Potential linking RBC, glycolysis, air hunger, thyroid, ATP dumping, pregnancy improvement and...

dejurgen

Well-Known Member
When working together with Issie to better understand our wired-and-tired behavior I did found this https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944128/

"Although it is not entirely clear how intracellular phosphate level is regulated, extracellular phosphate seems to affect it to a certain degree as hypophosphatemia is known to induce tissue hypoxia by lowering 2,3-diphosphoglycerate level in red blood cells.3"

That hypoxia link certainly drew my attention.

That is link number [3] https://www.ncbi.nlm.nih.gov/pubmed/10670405

"We observed that depletion of adenosine triphosphate (ATP) would explain most of the derangement noted in cellular functions. Phosphate plays a key role in the delivery of oxygen to the tissue. Lack of phosphate, therefore, leads to tissue hypoxia and hence disruption of cellular function. Severe hypophosphatemia becomes clinically significant when there is underlying phosphate depletion. Otherwise, short-term acute hypophosphatemia is not usually associated with any specific disorder. Chronic hypophosphatemia, on the other hand, results in hematologic, neuromuscular, and cardiovascular dysfunction, and unless corrected, the consequences can be grave."

And from https://en.wikipedia.org/wiki/2,3-Bisphosphoglyceric_acid
Look at https://en.wikipedia.org/wiki/2,3-Bisphosphoglyceric_acid#/media/File:Pathway_of_generation_of_2,3-bisphosphoglycerate.png

It may not say much at first sight but IMO it is major! When looking at the straight arrow from left to right, it seems this is step number 7 in glycolysis https://en.wikipedia.org/wiki/Glycolysis.
Glycolysis is the fast process breaking down glucose to pyruvate, both used in fast anaerobic energy production as well as for generating pyruvate for the mitochondria / Krebbs cycle.

Now the arrows up and down are a "side step" existing in place of the straight step. I had never seen it before. It generates this "2,3-Bisphosphoglycerate" (down the "triangle) from "1,3-Bisphosphoglycerate" (left product) instead of generating ATP and the next step in glycolysis generating energy and furthering the energy producing chain.

"2,3-Bisphosphoglyceric acid (conjugate base 2,3-bisphosphoglycerate) (2,3-BPG), also known as 2,3-diphosphoglyceric acid (conjugate base 2,3-diphosphoglycerate) (2,3-DPG), is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid (1,3-BPG). 2,3-BPG is present in human red blood cells (RBC; erythrocyte) at approximately 5 mmol/L. It binds with greater affinity to deoxygenated hemoglobin (e.g. when the red blood cell is near respiring tissue) than it does to oxygenated hemoglobin (e.g., in the lungs) due to conformational differences: 2,3-BPG (with an estimated size of about 9 Å) fits in the deoxygenated hemoglobin conformation (with an 11 angstroms pocket), but not as well in the oxygenated conformation (5 angstroms). It interacts with deoxygenated hemoglobin beta subunits and so it decreases the affinity for oxygen and allosterically promotes the release of the remaining oxygen molecules bound to the hemoglobin; therefore it enhances the ability of RBCs to release oxygen near tissues that need it most. 2,3-BPG is thus an allosteric effector."

=> It's a bit technical but basically IMO it says: you need enough of it in order to get the RBC to release the majority of their oxygen. With too few of this "2,3-Bisphosphoglycerate" much of the oxygen "keeps sticking" onto the RBC "for another tour of the body". In ME language: blood oxygenation is high but it seems as if cells can't use the oxygen; that is a *very* common observation in ME.

=> This "extra" step in glycolysis is also specific to RBC and occurs in no other cell (rather then a very important exception I'll discus later).

