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

[trails]

@Hip, thank you so much for taking the time to put this together! I always find your posts extremely helpful.

 

[Deepwater]

@skipskip30

She has indeed changed her website about placement of babies in the crib. Whether this is one of the issues she was ordered to change by the GMC or something she changed herself, I don't know.

That's the crux of the problem, it's hard to tell how much she has changed her website because the GMC ordered her to or how muuch are now her personal beliefs.

QUOTE][/


Hi,
I also took Dr Myhill's mito tests a few years back, and received a score in line with my problems (25% over all).
I was following Dr Myhill's website at the time of the GMC complaint, and recommendation to lie babies on their tummies was not amongst the complaints. Perhaps it was up on her website many years ago. Of course, lying babies on their tummies was the medically recommended thing to do at one time - certainly was when I had my babies back in the 1980s.
Sorry I can't get this post to show up out of the yellow box.

 

[Hip]

If the AMP was really being dumped into the urine this would be really easy to test for, and this paper was published a few years ago now, yet hasn't been followed up despite proposing a really convincing argument, as you said it hasn't even been mentioned much by people here. Perhaps the researchers could shed light as to why this is.

That's a good point. This dumping of adenosine monophosphate (AMP) in the urine during exercise would be worth testing for. Apparently it is what Myhill et al classify as the Group B ME/CFS patients (which are the patients whose oxidative phosphorylation is partially blocked) who likely most rely on the adenylate kinase reaction (which produces AMP) in order to generate "emergency energy" (to try to make up for the poor energy output of the mitochondria).

It is the the adenylate kinase reaction which combines two molecules of ADP to make one molecule of ATP (to supply energy) and one molecule of AMP (which tends to get dumped in the urine, because AMP is not easily recycled).

By contrast, the Group A ME/CFS patients rely on anaerobic glycolysis (the breakdown of glucose to lactic acid) to generate to generate their "emergency energy."

Also with the coxsackievirus B thing, I was going to say antibodies dont usually cross the cell membrane so they couldn't possibly interfere with mitochondria

When I was looking into this, I saw quite a few people online saying that: "antibodies don't cross the cell membrane;" however, it seem that this is not strictly true, and in fact antibodies can and do cross the cellular membrane, though there is not much research on the mechanisms by which they penetrate the cell. The mechanisms will likely be different for each antibody and each cell type. I read that in some cases, the antibody will attach itself to a cell membrane receptor in order to gain entry to the cell, like viruses do.

I was trying to find out what mechanism is involved in the case of adenine nucleotide translocator (ANT) antibodies, because if you knew the mechanism, then you might be able find some ways to inhibit it — which may lead to improved ME/CFS symptoms, by preventing the autoantibodies from attacking and disabling the ANT protein).

In the case of adenine nucleotide translocator (ANT) autoantibodies, it is known that these can cross the cell membrane and then attach to and disable ANT, because this has been studied in coxsackievirus B myocarditis and dilated cardiomyopathy. See here, here and here.

In these viral heart diseases, it is not just a case of a chronic viral infection of the heart muscle; there also appear to be autoimmune processes that target mitochondria and reduce the energy output of the heart cells. So in this way, myocarditis / dilated cardiomyopathy may be very similar to ME/CFS at the cellular level.



One other mitochondrial autoantibody that is known to be present in ME/CFS is a mitochondrial cardiolipin autoantibody; see this ME/CFS study. If you look at the multiple functions of cardiolipin in mitochondria, one of cardiolipin's roles may be to support the all-important oxidative phosphorylation process that produces 90% of our ATP (cardiolipin may act as a proton trap in oxidative phosphorylation).

So possibly the cardiolipin autoantibodies found in ME/CFS patients may be one the reasons that some ME/CFS patients (the Group B patients) have partially blocked oxidative phosphorylation, which then leads to poor ATP production in the mitochondria.

