Heresy / Conjecture on the nature of PEM PESE PENE

FStevenChalmers

FStevenChalmers

Established Member
New here. An ME blogger suggested I bring this idea here for discussion. Will leave out 9/10ths of this idea, looking to see if there's interest in discussion, and most importantly...facts which make this wrong.

There’s a protein called myoglobin. It is expressed on muscle cells. One end of the myoglobin is folded in an almost spherical shape (the “globin” end) and is extraordinarily good at pulling oxygen off passing hemoglobin. The globin also stores a single oxygen molecule; the storage site has that molecule at rest, and most of the time. Myoglobin somehow helps oxygen into the muscle cell; science doesn't know exactly how; I assume the other end of the protein folds into a molecule selective tunnel through the cell wall like so many others.

Neuroglobin does the same things for certain neurons.

So here’s my conjecture: (assume this is wrong)

Exertion leads the cells to use oxygen stored in their myoglobin/neuroglobin

There is a molecule loose in the bloodstream which happens to geometrically fit the “globin” oxygen storage site, but can only land there when the oxygen site is empty

That molecule acts as a hapten

The immune system then (at its leisure, which can be a considerable delay if it has to destroy a lot of them) destroys the combination of the globin (sticking up out of the cell like a dandelion) and that loose molecule

This results in a decrease of the number of tunnels which bring oxygen into that cell (times nearly every cell in the body), which reduces the peak rate at which oxygen can enter the cell, and the sustained rate at which an (aerobic) performance athlete can use energy in that cell (a muscle cell stores glycogen, the energy limit is getting oxygen into the cell)

The body will keep trying to make more myoglobin / neuroglobin and get more tunnels through the cell wall, but a new tunnel has no oxygen, so it’s playing a probability game of whether an oxygen lands on it first, or that loose molecule does

If the body loses 10% of its peak oxygen capacity, the performance athlete will notice; no one else will

If a person with ME (PEM PESE PENE) loses, say, 80% of their peak oxygen capability, they will notice a rate of consuming energy beyond which a temporary or permanent “crash” occurs. Medicine doesn’t believe in that ceiling and has no way to measure it. My conjecture is this ceiling occurs when the remaining myoglobin / neuroglobin has so little capacity that when exertion occurs the oxygen binding site stays empty for an extended period of time (the cell grabs whatever oxygen lands on one immediately). Cells are starved for oxygen, somewhat. This makes the surviving tunnels vulnerable to that loose molecule landing, and the immune system destroying further tunnels.

If all of the myoglobin and/or neuroglobin is destroyed, the cells stay alive by diffused oxygen, but every bit of energy use is by anaerobic metabolism. That is the patient who is bedbound unmoving in a dark silent room.

Buried in the conjecture I just proposed is medical blasphemy, because if it’s true there are three beliefs medicine teaches as absolute to every new doctor, which turn out to be models or approximations which simply do not hold in the bodies of the % of the population with complex chronic illness. It would be career ending for a researcher, much less a clinician, to discuss, much less attempt to publish, work even adjacent to this conjecture.
 
Hoopoe said:
Why do you focus on myoglobin in particular?
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My conjecture is that PEM is progressive autoimmune destruction of myoglobin (muscle) and neuroglobin (neurons), which occurs when (1) a molecule shaped to fit and get stuck on the oxygen storage site of both globins gets loose in the bloodstream, and (2) the immune system learns to recognize and destroy the combination of the globin and that hapten-molecule.

This comes from a truly Alice Through the Looking Glass way of looking at the human body (the way in which the body inventories and distributes molecules so they are available within a millimeter and a millisecond of where and when the body wants to use them). It took me 25 years to figure out myoglobin and neuroglobin exist. That's how uneducated in medicine I am. I'm just a retired computer designer who went looking for the body's decoupling capacitors, because in my field when a weird semi repeatable syndrome occurs which defies controlled experiment, I learned 40 years ago to ignore the logic and put the fastest oscilloscope money could buy on the power and ground pins of the chip giving erratic results.
 
Keela Too said:
I’m going to need to read this again more slowly and carefully.
:bookworm:
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Thank you for reading even once.

