Elevated Energy Production in Chronic Fatigue Syndrome Patients

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Low serum phosphate is mentioned in the grey literature, but I don't believe it's been found (maybe not even looked for?) in any published research. I've had this as well, intermittent low serum phosphate with no other reasonable explanation.
One study found low phosphate in a proportion of CFS patients:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360873/

I had this when my illness was severe and of course no doctor ever showed the least bit of interest in this finding.
Interesting! Thanks for the reference - so much not yet adequately explored. Yes, there was little interest in either my elevated or decreased phosphate level.
 

J.G

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Low serum phosphate is mentioned in the grey literature, but I don't believe it's been found (maybe not even looked for?) in any published research. I've had this as well, intermittent low serum phosphate with no other reasonable explanation.
Regarding phosphate, Cort's recent Health Rising blog on Ritux research notes the following:
Fluge and Mella reportedly found reduced levels of phosphate – the P in ATP – in immune cells in ME/CFS.
 

ZeroGravitas

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My understanding of Naviaux's cell danger response hypothesis is that elevated levels of extracellular ATP (which is coming out of damaged/dying cells) is what signals danger to neighbouring cells via its actions on the purinergic receptors.
Indeed. I think cell death might be the most well established source of ATP danger signalling, but also (from Naviaux's 2014 "Metabolic features of the cell danger response", with my emphasis):
4.3. ATP
Purinergic signaling nucleotides like ATP, ADP, UTP, and UDP are released in increased amounts from cells under stress and activate inflammation (Xia et al., 2012). Cells need not be broken or lysed to increase the release of ATP, other nucleotides, and metabolites. ATP and sodium urate crystals are activators of NLRP3 inflammasome assembly (Riteauet al., 2012). Purinergic signaling via ATP directly stimulates cortisol synthesis and release from the adrenal cortex, independent of ACTH stimulation (Kawamura et al., 1991).
So directly released for danger singaling, from live (but stressed) cells. And also as an ubiquitous neurotransmitter:
Skepticism was high in the early days that extracellular ATP could actually be a neurotransmitter. With the cloning of 19 different purinergic receptors that are widely distributed in every neural and non-neural tissue of the body, this early skepticism has been soundly extinguished [...]. Today, the role of purinergic signaling continues to expand virtually into every fundamental cell communication, stress response, autonomic, vestibular, and sensory integration pathway known [...].
(Could it be possible to exhaust ATP too fast via (excessive) neurotransmission? Wired leads directly to tired?)

See also Wikipedia on ATP extracellular signalling. Also from there: your entire body (should) contain about 100g of ATP in total, with each molecule recycled about 500 to 750 times each day, you should burn through your entire body weight in ATP daily! (Wow.)

Even though ATP levels fluctuate, total ATP + ADP should stay as roughly constant. So I wonder what the new study has to say about ADP levels? (Not a single mention of "ADP" in there.) If our ATP is supposed to be raised, is the total pool still the same, higher or lower?

The Myhill paper talks about reduced ADP transfer into the mitrocondria via the ADP-ATP translocator protein (on the mitochondrial impermeable inner membrane), which they say is being blocked (in some cases). They lament that:
In many studies of mitochondrial function, mainly concerning the individual complexes I-V of the ETC, the role of the ADP-ATP translocator protein TL is largely ignored.
Which does kind of sound like what this new study did (including looking at, and finding no, differences in the electron transport chain complexes I-IV activity). And they say they've responded to other (similar) studies that used blood mononuclear cells (PBMCs), as this one did. (But I don't know where their comment to this one, linked as an example, can be found...?)

In the new study they used "oligomycin to block mitochondrial ATP synthesis, and thus the remaining ATP content represented that from non-mitochondrial reactions such as glycolysis". But the Myhill study went a step further, using "sodium azide to inhibit ATP production prior to a two-stage re-measurement of ATP" - first with mitochondria having been inhibited for 3 minutes (that's how quickly an entire cell's ATP store is totally depleted). And then again after washing away the azide inhibitor, to see how fast ATP replenished (I couldn't grasp the results of this, possibly due to getting lost in their nomenclature).

ijcem0005-0208-f3(sml).jpg

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403556/figure/fig03/

Above histogram shows that healthy controls had their ATP synthesis cut down to an average of 7.5% of total when the electron transport chain (ETC, in mitochondria) was blocked. Roughly as expected, since the ETC produces an extra 30 ATP molecules for the 2 that come from glycolosis, alone, of a single glucose molecule - i.e. 1/16th efficiency (or 6.3%). While ATP synthesis of those in the B sub-group of CFS-ME patients, in green, was massively less effected by blocking the efficient ETC pathway.

It's quite startling how much more efficient the mitochondrial ETC makes cellular energy creation. 16 times more than glycolosis alone. A very potent 'afterburner'... So I guess, with either paper, whether enhanced glycolosis (or some other route?) is just compensatory, or if it is in fact stealing the show in being over-active, somehow, either ways, it's going to make for a whole lot less useful energy output per calorie in! (Even with just a relatively small deviation.)

