Is ME a metabolic problem or a signalling problem?

[sb4]

That looks to me like a redox change, not an acid-base change. Adding two uncharged hydrogens does not generate positive hydrogen ions. The added hydrogens are not part of the dissociating carboxyl group.

Two things that I don't understand. First is the diagram shows a H from NADH joining pyruvate then a H+ leaving pyruvate. There is a change in charge here. Yet after LDH there is 2 extra hydrogens on lactate. It would only make sense if the H+ arrow going off was an arrow going on.

I also am not sure why the OH group on the top left of lactate cannot dissociate. Perhaps it would disrupt the shape of the molecule too much or maybe be too easily pulled back on?

 

[Jonathan Edwards]

Yes, the H+ should have the arrow in the other direction. Where does the diagram come from?

OH gross attached to carbons do not dissociate. The OH group in a carboxyl complex can shed an H+ to become an anion for some reason relating to the two carbon-oxygen bonds existing together. Pretty much all common organic acids have carboxylic groups. Throwing out a hydroxyl ion would leave a positively charged organic ion and as far as I know this pretty much only happens if there is a nitrogen present that wants to shed an electron to drop to 4, (which presumably makes bonding more stable, not needing to end up with 10 in the second shell).

 

[sb4]

@Jonathan Edwards the diagram is from wikipedia. If the H+ is coming from the cytosol and combining with pyruvate to form lactate then that H+ is getting mopped up and this should result in higher PH. I remember hearing that pyruvate was more acidic than lactate. But if the cell is importing more pyruvate to try to keep up with energy demands then this should shift the PH I think because you have a build up of pyruvate / lactate more than usual in the cytosol and they aren't neutral.

 

[Midnattsol]

That looks to me like a redox change, not an acid-base change. Adding two uncharged hydrogens does not generate positive hydrogen ions. The added hydrogens are not part of the dissociating carboxyl group.

It is a redox change, lactate is the reduced form of pyruvate. To do this, cells use NADH as a reducing agent.

To keep up with energy demands, cells import glucose, pyruvate gets turned into lactate and then transported to the liver to make more glucose. Why would there be so much pyruvate be in the blood in an energy demand situation (or in any situation, increased levels of pyruvate in the blood is not normal)? It is produced in the cell after all, and these cells are presumably also demanding energy and would not export pyruvate to others?

 

[deleder2k]

Actual lactic acidosis is usually fatal without treatment. Elevated lactic acid is not the same thing, but can become lactic acidosis if it persists. However our lower than normal oxygen utilisation might confer some resistance to the problem. I do know we get elevated lactate, but it has to be continuous to lead to the main problems. In the process it results in the lactic acid version of hypoxia. Now for us the threshold is probably higher than for other people ... we can probably, not reliably, tolerate more lactic acid than regular people.

This leads me to speculate that if someone with ME kept pushing and pushing, through a crash, through PEM, and through all the symptoms, then after some days they might wind up with genuine lactic acidosis, which can be fatal. I do wonder though if we might compensate by severely worsening the ME ... its hard to overdo things if you cannot even move.

If resting restores the situation, if pacing restores the situation, its probably not lactic acidosis.

Endurance athletes can have elevated lactic acid, but marathons and ultra marathons are not several days of continuous running, and often rely on working up to the anaerobic threshold, rather than beyond it.

Someone with genuine lactic acidosis would have required urgent hospital treatment, or they would most likely have died.

That does not mean we are not at risk, only that its not the usual case.

Prolonged elevated lactic acid is a trigger condition for lactic acidosis, but its only the beginning of it.

i bought myself a device to test lactate. Over the years I’ve deteriorated with more fatigue, leg pain, cramps and the feeling of lactic acid. Nowadays it feels like the lactic acid is there 24/7. A couple of years ago I didn’t feel it before I walked few hundred steps.

The readings are not sky high, but I am never under 2.0 nmol/L. Mostly at 2.5-3.0. I am at a point where it impossible to recover since my muscles are exhausted when I’ve rested.

I have not tried Mestinon, but I am considering it. Saline IV is also an option, a long with Florinef. Not sure if it will work or not.