This is a really, really different way of looking at PEM

It's based on a really, really different way of looking at the human body. There are basic assumptions medicine makes about how the human body works which would be invalidated if this conjecture turned out to be useful.

And I wasn't kidding. This is at most a tenth of the whole story. Which has to be wrong. After nearly a century of denying PEM and ME, it can't be this simple.
 
Trying to follow this with a foggy brain. So: this molecule loose in the bloodstream interacts with globins so as to impede cells' oxygen uptake in healthy people normally, but in people with ME this interaction occurs much more frequently and problematically, because... ?
 
So my understanding of myoglobin was that it is a molecule within muscle tissue that acts as an oxygen store, releasing oxygen when muscles work, and delivering oxygen to muscle mitochondria before diffusion rates from blood haemoglobin catch up with demand?

Is it also a transport molecule bringing oxygen through the muscle membrane?

Admittedly my knowledge may be dated.
 
Hi & welcome to S4 :)

Always good to have 'left field' ideas, who knows when one of them might pan out. I have absolutely no expertise to understand what you're saying, and at the moment not even a laymans idea of wgat it might mean as am much too foggy.

But if a discussion about PEM is going to be had, I think it's pretty paramount as a first step, to ensure that everyone is using the term to mean the same thing. In our experience, quite a few researchers & even some people with ME/CFS use the term to mean different things, causing, among other things, great deal of confusion!

Here is our own @Trish giving a good run down of the differences between PEM/PEF etc. Its written on one of the threads on PEM here, i dont know which one because (with permission) I copied it for my own reference offline. But there several threads about PEM that might be useful reading as you're developing your theory, particularly because people's experience of it varies a lot.

Anyway here is Trish's excellent summary

So here's my summary:

PEF - Post exertional fatigue: fatigue lasting minutes, hours or a day or two in healthy people, particularly associated with deconditioning
DOMS - Delayed Onset Muscle Soreness: Feeling sore/aching the next day following more exercise than usual, also associated with deconditioning.

In ME/CFS PEF and DOMS are likely to occur, but they are not the same as PEM. Promoters of the psychosomatic view of ME/CFS, including the PACE triallists, wrongly attribute ME/CFS symptoms to deconditioning and interpret PEM as exaggerated perception of symptoms of PEF and DOMS.

Exercise intolerance - reduced ability to exercise, eg in heart and lung conditions. Includes symptoms such as breathlessness and fatigue.

Exertion intolerance / Fatiguability in ME/CFS. An immediate and cumulative response to physical and/or cognitive exertion that reduces ability to continue exertion, and leads to an immediate increase in ME/CFS symptoms, including not just increasing fatigue, but other symptoms such as muscle pain, OI, congnitive dysfunction etc. Takes longer than in healthy people to return to pre-exertion symptom level, but if sufficient rest between activities, not followed by PEM the next day/days.

PEM - Post-exertional malaise (PESE, crash)
Results from physical, cognitive and or social exertion outside the individual's current capacity. May be a single trigger or cumulative effect of too much exertion.
Delayed onset (12+ hours), lasts more than a day, usually longer, often more than a week, increase in symptoms plus additional symptoms, much reduced capacity to function.

pwME are likely to have all of the above, but as far as we know PEM only occurs in ME/CFS and some people with Long Covid.
Click to expand...
 
Eleanor said:
Trying to follow this with a foggy brain. So: this molecule loose in the bloodstream interacts with globins so as to impede cells' oxygen uptake in healthy people normally, but in people with ME this interaction occurs much more frequently and problematically, because... ?
Click to expand...

This is a detail I hadn't provided yet. In a healthy person, there would be a circulating protein in the blood albumin with a binding site for such a molecule, which would hold that molecule in the blood albumin for however many hours it took the detox system to get rid of it. In a healthy person, it would never reach or block the myoglobin or neuroglobin. So in a healthy person there would be no autoimmune destruction of myoglobin or neuroglobin.