Now there is another piece of the puzzle:

"The normal glycolytic pathway generates 1,3-BPG, which may be dephosphorylated by phosphoglycerate kinase (PGK), generating ATP, or it may be shunted into the Luebering-Rapoport pathway, where bisphosphoglycerate mutase catalyzes the transfer of a phosphoryl group from C1 to C2 of 1,3-BPG, giving 2,3-BPG. 2,3-BPG, the most concentrated organophosphate in the erythrocyte, forms 3-PG by the action of bisphosphoglycerate phosphatase. The concentration of 2,3-BPG varies proportionately to the [H+].
There is a delicate balance between the need to generate ATP to support energy requirements for cell metabolism and the need to maintain appropriate oxygenation/deoxygenation status of hemoglobin. This balance is maintained by isomerisation of 1,3-BPG to 2,3-BPG, which enhances the deoxygenation of hemoglobin."

=> When we are already short on ATP, the body (actually RBCs) can "chose" to go for all ATP and "forget" to make this product that increases oxygen release from the RBC. Worse, if some of the 2,3-Bisphosphoglycerate (product underneath the triangle) would be converted to the right hand product (to further the "energy chain by producing another ATP in yellow step 10 of https://en.wikipedia.org/wiki/Glycolysis as the body could do it if were really starved of energy) then... ...We will breath after our first energy burst (the burst of energy we produce during anaerobic metabolism) but to no avail. It will be like oxygen has gone from the air and we will breath our lungs out and near suffocate: massive air hunger explained?

=> So after using a "strong burst of energy" or simply overdoing it, we get locked into a long time of a mechanism with really poor oxygen release from cells, air hunger (my breathing like a horse at night, not being apnea but more hyper breathing / ventilating to no avail) and the brain starving from both ATP and oxygen, starting to release glutamate into the intercellular space till it reaches toxic levels.

=> OUCH!

Note this topic is a "side track of https://www.healthrising.org/forums/threads/potential-linking-fm-mast-cells-sleep-deprivation-food-intolerance-exercise-intolerance-and-me.6217/ that I wrote now as it fits with Corts current blog. It is therefore still *a work in progress*! I don't change anything yet on my routines nor supplements and so I strongly advice the reader of this info to not do this yet! Let us first discuss opinions on this HYPOTHESIS and share thoughts about potential consequences before diving in head first!
 

dejurgen

Well-Known Member
If the brain or lungs use oxygen sensors to increase breathing rate (compared to CO2 censors or use both but panic due to oxygen sensor readings) as the low release rate of oxygen from RBC is seen as bad lack of oxygen, then we start hyperventilating. And that reduces blood acidity and the Bohr effect, further decreasing oxygen release. Those Buteyko people may have been even more right with their special breathing technique then I realized.

Note that the Buteyko breathing method is quite controversial in ME/CFS as suporters claim large improvements to full recovery based on nothing more then doing a special breathing technique. It is also hidden behind a "paywall". But in my experience good breathing can make a real difference in health and some elements of the breathing techniques I learned do resemble those likely (I did not pay to get full access to the Buteyko method) used in the Buteyko method. Others however I disagree with. I think learning to breath well from a good Physical Practicioner can get you just as far or further with a lower difficulty level to start with. And just like pacing, I believe good breathing can only help to some extend. In the "easiest cases", sufficient pacing can lead to recovery too but they are equally rare.

Also: https://en.wikipedia.org/wiki/2,3-Bisphosphoglyceric_acid

"In pregnant women, there is a 30% increase in intracellular 2,3-BPG. This lowers the maternal hemoglobin affinity for oxygen, and therefore allows more oxygen to be offloaded to the fetus in the maternal uterine arteries."

=> SOOOOO many pregnant woman (those who don't have an auto-immune reaction to the pregnancy) say that they have a temporary release from ME/FM... or no symptoms at all but they tend to return in full after the pregnancy. This could be the best explanation ever for the pregnancy mystery so far! Far higher reserves in chemicals that help with RBC letting them release their oxygen.

