Elevated Energy Production in Chronic Fatigue Syndrome Patients

Hip

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I have just been wading through some of Dr Sarah Myhill et al's original studies on mitochondrial and energy metabolism dysfunction in ME/CFS, and posted a new thread summarizing the findings:

The ME/CFS Mitochondrial and Energy Metabolism Dysfunction Papers of Dr Sarah Myhill et al

The Myhill et al papers have not be adequately covered on this forum, for some reason; now with this new rash of studies finding energy metabolism defects in ME/CFS, these Myhill et al papers make very good reading.
 

ash0787

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Chris you said the immune cells seem like they may be proliferating, where would the extra cells be going to if
there is no measurable increase of their count ? are they dismantled or excreted somehow or do they self destruct
when attacking a pathogen ? if the latter is happening on a large scale wouldn't it produce visible macro scale results, looking like a 'war' was going on all over the body ? or could something as small as a 25% increase in immune events cause this drain on the body ? Also how would PEM tie into this ?

With regards to the initial sustained infection theory, I never noticed any stomach problems during the initial sudden onset, and the 'viral' phase seemed to end after 3 or 4 days,
I knew this because it caused acute balance problems which I haven't experienced since,
I also got the hospital to run full blood tests within 4 to 6 weeks and they said no infections were detected.
 
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Chris you said the immune cells seem like they may be proliferating, where would the extra cells be going to if
there is no measurable increase of their count ? are they dismantled or excreted somehow or do they self destruct
when attacking a pathogen ? if the latter is happening on a large scale wouldn't it produce visible macro scale results, looking like a 'war' was going on all over the body ? or could something as small as a 25% increase in immune events cause this drain on the body ? Also how would PEM tie into this ?

With regards to the initial sustained infection theory, I never noticed any stomach problems during the initial sudden onset, and the 'viral' phase seemed to end after 3 or 4 days,
I knew this because it caused acute balance problems which I haven't experienced since,
I also got the hospital to run full blood tests within 4 to 6 weeks and they said no infections were detected.
Well if they are proliferating then I imagine the count would increase. Immune cells will self-destruct though. The immune cells component of the blood isn't extremely large. i couldn't see if they measured for them in this study. But these are important questions to deduce what is occurring. If it's not proliferation then I'd have to look deeper into their methods to determine what it might be that is finding a variation between them and the current weight of literature.

In the case of sepsis the drain on the body from a full immune response is exceptional. It does look like a 'war' going on all over the body. In the case of ME/CFS it's likely not to be that extreme or that acute. The gut is an important component of this working model, it may not be a chronic immune activation alone but a contributing factor to hypometabolism. This is the importance of patient stratification because from the clinical perspective there seems to be a significant variation in disorder expression.

PEM is something we will be looking into so hopefully I can bring data to answer that question within the next year.

That's very interesting information regarding your disease onset. I think it's common that people have different symptoms at onset to what they have during the disorder. What symptoms do you have now?
 

ash0787

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That's very interesting information regarding your disease onset. I think it's common that people have different symptoms at onset to what they have during the disorder. What symptoms do you have now?
Yes, it seemed to be that the changes occurred overnight, so within a 12 to 24 hour period. I was stressed and exercising heavily, then a few days later started feeling as if I had a cold, suddenly threw up just before going to bed, and then when I woke up I had most of the physical symptoms of a severe CFS crash plus feeling off balance.

Its been 13 monthes now and at the moment its mainly varying but consistent aches in the legs and arms,
stiff neck, slight photosensitivity, general tiredness and low tolerance for physical activity, fingers become temporarily unusuable if overworked, toes the same but with bone spurs at 2 joints. Some stomach issues like lactose intolerance following crashes but recovered from them. The usual memory / concentration problems at times.

There was one thing to do with the stomach early on though, in the first few monthes I often had a feeling of slight nausea in the stomach, or perhaps acid, it seemed quite high up in the stomach and the doctor found physical inflammation during an examination, suggested to treat it as though it were excess acid. This acid feeling would often arise after walking ( increased exertion ).
 

anciendaze

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@ChrisArmstrong,

Not sure if this will be considered off-topic, but there is a large subset of long-term ME/CFS patients with orthostatic problems and symptoms of episodic localized hypoxia, even though standard measures of O2sat usually show good saturation overall.

Having experienced vasovagal syncope, and seen it in others, I started to wonder about the process which corrects localized hypoperfusion during exercise. The change to upright posture, even without conspicuous exercise, requires activation of the sympathetic nervous system and vasoconstriction to avoid having blood pool lower down. Relaxation of this in blood vessels associated with those muscles requiring more blood to maintain upright posture is a form of "functional sympatholysis".