This idea that the body needs to manage certain molecules in the bloodstream in an orderly way rather than just let them get underfoot like a toddler is a very, very new way of thinking about the system of circulating proteins in the blood albumin, which medicine tends to consider only individually.
 
Hi, @FStevenChalmers,

I think you are right, this is wrong, but discussion of these things often reveals unexpected ignorances in all of us and we learn a bit.

I am unclear why you want to invoke a hapten. Autoimmunity has nothing to do with haptens or trigger antigens as far as we know, other than in very exceptional cases like procainamide induced ANA. There is a popular myth that you need a trigger but you don't.

Looking at the literature, the function of myoglobin seems a bit less clear than we might like. Knockout mice without myoglobin apparently survive. Sea-diving mammals have a lot of myoglobin. Myoglobin has a higher affinity for oxygen than haemoglobin so it would make sense for it to act as a local oxygen store that can be used when muscle work rate exceeds oxygen supply rate from blood - Usain Bolt stuff, or long dives for fish. Some sites talk about assisting diffusion but I am sceptical about that. A molecule that has a higher binding affinity will actually impair access to oxygen by simple diffusion by competing for it, in the non-equilibrium state. I know of no mechanism for increasing diffusion. Some sort of triggered flip across the membrane might work but I doubt there is any need. Oxygen crosses the red cell membrane without haemoglobin moving about. I suspect that oxygen diffusion is so rapid through cells at the relevant scale that it isn't an issue.

Antibodies to muscle proteins involved in contractile function should produce an illness a bit like myasthenia. If antibodies bind to free surface then complement should be engaged and there will be myositis - which there isn't in ME/CFS. If the antibodies bind to intracellular myoglobin, as they could do, then you might just see a loss of the relevant function. That would seem likely to be inability to go on contracting muscle repeatedly over a short period - a bit like myasthenia but with slightly different kinetics. It wouldn't in any way explain loss of function later, as in PEM. A period of rest should rapidly restore ability to use the muscle for another short period. So there would be no reason for a second CPET to show reduced function.

Antibodies do not get into brain much and an autoimmune response to both myoglobin and neuroglobin seems a bit unlikely anyway. Similar kinetic arguments would seem to apply.
 
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Keela Too said:
So my understanding of myoglobin was that it is a molecule within muscle tissue that acts as an oxygen store, releasing oxygen when muscles work, and delivering oxygen to muscle mitochondria before diffusion rates from blood haemoglobin catch up with demand?

Is it also a transport molecule bringing oxygen through the muscle membrane?

Admittedly my knowledge may be dated.
Click to expand...

You probably know more than I do. I only found out myoglobin and neuroglobin exist about 6 months ago, although I had been looking for what filled that role for about 2 years.

I am ignoring the role of myoglobin as oxygen transport within the cell, and focused entirely on its role efficiently capturing oxygen off passing hemoglobin, storing one oxygen molecule for use by a specific cell, and getting that molecule across the cell wall on demand. That last function, as best I can tell, has not been studied by science or medicine and I am proceeding on the assumption that the myoglobin (or neuroglobin) folds itself into a molecule-geometry specific tunnel which then penetrates the cell wall, very likely only where the cell wall meets a capillary, with the globin end outside the cell like a dandelion. As a retired tech guy, I have no real library access, just the Internet, so could easily have missed a whole area of research in the medical/science journals.

As a computer designer, I don't think the oxygen crosses the cell wall by diffusion as medicine seems to assume. Just as computer chips draw huge spikes of current for tiny amounts of time when they switch, I assume a neuron which is using an ATP-ADP pump to recharge its ion channel ions in the refractory period after firing uses a burst of ATP to pull in a burst of ions, starting rapidly and declining probably exponentially over the refractory period. That means a burst of oxygen to make that ATP on a tight schedule, since there isn't enough stored for a whole cycle. This would imply a very nonlinear consumption of oxygen. I don't understand the operation of a muscle cell well enough to make a similar argument about whatever resources it pumps in using ATP-ADP to prepare for the next contraction.