The only thing that has made me significantly better is alcohol. Loads of alcohol. A couple of years ago 12 beers made _all_ my ME symptoma go away for 12 hours. Even after 24-48 hours I felt better. Then after 3 days I got worse.
Alcohol = ethanol. If there is a problem with glucose, then perhaps the body is utilizing the energy in ethanol?

 

[sb4]

@deleder2k I tried to get alcohol to work for me. If PDH is indeed inhibited in ME then you could supply sufficient acetyl CoA through ethanol. However even very small amounts made me feel like my nervous system was completely fried. Perhaps not drinking in 7 yrs could be contributing to that but I think, for me, it is part of the illness.

 

[Gdel]

I am trying to get my head around the question of whether ME could be a metabolic problem, as suggested by the 'something in the blood' findings by several different researchers, and by the problems with pyruvate dehydrogenase possibly blocking or reducing complete breakdown of glucose, and by the seahorse oxygen uptake studies.
Or, as @Jonathan Edwards suggests here, a signalling problem involving some sort switching off coming from the brain that might better explain PEM.

This discussion has cropped up on several threads recently, and rather than derail them further, I've decided to gather the information and ideas here.

Relevant thread discussions:
Blog: 'Summary so far of "Something in the blood"' by Simon McGrath

US NIH: Responses to NANDS Request for Information: How to advance ME/CFS Research

Discussed further here, here and here and onward.

There is also the question of how much activity a person with ME can sustain day after day compared with a healthy person, as discussed here:
Andy's attempt to create a reasonable descriptive model of ME
which again raises the question of whether there is a problem metabolically in creating enough energy for activity above basal metabolic level, and how much we can exceed our sustainable level before PEM, and whether PEM is about lack of energy for basal functions, leading to a wide range of horrible body wide symptoms, or whether it is signals from the brain that are setting off PEM symptoms, or something else.

Hello, just reading this thread.

I'm new on the forum, so apologise if something is out of place (still trying to navigate this site and see how things work here)….

My 2 cents on this: I think its both.

1) Metabolism problems: High PDK (Pyruvate Hydrogenase Kinase) levels are supposed to inhibit PDH activity (ref: Fluge, Mella, Armstrong). This impairs Pyruvate uptake into Mito from the Cytoplasm. Thereby downregulating/suppressing glucose metabolism efficiency / preferred Aerobic Energy Generation pathway (via Krebs/ETC cycle).

This may force body to adopt an alternative (less preferred) Anaerobic metabolism energy pathway which gives only 2 ATP + 2 Lactate from 1 mol of Glucose (as opposed to 32 - 36 ATP + CO2 from Aerobic energy pathway). I theorize this may happen when Aerobic pathway is not happening well enough, and the body is placed with increased energy demand. Another thing that may suppress Aerobic pathway, is the overall systemic Hypoxia (low O2) which is common in ME CFS (adequate O2 is mandatory for efficient Aerobic energy generation)

2) Signalling (something in the blood): This is impacted too. Constantly high pro inf cytokines like IL6, IL1 B, TNF A are being formed by continuous immune activation (Gilotaeux, Hanson etc/many immune studies). In my view, these cytokines signal to the brain of a "suspected" pathogen/ "agent", thereby causing an immune response in the brain (via activated microglia and subsequent neuro inflammation - > causing "sickness behaviour" ; ref Nakatomi/Younger/Elzakker/Natelson/ Shukla / Armstrong etc)

The signalling from the blood to brain (by pro inf cytokines), then cascade back from the brain to downregulate bodily functions (via classic "sickness behaviour" response). Sustained sickness behaviour response over many months/years then creates systemic Hypoxia (low O2 levels in tissues & cells), which then feeds the Anaerobic cycle.

I hope to post my theory on this blog and look forward to members' feedback/finding holes, gaps in this so I can build on this.

Sorry for the long post

Thanks
Gdel (Dubai / India)

 

[Trish]

Thanks for your ideas, @Gdel, and yes, this is a good thread to share them. A couple of questions that others will be able to answer better than I can:

Another thing that may suppress Aerobic pathway, is the overall systemic Hypoxia (low O2) which is common in ME CFS (adequate O2 is mandatory for efficient Aerobic energy generation)

Do we have evidence for this? Is the problem of low oxygen use by mitochondria to do with low supply or a breakdown in the pathway that leads to glucose being fully broken down by aerobic respiration in the mitochondria?