I couldn't find neurological connections causing this in research literature, but I did find that red blood cells entering a region where dropping the oxygen they carry is not enough to counteract hypoxia will dump ATP. Because there is a steady supply of RBCs from the rest of the body this can result in an increase in extracellular ATP that swamps locally made ATP from mitochondria. ATP receptors in blood vessels do play a role in vasodilation.

This has the potential to drastically alter arguments based on the assumption that ATP in cells is produced by local mitochondria.
 

Barry53

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I have just been wading through some of Dr Sarah Myhill et al's original studies on mitochondrial and energy metabolism dysfunction in ME/CFS, and posted a new thread summarizing the findings:

The ME/CFS Mitochondrial and Energy Metabolism Dysfunction Papers of Dr Sarah Myhill et al

The Myhill et al papers have not be adequately covered on this forum, for some reason; now with this new rash of studies finding energy metabolism defects in ME/CFS, these Myhill et al papers make very good reading.
I have her book "Diagnosis and Treatment of Chronic Fatigue Syndrome: Mitochondria, Not Hypochondria", not that I can understand all of it. But I do think Dr Myhill gets overlooked too often, because she is clearly passionate about researching ME/CFS, and furthering the cause of patients.
 

Hip

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What may be relevant to the paper discussed in this thread is a discovery by Myhill et al in their studies on the energy metabolism of ME/CFS patients.

Myhill et al found all ME/CFS patients in their cohorts had measurable mitochondria dysfunction, which reduces mitochondrial ATP production; but then in order to try to compensate for this reduced mitochondrial ATP output, ME/CFS patient either ramp up glycolysis as an alternative route to making ATP, or use probably the adenylate kinase reaction to make ATP.

In Myhill 2013 they say:
For patients in Group A, where there is no prior blocking of oxidative phosphorylation or the reactions leading up to it, cellular metabolism uses increased glycolysis to partially compensate for the dysfunction [in mitochondrial ATP production].

For patients in Group B, where there is partial blocking of oxidative phosphorylation or a reaction leading up to it, there is an alternative route to increased glycolysis which the cells use to partially compensate for the blocking. This route is most likely the adenylate kinase reaction in which two molecules of ADP combine to make one of ATP and one of AMP (Adenosine monophosphate).
(Note that Myhill et al found that ME/CFS patients divide into two main groups, according to whether their oxidative phosphorylation — the process by which mitochondria recycles ATP — is running normally (Group A), or whether oxidative phosphorylation is partially blocked and running at low efficiency (Group B)).


So when the paper discussed in this thread says:
We further show that the increased ATP largely comes from non-mitochondrial sources. O
these non-mitochondrial sources could well be the increased glycolysis and the adenylate kinase reaction that Myhill et al refer to.
 

Barry53

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What may be relevant to the paper discussed in this thread is a discovery by Myhill et al in their studies on the energy metabolism of ME/CFS patients.
Thank you, that helps a lot. I have some understanding of closed loop process control, and the human body amazes me - so many self-regulation mechanisms, with mind-boggling interdependencies ... most of the time it works fine. When something goes awry it is no wonder the complexities are hard to unravel, and the interdependencies' cause and effect relationships ambiguous.

So here it looks like both groups had the same underlying problem, but their bodies each adopted one of two different compensatory self-regulation mechanisms.
 
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Wow, so much great explanatory input in this thread now! :)

In light of this, would it be reasonable to contact the paper's authors directly, for some clarifications? Is there precedent (and proper procedure) for this? I don't want to be rude, presumptuous or step on toes. Maybe ask for @Cort to write up a piece on this and ask for comment? Or has there been any sightings of them out and about?:
i hope they will attend IACFSME.
They are mostly from the Xinnan Wang Lab, and seem to have previously focused on Parkinson's and (migration of) mitochondria within neurons. So, as a lay person, it makes me wonder about their seemly over-reaching conclusion:
We propose that the fatigue symptom in this cohort of patients is unlikely to be caused by lack of ATP and mitochondrial malfunction.
...Given the lack of discussion about how representative any measures of PBMN cells might (not) be of overall metabolism. Or exactly why these cells were chosen (presumably convenience)?
Proliferating cells (immune cells) use glycolysis to proliferate, they actively stop pyruvate from glycolysis entering the mitochondria in a process called the warburg effect.
The paper she linked to goes into a bit of what @ChrisArmstrong is talking about.
So the authors of the paper should be aware that this is exactly what one would expect to be occurring in an immune cell.
Were they completely aware of what Chris Armstrong and Maureen Hanson kindly laid out for us? (That if activated, these immune cells purposefully boost up their glycolysis.) I mean, obviously the results are the important information and speak for themselves (with experimental method very well documented), since fellow scientists will draw their own conclusions.