You can see my mental model is very different from that of medicine, which assumes average rates of use by cells and does not consider millisecond by millisecond variation in consumption, which I think is essential to understanding why we get so much anaerobic metabolism in ME/PEM when the average supplies are quite adequate. I've designed and more importantly debugged digital logic (computer innards) which simply didn't work because we weren't meeting that huge burst of energy the chip was demanding...for the time it takes light to go an inch or two. The average energy the power supply two feet away could deliver is completely irrelevant to that problem, as are molecules neurons (or muscle cells) consume at each firing and must recharge locally and quickly. The anaerobic metabolism could be much like an audio system "clipping", which can distort the sound you hear even though the clipping is way above the frequency the human ear is supposed to be able to hear. (Sorry for tangent, not sorry for the point it makes.)
 
JemPD said:
Hi & welcome to S4 :)

Always good to have 'left field' ideas, who knows when one of them might pan out. I have absolutely no expertise to understand what you're saying, and at the moment not even a laymans idea of wgat it might mean as am much too foggy.

But if a discussion about PEM is going to be had, I think it's pretty paramount as a first step, to ensure that everyone is using the term to mean the same thing. In our experience, quite a few researchers & even some people with ME/CFS use the term to mean different things, causing, among other things, great deal of confusion!

Here is our own @Trish giving a good run down of the differences between PEM/PEF etc. Its written on one of the threads on PEM here, i dont know which one because (with permission) I copied it for my own reference offline. But there several threads about PEM that might be useful reading as you're developing your theory, particularly because people's experience of it varies a lot.

Anyway here is Trish's excellent summary
Click to expand...

Thank you

PEF isn't PEM. PEM is a temporary or permanent reduction in the body's ability to make and use energy, in response to use of energy above a threshold medicine can't measure.
I don't experience PEM (I have a different complex chronic illness). I do experience PEF, although a lot less as I get older!

DOMS isn't PEM. PEM is not soreness. PEM is a temporary or permanent reduction in the body's ability to make or use energy.

PEM can't possibly occur if the basic theory underlying medical practice and research today and for the last 100 years is correct and complete. The theory's wrong. The people who contort their brains into pretzels trying to fit the patient experience of PEM into that theory waste their time, and ours.
I think I'd better not post what I think about people who dismiss patient symptoms and history, substitute a disinformation narrative written by a special interest, and proceed to diagnose and treat the disinformation narrative.
 
FStevenChalmers said:
PEM is a temporary or permanent reduction in the body's ability to make or use energy.
Click to expand...

I don't know of anywhere it is defined as that. It is normally defined as a worsening of symptoms that includes fatigue, pain, and also things like nausea, orthostatic intolerance, sensitivity to light and so on (i.e. the patient symptoms we don't want to dismiss). We don't know whether it has anything to do with energy in a metabolic sense.
 
Jonathan Edwards said:
Hi, @FStevenChalmers,

I think you are right, this is wrong, but discussion of these things often reveals unexpected ignorances in all of us and we learn a bit.

I am unclear why you want to invoke a hapten. Autoimmunity has nothing to do with haptens or trigger antigens as far as we know, other than in very exceptional cases like procainamide induced ANA. There is a popular myth that you need a trigger but you don't.

Looking at the literature, the function of myoglobin seems a bit less clear than we might like. Knockout mice without myoglobin apparently survive. Sea-diving mammals have a lot of myoglobin. Myoglobin has a higher affinity for oxygen than haemoglobin so it would make sense for it to act as a local oxygen store that can be used when muscle work rate exceeds oxygen supply rate from blood - Usain Bolt stuff, or long dives for fish. Some sites talk about assisting diffusion but I am sceptical about that. A molecule that has a higher binding affinity will actually impair access to oxygen by simple diffusion by competing for it, in the non-equilibrium state. I know of no mechanism for increasing diffusion. Some sort of triggered flip across the membrane might work but I doubt there is any need. Oxygen crosses the red cell membrane without haemoglobin moving about. I suspect that oxygen diffusion is so rapid through cells at the relevant scale that it isn't an issue.