I have an impression that the cytokine results are not consistent enough across studies to be able to say they play a definite role in ME.

 

[butter.]

There is no good way to diagnose mitochondrial disease with absolute certainty in people with (somewhat more certain but not definite) or without (= secondary) genetic mitochondrial disease yet.

Hence, IMO, there is only a very low chance that there is not a significant group of people with mitochondrial disease that are now labeled me/cfs, especially people that are worse than moderate.

There is no me/cfs I am afraid.

That said, we have to make the world see that there are people with me/cfs in order to get funding to show that it is many different diseases. This will only work if there is better subgrouping in studies.

There should be a clear distinction between people with fatigue and low energy for example.

Also the notion that PEM only happens in me/cfs is just bogus, many people with mito disease suffer from it, just ask them!

If you have mitochondrial disease (just another wild mixture of complex, varying diseases) you automatically will have signaling issues I would guess, it is a result of a more „structural“ issue with mitochondria?

The current thinking about me/cfs and its diagnostics is absolutely crazy, it brings us absolutely nowhere.

 

[JES]

There is no good way to diagnose mitochondrial disease with absolute certainty in people with (somewhat more certain but not definite) or without (= secondary) genetic mitochondrial disease yet.

Yeah probably not. A doctor in my country used to diagnose lots of people with ME/CFS. Later it turned out a couple of them had a mitochondrial disease confirmed.

However, I do wonder about the temporary remissions many of us experience. I more or less get back to "normal" on the rare occasion I catch a cold, all autonomic issues etc. resolve. I have also experienced similar temporary improvements (although lesser) from certain drugs/supplements and from sleep deprivation. I understand for the more severe patients that is probably not the case, but even in this group people report strange temporary improvements. For example Whitney Dafoe regains ability to speak while on Ativan.

What do these temporary remissions mean? For me it seems to be an indicator that nothing is permanently broken, so it gives me hope things can be "tuned" back to normal one day with the right approach/drug. I think this would be more in line with a signalling problem and perhaps something wrong in the brain, as drugs like Ativan are able to restore some functionality for some of us.

 

[Marky]

At the moment ME/CFS could be due to one or multiple disease mechanisms. There`s no good reason to call it a mitochondrial disease either. It`s a syndrome, a diagnosis based on excluding more well known diseases

 

[Sisyphus]

Yeah probably not. A doctor in my country used to diagnose lots of people with ME/CFS. Later it turned out a couple of them had a mitochondrial disease confirmed.

However, I do wonder about the temporary remissions many of us experience. I more or less get back to "normal" on the rare occasion I catch a cold, all autonomic issues etc. resolve. I have also experienced similar temporary improvements (although lesser) from certain drugs/supplements and from sleep deprivation. I understand for the more severe patients that is probably not the case, but even in this group people report strange temporary improvements. For example Whitney Dafoe regains ability to speak while on Ativan.

....

I thought mitochondrial malfunction was a part of our disease? What else can explain delayed PEM?

 

[Guest 2176]

"true" mitochondrial disease is inherited, and often more severe than the metabolic dysfunctions in me/cfs. That doesn't mean there can't be analogies. The treatments for pyruvate dehydrogenase complex deficiency, which is usually fatal more than me cfs, tend to yield temporary improvement in me/cfs cfs patoents. Like high dose thiamine or dca. This points to there being something upstream of the metabolic dysfunctions imo.

 

[Guest 2176]

I thought mitochondrial malfunction was a part of our disease? What else can explain delayed PEM?

Mitochondrial malfunction is pretty brpad. As mitochondria are involved in most bodily processes one could say their malfunction is part of almost any illness--from heart disease to cancer to infectious disease. We need to be more specific than that.

 

[Gdel]

Thanks for your ideas, @Gdel, and yes, this is a good thread to share them. A couple of questions that others will be able to answer better than I can:


Do we have evidence for this? Is the problem of low oxygen use by mitochondria to do with low supply or a breakdown in the pathway that leads to glucose being fully broken down by aerobic respiration in the mitochondria?

I have an impression that the cytokine results are not consistent enough across studies to be able to say they play a definite role in ME.