 

[Undisclosed]

Dr Sarah Myhill is a GP with a lot of research interest and expertise in treating ME/CFS. Norman E. Booth is a physicist and
molecular biologist. John McLaren-Howard is cofounder of Biolab Medical Unit, and medical director of Acumen Labs, UK.

The studies used the "ATP Profiles" test (Acumen Laboratory, UK) to measure the efficiency of five metabolic pathways involved in energy production. The "ATP Profiles" test provides five numerical figures that indicate the functional efficiency of each of the five energy pathways.

perhaps now we should more closely examine the three very incisive studies of Dr Sarah Myhill, Norman E. Booth and John McLaren-Howard (published in 2009, 2012 and 2013) on the dysfunctional energy metabolism of ME/CFS.

Huge red flags related to all three of the research papers = Huge conflicts of interest.

Sarah Myhill supplied the patients for the research. Dr Myhill uses the results of the ATP profile test to recommend nutritional supplements in order to 'boost' mitochondrial function. She sells these supplements (HERE). She sold the supplements at her practice prior to setting up the website to sell the supplements. She also charges money for the interpretation of the lab test which is based on her/their research. From this interpretation, she suggests and sells the supplements. These are a huge conflicts of interest.

The tests used in the research (ATP profile test) were provided by Acumen Laboratory which John McLaren-Howard (Author on the paper) is the medical director of, he also owns it. This is a huge conflict of interest.

One really has to wonder about bias introduced into the research as a result of these conflicts of interest. Are the ATP tests valid/reliable etc, were the results skewed in any manner due to bias. So many questions which I think are very relevant related to this research.

On the mod side of things -- please refrain from personal attacks, focus on the content, not the poster.

 

[daisybell]

@Kina I think that's why the MEA has given some funding to a study looking at whether the Acumen test can be independently replicated....

 

[Hip]

Huge red flags related to all three of the research papers = Huge conflicts of interest.

Possibly, but then would you say that these same conflicts of interest also apply to the excellent research of Dr John Chia, whose own lab provides a biopsy test for $250 that detects chronic enterovirus infections of the stomach, and Dr Chia has formulated and sells his own oxymatrine product called Equilibrant in order to treat enterovirus infections?

 

[Hip]

@Kina I think that's why the MEA has given some funding to a study looking at whether the Acumen test can be independently replicated....

That's interesting, I did not know that.

 

[Undisclosed]

Possibly, but then would you say that these same conflicts of interest also apply to the excellent research of Dr John Chia, whose own lab provides a biopsy test for $250 that detects chronic enterovirus infections of the stomach, and Dr Chia has formulated and sells his own oxymatrine product called Equilibrant in order to treat enterovirus infections?

I am pointing out the huge conflicts of interest related to the Myhill research, Chia isn't under discussion here.

 

[Mary]

@Kina - I don't think selling a few nutritional supplements at reasonable prices is a huge conflict of interest by any means. No one's going to get rich off of selling niacinamide or P-5-P. I think @Hip makes a very valid point in wondering whether you would have the same objections to Dr. Chia's research.

I'm also curious what you think of oncologists making huge profits off of the sale of chemo drugs - it's estimated that 2/3 of their income is from the sale of these drugs, and this is where the big money is, thousands and thousands of dollars per patient every month. Here's some info: https://www.washingtonpost.com/news...s-profit-from-using-the-most-expensive-drugs/

 

[daisybell]

That's interesting, I did not know that.

From the MEA website, under current research..
4) Comparison of results from a commercial and NHS blood test to assess mitochondrial function

This study will be comparing the results of a commercial blood test for mitochondrial function that has been developed by Dr Sarah Myhill and colleagues with the results from an international and widely accepted test of mitochondrial function which has a long and successful track record in clinical diagnosis and research of muscle disease particularly in the UK.

The aim is to determine the efficacy of each set of tests in relation to ME/CFS. In the exciting case that a synergy between the two diagnostic approaches exists, it is hoped that this preliminary study will promote an investigation into a more inclusive and highly resolved analytical technique for metabolic testing of people with ME/CFS.