Note: This extra 2,3-diphosphoglycerate is generated in the placenta where it is released near the RBC where it can easily reach the RBC themselves. That is a mechanism to release more oxygen near the fetus barrier (no RBC from the mother pass into the bag in which the fetus grows). That oxygen can then pass this barrier and be taken up by fetal RBC (who have the reverse effect, they are modified to take up more and cling on to oxygen harder.
https://en.wikipedia.org/wiki/Fetal_hemoglobin

Note that these dissociation curves are hard to follow. The Fetal hemoglobin is the blue curve, the adult one is the red one and the curve of adult hemoglobin that is "bathed" in plenty of 2,3-diphosphoglycerate (like maternal blood in the placenta) is placed to the right hand side of the red curve.
Note that for a better understanding of how "RBC oxygen affinity" affects oxygen release and cellular oxygen usage, we have to look at https://en.wikipedia.org/wiki/File:Oxyhaemoglobin_dissociation_curve.png

The more the curves are placed to the left hand side, the more the RBC "cling on" to their oxygen. So the less they release. If we for example look at the grey horizontal line in the picture at 82% oxygen saturation, the we see that the green curve has a "partial O2 pressure" of about 43 mmHG, the blue one of about 52 mmHG and the red one of about 60 mmHG.

The further the RBC get into the tissue and the smallest capillaries, the more oxygen has been given to the tissues and the lower the oxygen saturation gets.

To interpret what this means:

If, for ease of explanation, the cells all start with 90% oxygen saturation coming from the lungs, then as the RBC get deeper in the tissue they all will give some oxygen too the cells. But the green curve will always do so at a slower rate then the other two curves. Why? Because for every point on the curve, the green curve has the lowest partial pressure for oxygen at any given percentage of RBC oxygen saturation. A lower partial pressure equals to less gas released from the RBC into the blood and given to the cells. It is nearly the equivalent of turning down the oxygen concentration in the air we breathe. I said before that when I am in really bad "air hunger" it feels like someone dropped the oxygen concentration in air from 19% to 5%.

Or said otherwise, as the concentration of oxygen is lower in the mountains it feels like we breathe at high to very high altitude.

Now this green curve is still very optimistic when we would be really short on 2,3-diphosphoglycerate. The curve would be even *a lot* more to the left then the green one: bad air hunger!

As oxygen shortage also creates more hydrogen peroxide, and that every hydrogen peroxide molecule attached to the RBC prevents four molecules of oxygen to attach to the RBC, things could become quite a bit worse when we hit this combination.
 

dejurgen

Well-Known Member
When looking at https://en.wikipedia.org/wiki/2,3-Bisphosphoglyceric_acid
There is another interesting point to be made: look at the table:

People with hyperthyroidism have nearly a quarter more 2,3-diphosphoglycerate in their RBC then people with a normal thyroid function. This could well explain why ME patients with thyroid hormone values "in range" often benefit from thyroid hormone supplementation: their 2,3-diphosphoglycerate "oxygen releasing" chemical goes up with about 23% when they started from average if they "over supplement" thyroid hormone. It they start from the lower edge of the range and push it to the higher edge of the range the improvements will be even greater.

NOTE that I do not promote thyroid supplementation here. There are plenty of downsides with "messing" with hormones and high quality doctors should look at it in a case per case way before deciding upon it. I myself had once a supplementation of 4 hormones simultaneously at once by a doctor prescribing this "easily" for ME patients and it included thyroid hormone. But the total regime did not benefit me. I know someone who had really good results but there are also patients getting worse from it.

NOTE when supplementing with hormones, NEVER just stop using them at once! It can kill you! The doctor prescribing these large amount of hormones "forgot" to tell me and I was going to do just that when they did not work. Luckily another doctor warned me to NEVER EVER do such thing just one or two weeks before I planned to do so. So yes, there are potential downsides to hormone supplementing.
 

dejurgen

Well-Known Member
What also fits into that idea: why do ME cells dump ATP out of themselves if they are already so short on it? (A remark of Ron Davis and Naviaux and still a mystery as in "never seen in any other disease")

My hypothesis:

Tests all have been done on cells with mitochondria (like immune cells). RBC don't have mitochondria and depend 100% on glycolysis (the "anaerobe" step of producing ATP) for their own energy production. They don't have mitochondria as that takes a lot of space and would make RBC far to big to flow through small blood vessels.