Antibodies to muscle proteins involved in contractile function should produce an illness a bit like myasthenia. If antibodies bind to free surface then complement should be engaged and there will be myositis - which there isn't in ME/CFS. If the antibodies bind to intracellular myoglobin, as they could do, then you might just see a loss of the relevant function. That would seem likely to be inability to go on contracting muscle repeatedly over a short period - a bit like myasthenia but with slightly different kinetics. It wouldn't in any way explain loss of function later, as in PEM. A period of rest should rapidly restore ability to use the muscle for another short period. So there would be no reason for a second CPET to show reduced function.

Antibodies do not get into brain much and an autoimmune response to both myoglobin and neuroglobin seems a bit unlikely anyway. Similar kinetic arguments would seem to apply.
Click to expand...

My conjecture, and it is only a conjecture, describes a mechanism by which a molecule acting as a hapten -- a well known mechanism in allergy, responsible for poison oak/ivy/sumac reactions -- lands on the opening of a tunnel a cell uses to bring in oxygen, and the immune system destroys the combination of hapten and tunnel opening. My conjecture proceeds to describe how widespread destruction of such tunnel openings across the body would produce PEM symptoms ranging from the performance athlete who notices a small drop (and then continues exercising, becoming severe), to the normal ME person with PEM, to the bedbound unmoving patient in a dark silent room.

I understand the EBHD (elite breath holding diver) research, and the observation about myoglobin in whales. The oxygen storage is important to those cases, but is only central to my conjecture when the oxygen storage site is empty, making it vulnerable to this attack.

You are correct to be skeptical about the way oxygen gets across the cell wall. I firmly believe it's not by diffusion, not because science has figured it out, but because I understand high speed power distribution as a (retired) computer designer. You are absolutely right to stand your ground and say I'm making an assumption not supported by science, which is correct. Science seems to not know how oxygen gets across the cell wall into a cell. I think that's a huge gap, especially if one is researching an energy disorder like PEM.

I understand that current medicine and science around autoimmune diseases of the muscles simply does not include the known-to-allergy mechanism I describe, nor PEM. We can let medicine decide, in the unlikely event I am correct, whether I have described a novel kind of autoimmune disease, whether to call it autoimmune at all (it's a known allergy mechanism, not a known autoimmune mechanism), or something else. And yes, I am familiar with myositis: my adult daughter's sudden onset disabling post viral syndrome 4 years ago -- which is the reason I started looking at Long Covid -- was ultimately diagnosed and treated as dermatomyositis and is now under control. ME is totally different from myositis.

If the first day CPET resulted in oxygen tunnels being blocked or destroyed, the second day CPET would indicate a reduced ability to bring oxygen into cells. So long as some threshold isn't reached, the body can (mostly) regrow the oxygen tunnels. Past that threshold, I think the immune system simply destroys every new tunnel (at least on average), because the cells have so few tunnels they are constantly pulling that oxygen in leaving those storage sites empty.

We can debate antibodies in the brain. I think they're still there in the capillaries, just don't cross the capillary wall. So if this all happens in the capillary with the globin sticking up like a dandelion to capture oxygen off hemoglobin on passing red blood cells (which can just barely deform enough to squeeze through those capillaries), the loose molecules I describe can certainly get to them.

Your skepticism is warranted. I am a heretic, describing something medicine doesn't think can happen. And I'm OK if you simply reject my arguments. Most people do, especially those trained in medicine or biology.

Thank you for engaging!

-steve
 
Jonathan Edwards said:
I don't know of anywhere it is defined as that. It is normally defined as a worsening of symptoms that includes fatigue, pain, and also things like nausea, orthostatic intolerance, sensitivity to light and so on (i.e. the patient symptoms we don't want to dismiss). We don't know whether it has anything to do with energy in a metabolic sense.
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You are correct. I am using too simple a model and jumping to a conclusion. Thank you!
 
I have been looking for relevant articles to learn more about the myoglobin and oxygen getting from blood into cells.
So far I've found these, both from the NIH library:

Biochemistry, Myoglobin
Trey Vanek; Arpan Kohli.
Author Information and Affiliations
Last Update: July 17, 2023.
This makes it clear myoglobin is in the sarcoplasm, which is cytoplasm in striated muscle cells.