Hello Trish,

Thanks for your response. This is going to be a long reply, since I am citing research studies & putting my inferences

(please read when able, since this is data heavy)

Here are my thoughts:

1) Low Oxygen/Hypoxia - There are several studies that indicate oxidative stress/low oxygen state across the body and low oxygen uptake capability in the body. Here are a few listed below:

(a) "Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome"- by Vermeulen et all -

Conclusion
Low oxygen uptake by muscle cells causes exercise intolerance in a majority of CFS patients, indicating insufficient metabolic adaptation to incremental exercise. The high increase of the cardiac output relative to the increase of oxygen uptake argues against deconditioning as a cause for physical impairment in these patients.

(b) "Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology" - Germain, Ruppert, Hanson, Levine

(c) "Erythrocyte Oxidative Damage in Chronic Fatigue Syndrome" - Richards et al

Extract -There is a strong likelihood that the increase in erythrocyte antioxidant activity is associated with the presence of stomatocytes.

(d) "Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome" - Richards, Roberts, McGregor, Dunstan, Butt

(e) "Old muscle in young body: an aphorism describing the Chronic Fatigue Syndrome" - Pietrangelo et al

(d) Blog - Health Rising - "Metabolomics Study Suggests Chronic Fatigue Syndrome May Be Oxidative Stress/Low Oxygen Disease"

(e) ME Association - "MEA Summary Review: Red blood cells in ME/CFS demonstrate reduced ability to change shape" -

Extract - "Reduced blood flow has been suggested previously in ME/CFS pathology, particularly in relation to orthostatic symptoms and ME/CFS has also been described as a ‘state of hypoxia’ (shortage of oxygen to cells). This latest finding could help to explain many of the symptoms experienced"

(d) Plenty of PEM studies thru CPET 1 & 2 testing, will show low peak VO2 and low Anaerobic thresholds in ME CFS

(e) Plenty of Lactate studies showing elevated lactate levels (which indirectly imply low oxygen, since lactate is produced during Anaerobic metabolism)

Inferences can also be drawn from other hypothesis like - "Hibernation or Dauer State /Cell Danger Response Theory" by Dr Naviaux / "Hypometabolic state" - Armstrong and other metabolomics studies, showing slowed metabolic activity

My inferences are ---- "Sickness Behaviour" (caused by neuro-inflammation - Younger/Elzakker etc) down regulates the body's metabolism to reduce overall metabolic activity (ie puts everything in "slow motion").

This is normally meant to be a temporary feature, to conserve the body's energy to fight off infection (this allows most energy to be diverted to immune system to fight off the pathogen / also forces you to stay in bed).

However, when this happens chronically (over a prolonged duration ie months, years), this will eventually result in a systemic low oxygen/oxygen deprived state in the body. Personally, I can "sense" this since I know I am hardly breathing (I have to remind myself to breathe at times....breathing is very shallow and slow. At night, during sleep its even slower)

This may explain why some people feel better on HBOT treatment (Hyperbaric Oxygen Therapy) since this forces pure Oxygen at higher Atmospheric pressure into the body (via pressurized oxygen chambers). Same may apply to Ozone therapy. But these are temporary solutions in my view.

To answer your question (Is the problem of low oxygen use by mitochondria to do with low supply or a breakdown in the pathway that leads to glucose being fully broken down by aerobic respiration in the mitochondria? ) ----

I do not believe there is an inherent problem with the mitochondria. My sense is the supply to mitochondria is disrupted (not enough oxygen reaching the cells or mito) via prolonged sickness state. Low blood circulation, poor oxygen uptake causes mito dysfunction (low input = low output). This then turns into a self feeding Anaerobic Cycle, ie the disease is feeding itself (will present my detailed theory on another thread).

An inherent mito problem may be in a smaller subset of patients where there are primary genetic causes.

If this was an inherent mitochondrial condition, the vast majority of people would have got this very early on in their childhood (only a few do).

Also, if mitochondria were inherently dysfunctional (ie genetic), a vast majority would have this condition running in families (only a small number have this as far as I know)

2) Ref cytokines studies - Yes, this is not robust enough across patients. I believe this is because this is a spectrum disorder - this by nature implies that some people are very mild, mild, moderate, severe, very severe. The cytokine severity & profile will vary a lot, depending upon the severity of condition and a few other factors. This "spectrum conundrum" is a part of the problem in identifying a robust, definitive biomarker that applies uniformly to everyone.

