CFS can appear in a timescale of days, in someone that was previously very healthy. That's why an autoimmune etiology to ME/CFS seems very plausible; that and the fact that rituximab, which destroys the autoantibody-creating B cells in the blood, appears to cure ME/CFS.

I agree the above is a very plausible theory and may be part of the answer. But what about all the people who don't have sudden onset (I don't think I'm the only one). And how do you define sudden onset in the first place? I suspect there is likely to be multiple paths that lead to the same condition but there must be a common mechanism that traps us in a vicious cycle.

 

[Hip]

I agree the above is a very plausible theory and may be part of the answer. But what about all the people who don't have sudden onset (I don't think I'm the only one). And how do you define sudden onset in the first place?

We are getting a bit off topic now, but to answer you question: sudden onset ME/CFS is defined as appearing within a matter of days, whereas gradual onset is defined as a slower processes which takes many months. Mine was gradual onset. The gradual onset could also be due to an autoimmune response, but with the immune system taking more time to produce the autoantibodies.

Viruses like coxsackievirus B can also infect the brain, so autoimmunity may be a major part of the picture in ME/CFS, but brain inflammation due to infection may also play a role in creating the symptoms of ME/CFS.

 

[arewenearlythereyet]

hmm. Bit Wooly that one. Begs the question why does it take more time....3-6 months for an immune response? I wonder whether there is some interplay with adrenal fatigue somewhere along the line for the gradual onset. Flight or fight response generally overrules most things and a lot of gradual onset seem to have things like high stress workload or bereavement as a potential trigger? You also hear a lot about adrenalin fuelled activity protecting the body against infection? A thought before bed.

 

[Hip]

Bit Wooly that one. Begs the question why does it take more time....3-6 months for an immune response?

I can think of a number of potential reasons.

 

[arewenearlythereyet]

Just had this arrive in my in box so thought I would post it here:

http://www.doctormyhill.co.uk/wiki/Reply_to_Lawson_Paper

Response from Myhill suggest that this New study on cultured cells could mean that CFS sufferers with dysfunctional mitochondria can make a full recovery if the Oxidative phosporylation pathway blocks can be lifted. This is much more hopeful than potentially permanent Mitochondrial DNA damage etc. Also suggests that the block is metabolic in origin?

 

[Hip]

Very interesting link, @arewenearlythereyet, thanks for posting it.

Dr John McLaren-Howard very nicely explains the likely reason for this apparent contradiction in results from the Lawson et al study (which found higher than normal ATP levels the cells of ME/CFS patients), and the Myhill, Booth and McLaren-Howard study (which found lower than normal ATP levels the cells of ME/CFS patients).

The likely reason for this contradiction is this: the Lawson study used cultured cells (cells taken from ME/CFS patients and then grown in vitro), and McLaren-Howard says using cultured cells would likely fail to account for the effects of any mitochondrial blocking agent that was present in the blood and in the original cells taken from ME/CFS patients.

This is because as you grow new generations of cells in vitro, the blocking agent that was present in the original cells taken from the ME/CFS patient will get diluted down in the new cells, so that the agent will no longer block the mitochondria. Thus the previously blocked mitochondria in the ME/CFS patients' cultured cells are then able to start functioning normally again, and thereby increase their ATP production.

By contrast, the in the Myhill, Booth and McLaren-Howard study, they used cells taken directly from the ME/CFS patients' blood, so they tested the actual cells freshly extracted from the ME/CFS patient.

Dr John McLaren-Howard explains it thusly:

Their work [the Lawson study] was done on cultured cells, while all of our test data is on the patients’ cells as separated from a whole-blood sample.

If the ATP levels are measured on cultured cells the effect of any blocking agent may be negated. For argument’s sake, let’s take a situation where 20% of the TL sites are blocked by a chemical we will call X. If the cells are cultured the ‘new’ cells will be unaffected by the blocking agent X which is not itself cultured: X probably being an environmental chemical, drug or metabolic biochemical. In our hypothetical example, when in the culture 10 times the original cell number is reached only 2% would be affected by X. When a very moderate amplification of 100 times the cell numbers is reached only 0.2% of the cells would be affected by X

Source: Reply to Lawson Paper - DoctorMyhill

This also links up to the latest metabolic findings from Fluge and Mella, where they found that healthy muscle cells (myoblasts), when exposed in vitro to the blood serum of ME/CFS patients, developed energy metabolism alterations, including excessive lactate secretion. This finding suggests that there is a mitochondrial blocking agent in the blood serum of ME/CFS patients.