Sorry, more waffling...:(:sleep:
 
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Indeed, one needs to remember that blood metabolomics measures the average of all the body's metabolism. Here they looked at peripheral blood mononuclear cells. Maybe this is a local effect, while the global situation is that of hypometabolism.
I am afraid that there may be a very mundane explanation for both the Naviaux and this result without any conflict. Both might relate in different ways to low levels of activity. The mononuclear cells may behave differently simply because in ME they are not being shunted off to overworked muscle to do some repairs. The average age of monocytes in ME and healthy blood may be different. All sorts of explanations are possible - with nothing to do with the root cause of ME. What I think we need are studies where ME patients are matched to controls not just by age and gender but also by average daily actometer scores, calorie intakes and sleep schedules.
 

TreePerson

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Long term ME sufferer here with no specialist knowledge. Have any similar studies (either metabalomic or mitochondrial) been carried out on people with similar physical limitations? bed-bound or housebound? Or people undergoing chemotherapy whose immune systems have taken a battering? I would have thought that might be a useful comparison.
My other thought is (and I apologise if it's in any way a stupid thing to say because I stress that I am only just learning about all this), if the general energy delivery system i.e. the blood supply is inadequate in some way what would the response be within mitochondria? Is it possible they are getting the right things but just not very much of it?
 

ash0787

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I understand that the metabolomic analysis techniques used in other studies have not been available for long,
but I have to ask is there any particular reason this specific study couldn't have been done say 10 or 20 years ago ?

I was really surprised when signs of metabolism problems were discovered in the past few monthes because I assumed that it would be one of the first things you would evaluate ( though I understand why people tend to focus on the immune system )
 
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I understand that the metabolomic analysis techniques used in other studies have not been available for long,
but I have to ask is there any particular reason this specific study couldn't have been done say 10 or 20 years ago ?

I was really surprised when signs of metabolism problems were discovered in the past few monthes because I assumed that it would be one of the first things you would evaluate ( though I understand why people tend to focus on the immune system )
I think that is a good point. Metabolites like lactate have probably been studied for 20 years but it may be because nothing very startling was found nothing got published.
 

user9876

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I am afraid that there may be a very mundane explanation for both the Naviaux and this result without any conflict. Both might relate in different ways to low levels of activity. The mononuclear cells may behave differently simply because in ME they are not being shunted off to overworked muscle to do some repairs. The average age of monocytes in ME and healthy blood may be different. All sorts of explanations are possible - with nothing to do with the root cause of ME. What I think we need are studies where ME patients are matched to controls not just by age and gender but also by average daily actometer scores, calorie intakes and sleep schedules.
Why not look at having a Rituximab study and before and after with the same patient? Or maybe multiple points as peoples health varies.
 

Ben H

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My understanding of Naviaux's cell danger response hypothesis is that elevated levels of extracellular ATP (which is coming out of damaged/dying cells) is what signals danger to neighbouring cells via its actions on the purinergic receptors.
Exactly.

I have read the new paper but my cognition is very bad at the moment. However I don't see its as completely contradictory to Naviaux. If Naviaux's hypothesis is correct it could account for the elevated levels of atp, perhaps.

I'd really love to hear Dr Davis's view on this, and im sure we will at somepoint.

One thing to mention if it hasnt already is that from my albeit limited knowledge, these techniques used are very sensitive. Some differences could simply be down to technique used. Though I don't think that is true for the results of this particular study.



B
 
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Sidereal

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I'd really love to hear Dr Davis's view on this, and im sure we will at somepoint.
It's unclear to me what the severity of these patients was. My recollection of Davis' talk at the London IiME conference is that in his son and other severe patients he's studied, glycolysis is inhibited, not enhanced.
 

Countrygirl

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Gerwyn Morris suggests elsewhere that we should be aware of the following paper.

He also points out that the mitochondrial parameters measured in this study are not the ones measured and found to be defective by Dr Sarah Myhill. He suggests it is strange that these authors would not try and replicate these findings

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354345/

Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors
 

alicec

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but then the graph shows that there is actually LESS ATP in the mitochondria than expected.... why?
It doesn't - there is no significant difference in mitochondrial ATP production in both groups. The apparent difference shown in the graph is entirely within the error range of the measurement The authors summarise the results of this part of the study as

We found that the ATP levels from non-mitochondrial sources after oligomycin treatment were proportionally increased in CFS patients as the total ATP levels, while the mitochondrial ATP levels remained the same (Fig. 1B).
 

alicec

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Are these findings contradictory to Naviaux´s findings?
Not necessarily.

As has already been pointed out, Naviaux wants us to understand that mitochondria have two functions - energy production and cellular defence. They can't carry out both functions at 100% capacity at the same time. If one function is overactive, it will be at the expense of the other.