Sorry, long post...

Thanks,
Gdel (Dubai/India)

 

[lansbergen]

This is normally meant to be a temporary feature, to conserve the body's energy to fight off infection (this allows most energy to be diverted to immune system to fight off the pathogen / also forces you to stay in bed).

Yep

Personally, I can "sense" this since I know I am hardly breathing (I have to remind myself to breathe at times....breathing is very shallow and slow. At night, during sleep its even slower)

My breathing became worse and worse. It is much better now.

I am pretty sure the problem was caused by malfunction intercostal muscles, the pleura and diafragment.

The automatic breathing system was impaired.

 

[Gdel]

"true" mitochondrial disease is inherited, and often more severe than the metabolic dysfunctions in me/cfs. That doesn't mean there can't be analogies. The treatments for pyruvate dehydrogenase complex deficiency, which is usually fatal more than me cfs, tend to yield temporary improvement in me/cfs cfs patoents. Like high dose thiamine or dca. This points to there being something upstream of the metabolic dysfunctions imo.

Agreed

 

[Snow Leopard]

@Jonathan Edwards Not sure. I thought that excess NADH was used up by pyruvate to generate lactic acid. Pyruvate no excess hydrogens -> lactate 2 hydrogens.

Before getting bogged down with the details of this reaction, remember that pyruvate has a lower PKa than L-lactate. It is glycolysis overall that causes acidosis, not the final step of the formation of lactate. (I'll join the dots: anerobic glycolysis, has to occur at a much greater rate to deliver the same level of energy)

I just don't know but does anyone on the forum understand cellular pH control?

You already know the answer. Cells manage pH through ion channels/antiporters and buffering.

Classic example: https://en.wikipedia.org/wiki/Sodium–hydrogen_antiporter

Bicarbonate buffering on the other hand (in this case the bicarbonate is made from the CO2 we breath), occurs much more in circulation, rather than within cells because it would affect ion gradients. https://en.wikipedia.org/wiki/Bicarbonate_buffer_system

I will however point out (given the prior discussion) that the pH of cells and blood circulation is invariant to diet. If eating food with bicarb soda, or high carbohydrate foods is directly affecting the pH of a cell in your leg, then something has gone very horribly, badly wrong.

Is the problem of low oxygen use by mitochondria to do with low supply or a breakdown in the pathway that leads to glucose being fully broken down by aerobic respiration in the mitochondria?

What about on a physiological level? Earlier recruitment of faster-twitch muscle fibres which have lower oxidative capacity (but higher glycolitic capacity). (note that muscle fibre twitch speed has a Gaussian distribution, not a bimodal distribution of "fast" and "slow")
This becomes interesting when you consider the 2 day CPET results (including what happens with effort perception, which does not rely on afferent signalling)

 

[sb4]

Before getting bogged down with the details of this reaction, remember that pyruvate has a lower PKa than L-lactate. It is glycolysis overall that causes acidosis, not the final step of the formation of lactate. (I'll join the dots: anerobic glycolysis, has to occur at a much greater rate to deliver the same level of energy)

True but what I was thinking was if a cell is struggling to produce enough energy through mito would it not import more pyruvate such that this cell has a significantly higher level of pyruvate/lactate than a normal cell which could then lower the overall cytosol / mito pH because as you say, glycolysis happens much more in a cell like this to maintain normal energy.

 

[Jonathan Edwards]

Hi @Gdel,

I don't follow low oxygen and oxidative stress being evidence for the same thing. They are quite different.

I would also also agree with Trish that the cytokine findings are, taken as a whole, overwhelmingly negative. There is no rise in inflammatory cytokines and the cytokine most often found raised - TGFbeta - is usually regarded as anti-inflammatory.

I don't think there is any good reason to think there is immunosuppression either.

In general terms I am more impressed by a single piece of well established evidence and sceptical about lists of all sorts of maybes (and maybe unrelated maybes).

The answer probably has to lie somewhere in these sorts of pathways but I think we need to walk before we can run and make sure we are walking in a direction based on some reliable evidence.