Lead researcher: Dr Sarah Jayne Boulton

 

[Undisclosed]

@Kina - I don't think selling a few nutritional supplements at reasonable prices is a huge conflict of interest by any means. No one's going to get rich off of selling niacinamide or P-5-P. I think @Hip makes a very valid point in wondering whether you would have the same objections to Dr. Chia's research.

I'm also curious what you think of oncologists making huge profits off of the sale of chemo drugs - it's estimated that 2/3 of their income is from the sale of these drugs, and this is where the big money is, thousands and thousands of dollars per patient every month. Here's some info: https://www.washingtonpost.com/news...s-profit-from-using-the-most-expensive-drugs/

The research contains conflicts of interest which could have had an effect on the results -- conscious or not. Results can be skewed due to researcher bias. I am simply pointing out that this is and should be a concern. There is a lot of this kind of bias, conflict of interest out there. I think it's important to judge the merits of research which includes considering conflicts of interest and that goes for all researchers.

 

[Jonathan Edwards]

Since Myhill doesn't even get many basic medical concepts correct , I would look at her studies very very closely.

Maybe they are good oid studies as I haven't looked at hers very closely yet.

She is not highly regarded by most medical professionals and imho, for good reasons.l, and I would be wary in her participation in advocacy for us.

I know patients swear by her but that's a much different scenario than actually having her included in studies.

That would certainly be my impression. I tried very hard to see what her studies meant and they did not add up to anything I could make sense of. It is very easy to spin what appear to be scientific stories but they need to fit in with basic information from other sources to be credible. My memory is that the studies were on white cells under laboratory conditions and I doubt you can draw any conclusions about body metabolism from that.

We had several presentations relating to mitochondrial metabolism at the last IiME research colloquium from people from three continents and nobody mentioned anything about Myhill's paper (my memory is that there is only one).

 

[Mary]

The research contains conflicts of interest which could have had an effect on the results -- conscious or not. Results can be skewed due to researcher bias. I am simply pointing out that this is and should be a concern. There is a lot of this kind of bias, conflict of interest out there. I think it's important to judge the merits of research which includes considering conflicts of interest and that goes for all researchers.

I agree that we need to be aware of potential conflicts of interest. FWIW, I had the mitochondrial testing done at Acumen Labs, through Myhill's office in 2010, and she (Dr. Myhill) made several nutritional recommendations based on that testing, which showed marked deficiencies in ATP production. However, she never tried to sell me any of the products in her office (which are readily available elsewhere).

 

[Hip]

I tried very hard to see what her studies meant and they did not add up to anything I could make sense of.

It took me a week of reading and re-reading to begin to penetrate into these studies, party because I was not familiar with most of the biological pathways in these papers, and partly because there is a bit of complexity with the results they uncovered (they did not find a simple one-size-fits-all type of mitochondrial dysfunction in ME/CFS patients, but rather found a set of different mitochondrial dysfunctions, with each patient suffering from a subset of the dysfunctions — and in this way they have tentatively identified some subsets in ME/CFS).

Eventually I found the basic concepts of these studies seemed to make sense to me. For example, they found that oxidative phosphorylation in the mitochondria is running under par (partially blocked) in around half of the ME/CFS patients.

Oxidative phosphorylation I believe is responsible for around 90% of ATP production, so having this process partially blocked may well leave you short of energy. That seems to add up to a pretty straightforward possible explanation for the fatigue felt in ME/CFS.

(The subset of ME/CFS patients whose oxidative phosphorylation is partially blocked they call Group B patients; patients who do not have oxidative phosphorylation problems, with this process running at normal efficiency, they call Group A patents.)

So poor oxidative phosphorylation was one mitochondrial defect that they found in ME/CFS patients.

They also found that the operation of the mitochondrial translocator protein was often running under par in ME/CFS patients. Since translocator protein is responsible for transporting ATP produced in the mitochondria into the cytosol of the cell (and responsible for transporting ADP back into the mitochondria for recycling), an inefficiency in this process may again leave you short of energy.