Pathways of Oxygen Diffusion in Cells and Tissues
Hydrophobic channeling via networked lipids
Sally C. Pias1
2020
Abstract
Oxygen delivery to tissue mitochondria relies on simple diffusion in the target cells and tissues. As such, intracellular availability of O2 in tissue depends on its solubility and diffusivity in complex and heterogeneous macromolecular environments. The path of oxygen diffusion is key to its rate of transfer, especially where pathways of differing favorability are present. Most commonly, aqueous media, such as interstitial fluid and cytoplasm, are assumed to provide the dominant diffusion path. Here, the ‘hydrophobic channeling’ hypothesis is revisited, and several lines of evidence pointing toward lipid-accelerated oxygen diffusion pathways are discussed. The implications of hydrophobic channeling are considered in light of extended membrane networks in cells and tissues.
 
Jonathan Edwards said:
I don't know of anywhere it is defined as that. It is normally defined as a worsening of symptoms that includes fatigue, pain, and also things like nausea, orthostatic intolerance, sensitivity to light and so on (i.e. the patient symptoms we don't want to dismiss). We don't know whether it has anything to do with energy in a metabolic sense.
Click to expand...

PEM involves, as Jo says, significant increase in symptoms. It also includes significant reduction in the ability to function. If you imagine the feeling when you have a nasty bout of influenza and feel to ill and weak to get out of bed, that's how my PEM affects me. I have no idea whether mitochondrial metabolism becomes less efficient, or whether it is more the effect of much worse orthostatic intolerance, nausea, pain and the rest. I have sometimes resorted to crawling to the bathroom. That's not a lack of mitochondrial function - crawling probably uses as much muscle power as walking slowly, it's more a loss of balance, stability etc.
 
@FStevenChalmers just in case it was ambiguous, my intent wasnt to be patronising, suggesting you didnt know what PEM is....

Its just that its staggering how much difference of ideas there are when discussing PEM. You can be going along for ages, happily discussing it with another patient only to find you're both talking about different phenomena & both calling it PEM, or be discussing it with a researcher who's been working in the field for years who believes they're studying PEM, only to discover they aren't studying what we would call PEM at all!

As you were new here and may not have ME/CFS yourself, I just wanted to establish we were all discussing the same thing! :)

well I say 'we', LOL I shouldnt think i'll have anything useful to add, but I'll read with interest.
 
Trish said:
I have been looking for relevant articles to learn more about the myoglobin and oxygen getting from blood into cells.
So far I've found these, both from the NIH library:

Biochemistry, Myoglobin
Trey Vanek; Arpan Kohli.
Author Information and Affiliations
Last Update: July 17, 2023.
This makes it clear myoglobin is in the sarcoplasm, which is cytoplasm in striated muscle cells.

Pathways of Oxygen Diffusion in Cells and Tissues
Hydrophobic channeling via networked lipids
Sally C. Pias1
2020
Abstract
Oxygen delivery to tissue mitochondria relies on simple diffusion in the target cells and tissues. As such, intracellular availability of O2 in tissue depends on its solubility and diffusivity in complex and heterogeneous macromolecular environments. The path of oxygen diffusion is key to its rate of transfer, especially where pathways of differing favorability are present. Most commonly, aqueous media, such as interstitial fluid and cytoplasm, are assumed to provide the dominant diffusion path. Here, the ‘hydrophobic channeling’ hypothesis is revisited, and several lines of evidence pointing toward lipid-accelerated oxygen diffusion pathways are discussed. The implications of hydrophobic channeling are considered in light of extended membrane networks in cells and tissues.
Click to expand...

Thank you. I clearly have more reading to do. And I am not arguing that myoglobin isn't loose inside the cell with a critical role in transporting oxygen within the cell. I'm simply asserting that there's a gap in medicine's knowledge, an assumption that oxygen diffuses from the blood into the cell rather than being actively transported; I have seen (but can't cite) enough bits and pieces in the science literature to *guess* that oxygen is actively removed from hemoglobin and moved in response to demand through the cell wall, but it's only a guess. And that guess is central to my conjecture.
 
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