Also, if they have any thoughts on how culturing the cells in lab conditions might have (selectively) changed their behavior, as I wondered about already, and Chris Armstrong confirmed here:
If these experiments (and I think they do) require the researchers to remove the cells and put them into a metabolite pool then it is changing the environment they exist in and may not be representing how that cell actually functions in ME/CFS patients. Taking that into consideration will give important insight from their findings though. For instance, the cell may have upregulated proteins to conduct glycolysis because it was inhibited in the ME/CFS blood condition, once it's in a standard metabolite mix for growing cells it may have all the nutrients it needs but with its already increased enzymes and proteins it could cause a much larger flux through glycolyis than would be exhibited in a control immune cell.
(Could this even have caused incidental selection for over-producing cells, e.g. by killing off less-productive ones? Duplicating more productive ones?)

Let alone if physical inactivity in CFS sunjects, relative to controls, might have caused a pre-selection for the PBMC likely to be found:
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.
Also, with regards to Dr Myhill et al's studies, why they were referenced, but no discussion about using different cells and techiques:
[Gerwyn Morris] suggests it is strange that these authors would not try and replicate these findings
Finally, thanks so much, @Hip, for writing all that up properly (much better than my hamfisted attempts to inject some of the 2012 paper contents into this thread, earlier). :)
I have just been wading through some of Dr Sarah Myhill et al's original studies on mitochondrial and energy metabolism dysfunction in ME/CFS, and posted a new thread summarizing the findings:

The ME/CFS Mitochondrial and Energy Metabolism Dysfunction Papers of Dr Sarah Myhill et al
 
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Apologies for taking a long while writing my email to the paper's lead author, thankfully Xinnan Wang replied almost immediately, covering all the question points I had summarised (apologies if I failed to ask something or sounded dumb at all).
Xinnan Wang PhD.jpg < Stanford School of Medicine Profile.​
It seems that most of the answers come down to the fact that the investigating lab were working with the samples made available to them by the consortium. These came from the Biobank funded by the Chronic Fatigue Initiative set up by the Hutchins Family Foundation (previously used in the Lipkin,Hornig 2015 cytokine study), including samples from the CFS clinics of doctors Klimas, Bateman, Peterson, Levine, Felsenstein and Komaroff (as I'd missed stated in the paper). Also, Xinnan has been in touch with Hanson (directly, I think) which is great to hear. See her full reply after the break, below (with my emailed questions indented and italic).

PhoenixRising Seperator1 SmlThin.png

Thanks for your email. I did a quick read through of the blog and wow I was amazed by the responses including from both scientists and patients. I’m very glad to see our paper triggered such heated responses and I hope the study is useful for paving roads for new future directions.

A little background of this study may already answer some of your questions. This study was part of a collaborative effort or a consortium by many CFS experts and clinics and the Chronic Fatigue Initiative. The goal for my lab was to identify potential mitochondrial phenotypes in patients' samples collected by the consortium. Therefore, my lab was not involved in the sample collection and storage. The consortium could only provide frozen PBMCs from patients and controls at the time, so it was not possible to test it in other cell types. Here are my answers to your specific questions:

(1) Why was there little or no discussion about whether or not measurements of PBMN cell mitochondria would be representative of all subject's cells in general? (Was any content cut from the paper, for length, or such? The ultimate conclusion seemed somewhat unsupported.)

Although PBMCs do not necessarily represent the other cell types, they are mostly accessible and have been used in similar studies. Because our results were opposite to some studies (e.g. Castro-Marrero et al., 2013 using the same cell type), we were trying to emphasize the difference rather than attempting to conclude the causes. Our result shows that ATP levels are increased in PBMCs from CFS patients which suggests that the symptoms may not be caused by lack of ATP in PBMCs.

(2) Was your team aware of the potential for increased glycolysis in activated immune cells? (As per Dr Maureen Hanson's tweet and paper she linked.)

Yes we have also discussed this with Dr. Hanson. Please note that glycolysis shouldn’t be activated in immune cells in the control subjects because their immune system is not activated, and the potential increased glycolysis in the patients suggest that their immune cells may be activated. This is definitely a very interesting hypothesis and further studies should be conducted.

(3) Was the team aware of the potential for altering the PBMN cell's characteristics by having them in a growth medium (for 2-3 days, was it?), free of any factors that might be found in subject's serum? (The word from a number of metabolomics researchers is that they are sure there is something in patient's blood that is inhibiting mitochondria and are now trying to isolate this factor(s).)

Yes of course these cells are very different from in vivo. However, as explained in the background this was the only option at the time and even if cultured in vitro these cells are still useful for studying mitochondrial function and ultrastructure.

(4) Were your team aware of any other factors that might have selected for PBMN cells of different function in persons with ME/CFS? (Dr Jonathan Edwards talked of potential cell age differences, depending on amount of exercise dependant muscle repair taking place, for example.)