As has also been pointed out already, the extra-mitochondrial ATP production detected in this study could be consistent with purinergic signalling involved in the CDR.

It is not possible to make direct comparisons between the studies - they are studying different systems, using different techniques. More studies will hopefully sort out some of the issues.

Also as Naviaux reminds us, mitochondria are highly dynamic. Some differences between studies may indeed merely reflect technical issues, as @ZeroGravitas suggests.
 

alicec

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I understand that the metabolomic analysis techniques used in other studies have not been available for long,
but I have to ask is there any particular reason this specific study couldn't have been done say 10 or 20 years ago ?
Metabolites like lactate have probably been studied for 20 years but it may be because nothing very startling was found nothing got published.
It has been possible to measure a limited range of metabolites for many years. Each would have been measured separately, in separate samples, using various different assays, depending on the metabolite.

This would have given limited insight into a limited number of metabolic pathways. If, as @Jonathon Edwards insinuates, the reason we haven't heard about such studies is that nothing much was found, it is more likely to be the result of the limited capacity of the techniques available than because, inherently, there was nothing to be found.

Now it is possible to measure many, many more metabolites at the same time, with the same technique on a single sample; big data analysis techniques facilitate processing of the vastly increased amount of information obtained.

Now we are starting to see patterns that do appear to give insight into changes in metabolic pathways. More work is needed to understand the significance of the changes.
 
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halcyon

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I understand that the metabolomic analysis techniques used in other studies have not been available for long,
but I have to ask is there any particular reason this specific study couldn't have been done say 10 or 20 years ago ?
I believe the first metabolomics study (it wasn't called that yet) on ME was done in 1984. With the abnormalities they found, they concluded that excessive glycolytic activity was likely. Several following studies supported this, and several contradicted it. The problem, as @Jonathan Edwards points out, is that nobody tried hard enough to show that the abnormalities weren't just due to lower activity levels. Muscle disuse does cause measurable changes in oxidative capacity.
 

Simon

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ash0787 said:
I understand that the metabolomic analysis techniques used in other studies have not been available for long,
but I have to ask is there any particular reason this specific study couldn't have been done say 10 or 20 years ago ?
Yes - the technology didn't exist/wasn't affordable.

It was possible to study a few metabolites that you specifically tested for eg lactate. The new approach, using mass spectrometery (not a new technique, but now more sophisticated and a bit less exorbitantl- expensive) can detect hundreds of different metabolites, without having to specify in advance what you are looking for. NMR was used before mass spectrometry, but could only detect dozens of metabolites (used in the Armstrong paper) and was also very expensive.
 

RogerBlack

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Yes - the technology didn't exist/wasn't affordable.
To take an aside, what's become possible due to 'big data' type approaches and improvements in techniques in less than the last decade is awesome.
From getting a sequence of a single virus particle, to watching how and where viral proteins are assembled in cells, to creating tens of thousands of variants of a cell, each with a gene knocked out to find out how interactions work, to advanced microscopy techniques that can image 'deep' in tissue.

The downsides of all of these sort of methods are as of yet, yes they are enormously powerful, and can result in huge amounts of data, but they are expensive, and not quite at cheap investigative study budgets yet.
You need a good idea of where to point them, or a lot of funding.
 

anciendaze

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So far, all these big data approaches resemble the blind deep sea trawls of the Challenger in the 19th century. They aren't targeted much, and simply bring up whatever is down there in the deep unknown. What they tell us is, yes, there is something or other going on in ME/CFS patients that is quite different from what they find in healthy people or people with other diseases.

Trying to figure out what a particular piece of information means in context is like trying to deduce the life cycle and behavior of some strange beast from the ocean's abyss whose existence nobody had previously even suspected.

We are learning that a great deal of what we thought we understood about basic physiology and metabolic processes was only true if you ignored exceptions presented by some patients. We now see that the gap between medical understanding and biochemical reality was larger than anyone imagined. We are now in the situation of rebuilding the foundations of a great deal of fundamental human biochemistry without destroying the large structure it has been supporting. This is not an easy task, nor can changes be isolated by conventional disease categories. The end result will be a new understanding of a great deal we had previously thought we understood about health as well as disease.

There will necessarily be those who find it much easier to go back to the old paradigm of ignoring exceptions, but they are fighting a losing battle. The cracks in the foundations are already visible to far too many experts.

There have long been parallels between the problems of ME/CFS and problems of normal aging. People suddenly begin to behave in ways typical of those 20, 30 or 40 years older. Weakness, poor stamina, brain fog, aches and pains and problems with fluids and electrolytes are so common in older people you will have no trouble finding jokes about them. These are universal medical concerns made more prominent by the simple fact that more people now live long enough to experience them.

People are upset with the common medical situation of doing little or nothing until the patient is severely debilitated, then keeping them on life support. They want early interventions that extend useful life. A cohort of patients with sudden onset of these problems in midlife is an excellent place to seek such interventions. There will be change, but it will not be quick and easy.