Thus if you grow new cells in vitro, outside of the blood of ME/CFS patients, as they did in the Lawson study, those cells will be healthy and function normally, as they will not be exposed to the blocking agent in the blood. It's the blocking agent in the blood that is the likely cause of the energy metabolism dysfunction in the cells of ME/CFS patients.

 

[arewenearlythereyet]

Yes and the main point I think is that if the Krebs cycle can start functioning properly we can all get on with our lives.

In vitro experiments are always frought with interpretation problems since the body is a complex thing but at least this gives a little hope. The immune side of things is still very much a theory at this stage that needs far more meat on the bones in terms of research. We need to understand if immune response is primary or secondary symptomatic.

I suspect a cascade of events occur that worsen the condition. The key is to understand the sequence of events and that will lead to treatment for people at all stages. Poor methylation is one, poor energy metabolism another, immune response another, adrenal fatigue etc. Confusing feedback for the brain to process a suitable response generally (hormone in balances)? It would be great to do some symptom over time based multi factorial analysis that allows us to link all the detailed research.

 

[Adster]

Forgive me if this is a stupid question, I'm no biochem expert - but could my recently discovered significant energy boost from eating large amounts of coconut oil possibly be relevant to this discussion? https://nutritionreview.org/2013/04/medium-chain-triglycerides-mcts/

 

[Learner1]

It is, but you might look into C8, or caprylic acid nay be better than plain MCT oil.

https://ketosource.co.uk/caprylic-acid-c8/

It could be the due to your ability to use fat better than you can use carbohydrates to make energy that may be working better for you.

 

[Alexi]

Is it possible that Mast Cell Activation of mediators (histamine, adrenaline, cortisol and others I can't pronounce) are responsible for blocking mitochondrial membranes and causing CFS ? Just askin'.....

 

[Hip]

could my recently discovered significant energy boost from eating large amounts of coconut oil possibly be relevant to this discussion?

It is likely very relevant, but perhaps more relevant to the latest 2016 Fluge and Mella study, which found a blocked energy metabolism in ME/CFS patients due to reduced pyruvate dehydrogenase in their mitochondria. This decreased pyruvate dehydrogenase causes a blockage in the glucose energy metabolism (meaning you have trouble using glucose to supply energy). See this post.

Coconut oil contains medium chain triglycerides (MCT), and these are known to boost ketogenesis; ketogenesis is the production of ketone bodies by the liver; ketone bodies are alternative energy to source to glucose.

Several ME/CFS patients have reported benefits from a ketogenic diet, which often includes coconut oil or MCT oil. If you perform a full ketogenic diet, then 70% of the brain's energy will come from the ketone bodies that are produced by the diet. Normally the brain runs on 100% glucose, but if there is a blockage in the glucose energy metabolism, the brain may do better getting its energy from ketone bodies.

If you find coconut oil provides a good energy boost, you may well find that a going on a full ketogenic diet provides even more energy. Lot of details on the ketogenic diet thread.

 

[Adster]

It is likely very relevant, but perhaps more relevant to the latest 2016 Fluge and Mella study

Hah oops, that's the thread I meant to post this in! It was the bit about acetyl-coA that made me wonder about the link.

I'm also experimenting with supplementing Citrate using citric acid reacted with bicarb (in addition to magnesium and potassium citrate)

Cheers

It is, but you might look into C8, or caprylic acid

Cheers, will look into those!

 

[arewenearlythereyet]

Is it possible that Mast Cell Activation of mediators (histamine, adrenaline, cortisol and others I can't pronounce) are responsible for blocking mitochondrial membranes and causing CFS ? Just askin'.....

I think dysfunctional adrenal hormones could have an effect and may be behind strange inflammatory symptoms. Many gradual onset pwcfs report having undergone some form of stress such as bereavement or life changing events or simply burning the candle at both ends for too long before getting CFS.. This to me sounds like they could be candidates for poor functioning adrenals before onset of CFS proper. Perhaps this is linked to the infection theory or perhaps a different route to end up at the same point (high inflammation and dysfunctional mitochondria).

...... I started thinking about adrenal and flight or fight response after seeing a David Attenborough documentary the other week. Basically this tribe hunt an antelope and don't do anything in terms of attack, rather they just slowly follow the poor beast until it just lies down and dies from exhaustion. They then do a ceremonial stab with a spear for show, but basically they have used the antelopes adrenals to kill iT. I guess the point is flight or fight response is powerful thing. I wonder if the antelope escaped what it's mitochondria would be like after that experience?