Unfortunately our part of study did not involve any clinical manifestations of these patients involved. I cced Dr. March here who may be a better person to answer these questions. We received these cells in a limited amount (because of the IRB and because these cells were distributed to multiple labs) which was insufficient for us to measure both the features and compositions of these cells and the mitochondrial parameters shown in the paper.

(5) Your paper referenced Dr Myhill et al's 2012 and 2013 papers on mitochondrial dysfunction tests (references 10 and 11). Were there any thoughts on the validity of those tests and any reason your team used PBMN cells, rather than attempt to replicate the older findings which used neutrophils?

Again, great question but we were limited by what we could get (limited number of PBMCs per subject). So when we designed the experiments, we tried to maximize the mitochondrial parameters we could measure and meanwhile generate results that would be new to the field (such as mitochondrial ultrastructure and complex activities) rather than replicate one particular study exactly which already used different cells from a different cohort.

(6) Bonus (not presented in my thread post): do you have any information you could share about the functional severity of the patients sampled and/or their illness duration? (Also, the matching of the controls, presumably age, gender, etc, but not for activity level?)

Unfortunately I was not involved in the clinical part of the study and not part of the consortium that could share this information. Dana could further discuss this question with you.

Best,
Xinnan
 

Hip

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In this article, 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 "something in the serum" of ME/CFS patients that effects energy metabolism:

Fluge and Mella discovered that when healthy muscle cells (myoblasts) are 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 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 would appear cause of the energy metabolism dysfunction in the cells of ME/CFS patients.

Prof Ron Davis also thinks there is "something in the serum" of ME/CFS patients causing the energy blockage.
 
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anciendaze

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I'm going to revisit a post by Chris Armstrong, way back on the thread, for purposes of explaining why immune systems should be disturbing these pathways:
Proliferating cells (immune cells) use glycolysis to proliferate, they actively stop pyruvate from glycolysis entering the mitochondria in a process called the warburg effect. The reason for this is glycolysis provides about 5 times the amount of energy over time and metabolite flux through glycolysis promotes the metabolite flux through pentose phosphate pathway (this is where you make nucleotides for DNA replication). By stopping the entry of glucose into the mitochondria to make ATP it upregulates the use of amino acids and lipids for ATP production (possibly why we see a global decrease in blood amino acids and lipids). This process is called glutaminolysis, the purpose is when glutamine enters the TCA cycle, it must remove two of it's ammonia groups, it does this by transferring them to other carbon bodies and this transfer expands the variety of non-essential amino acids available in the cell. You need a variety of amino acids to build new proteins for replication an glutaminolysis provides this.
Why should there be changes in pathways involved in synthesis of nucleotides and/or proteins? One strong reason would be to fight pathogens within the cell, endocytic pathogens, as opposed to external pathogens seen in sepsis. These could be viral, (which replicate nucleic acids) but they could also be spirochetes, just for example. These could even be parasites which enter cells like plasmodium falciparum. We could even be talking about host cells themselves which have become neoplastic, as in leukemia. In all the cases mentioned here, it makes sense for the organism to enter a hypometabolic state to slow progress of disease.

This doesn't necessarily mean there is a conventional infection or cancer, only that the organism is responding as if it were dealing with such.
 

alex3619

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This doesn't necessarily mean there is a conventional infection or cancer, only that the organism is responding as if it were dealing with such.
This is a recognized effect, and one reason why it can take so long to recover from an infection, the immune system stays on overdrive for some time. In us it has been postulated many times that this mechanism is stuck. This may account for the first three years or so of illness, during which the immune system is in overdrive. Turning that off at this point would be the best solution, but way too many of us have been sick longer than that, and its unclear how long term patients differ from new patients. Long term patients may need additional help.
 
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I searched for 'warburg' and ended up here, hello! me nor my brainfog are capable of reading everyone's posts, so sorry if it has been covered yet but has mycoplasma, who can survive without oxygen, been one of the suspects for these metabolic shenanigans? since treatment my brain, throat and adrenals are twitching like mad and slooowly regaining function, it's a neurotransmitter party up there at times ;) I can speed it up or slow it down with thyroid supps & the myco seemed to be hiding behind some other uninvited guests that I got rid of alternatively
 
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Hip

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The cells are inhibited by something in the serum, and overcompensating when freed?
That sounds quite likely: if (as studies have suggested) mitochondrial ATP production is inhibited by something in the serum, then you might expect that ATP production from anaerobic glycolysis (which works independently to the mitochondria) will be ramped up in ME/CFS patients, in order to try to address the ATP shortfall resulting from the mitochondrial blockage.

Thus anaerobic glycolysis may be up-regulated in ME/CFS.

Then when you remove the mitochondrial blockage by taking the cells out of the serum, the mitochondria come back online, and start pumping out more ATP, and that in combination with an already up-regulated glycolysis may produce an excess of ATP.
 
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