So there was more than one way in which mitochondrial energy production was found hampered in ME/CFS patients.

Note that Myhill et al use the term "translocator protein" to refer to the adenine nucleotide translocator (ANT).


Some of the further complexity in the studies comes from the way that ME/CFS patients apparently try to make up for their defective mitochondria and the resulting energy and ATP shortfall:

• Group A patients try to compensate for the mitochondrial ATP shortage by increasing glycolysis to make ATP (glycolysis of course takes place in the cytosol of the cell, rather than the mitochondria);

• Group B patients try to compensate for the shortfall in mitochondrial ATP by another ATP production process; the authors are not entirely sure what this process is in Group B patients, but they think it is most likely the adenylate kinase reaction (which combines two molecules of ADP to make one of ATP and one of AMP).

Source: Myhill 2012.

My memory is that the studies were on white cells under laboratory conditions and I doubt you can draw any conclusions about body metabolism from that.

Yes, they use neutrophils to run the lab tests.

But if the major problem in ME/CFS is a dysfunction in the mitochondria themselves, it's possible this will be a global problem found in the mitochondria of most cells; in which case, mightn't a cell like a neutrophil be reasonably representative for all cells?

Myhill et al say this on the issue:

Our experimental results are all obtained from neutrophils. Neutrophils are similar to skeletal muscle cells and most other cells (but not cardiac muscle cells) in that the proton gradient across the mitochondrial inner membrane is about 50 % electrical and 50 % chemical. However, at this stage we cannot claim that the mitochondria in other cell types behave similarly, even though mitochondria are systemic. However, some of the features that we observe are very similar to some of the effects seen in exercise studies of patients with ME/CFS.

Source: Myhill 2012

 

[Izola]

Hip: Thank you for this research post. (I do not remember how to do the "@ your name" thing and am way too ill to do the mini- quotes. I am sorry. plus my laptop does't work well)

Q. Does "ADM" & ATM both mean adenosisine monophosphate?
Thanks. iz

 

[Hip]

Does "ADM" & ATM both mean adenosisine monophosphate?

Neither of those means adenosine monophosphate.

ATP = adenosine triphosphate (it has 3 phosphates)
ADP = adenosine diphosphate (it has 2 phosphates)
AMP = adenosine monophosphate (it has 1 phosphate)

 

[Izola]

Neither of those means adenosine monophosphate.

ATP = adenosine triphosphate (it has 3 phosphates)
ADP = adenosine diphosphate (it has 2 phosphates)
AMP = adenosine monophosphate (it has 1 phosphate)

Thank you, Hip. I must be worse than I thought. iz

 

[paolo]

I am particularly interested in group B (Hi Blk) which seems to have a dysfunction in ADP/ATP translcase (both functions of this enzyme are impaired) and also a bigger percentage of energy produced in an anaerobic way. I belong to this group.

It is interesting to me that another recent European study (Ciregia F et al. 2016) found a down regulation of two isoforms of this enzyme (3 and 2) in a CFS patient (Table S1), compared to his healthy twin. In this study mitochondria were from platets. Thank you @Hip for your work. I made a similar work in Italian in my blog.

 

[paolo]

In group A2 (HI TL IN) we have instead poor translocation of ADP inside mitochondrial matrix, and a higher than normal translocation of ATP outside mitochondrial matrix.

In this case I would expect an up regulation of ADP/ATP translocase, in order to compensate for poor translocation of ADP inside mitochondrial matrix. This up regulation would explain the higher than normal translocation of ATP outside mitochondrial matrix.

 

[ash0787]

Odd, it sounds reasonable to me but then again it wouldn't be difficult to fool a lot of us if 95% of it was correct but then something minor was fabricated, as I said it seems like Dr Myhill hasn't gone to much lengths to prove / share this theory, but then perhaps thats because she has been ostracized due to perceived corruption.

The best thing you could probably do in this situation is to contact her directly and ask precisely targeted questions
that would reveal the truth of the matter, such as 'why have you not done any follow up studies to this one'.