But this glycolysis pathway is exactly there where that "strange" step appears in, and only in RBC (not in other cells) and the placenta of pregnant women. So if RBC are starved of energy they must try and survive themselves first and produce ATP rather then this molecule I talked about that helps giving off oxygen. So in order to survive they must stop producing the molecule that makes them good at what they should be good at: giving oxygen to tissue. They could chose to give oxygen to tissue above own survival but that strategy wouldn't last long either as soon there would be not enough healthy RBC to transfer oxygen and one would die from lack of oxygen anyway.

But how does fit other cells dumping their hardly won ATP (when they are short on it too!) into the bloodstream? Then RBC can pick up that ATP and are a little bit less in urgent starvation so they can spend some more energy at producing the chemical that enables the RBC to give more oxygen to the tissue. And for each molecule of oxygen "won" this way by the tissue these "other normal cells" can make more ATP thanks to having mitochondria with oxygen producing a lot more ATP per molecule of glucose then the RBC can by using glycolysis. So per ATP the normal cells "freely donate" to the bloodstream / RBC they get enough oxygen to produce multiple ATP and hence have a net gain in energy production themselves.
 

dejurgen

Well-Known Member
As oxygen shortage also creates more hydrogen peroxide, and that every hydrogen peroxide molecule attached to the RBC prevents four molecules of oxygen to attach to the RBC, things could become quite a bit worse when we hit this combination.
It's been a time that I studied this topic. So I dived in for some more explanation. It is more accurate to say that:
For every molecule of hydrogen peroxide attached to hemoglobin, one RBC hemoglobin position is occupied and cannot be used for oxygen uptake and three other RBC hemoglobin positions have oxygen attached to it very firmly so these oxygen molecules wont easily release from the RBC at all. So in effect for each molecule of hydrogen peroxide attaching to the RBC, four positions of oxygen are lost for a long time (until the peroxide is released from the RBC and that takes many many "rounds" of the RBC through the body) when it comes to delivering oxygen to the tissues.

Note that most simple oxygen saturation meters are poor at seeing the difference in "usable" oxygen and oxygen blocked from use by methemoglobin / peroxide https://en.wikipedia.org/wiki/Methemoglobin: "A higher level of methemoglobin will tend to cause a pulse oximeter to read closer to 85% regardless of the true level of oxygen saturation."

Note of mine: that 85% is for very high levels of methemoglobin. If we have a 2,3-diphosphoglycerate shortage then we get in trouble far before we reach this point and this point will likely only be seen during the depth of a crash (as some badly affected patients report) and not during rest.

I can't immediately find the reference but did before. Too tired now. But let me illustrate it with the links I did found today.

(A "quick and dirty link to it" https://en.wikipedia.org/wiki/Hemoglobin, has four positions to hold oxygen per molecule and https://en.wikipedia.org/wiki/Methemoglobin "An abnormal increase of methemoglobin will increase the oxygen binding affinity of normal hemoglobin, resulting in a decreased unloading of oxygen to the tissues. [2]" => So the three other positions for holding oxygen won't release oxygen to the tissue neither. I had a better illustrated link but will have to search again later.)

https://bjanaesthesia.org/article/S0007-0912(17)52400-9/pdf
"Hydrogen peroxide is a powerful oxidizing agent and when large amounts are added to blood methaemoglobin is formed. "

Note: they use peroxide in this study to reoxygenate stored blood. They depend upon having enough catalase (anti-oxidants) in the blood to do this. We *very* likely are in the category "too much peroxide and too few anti oxidant" so adding peroxide won't help us with oxygenation at all.

Of importance to me is "methaemoglobin" sometimes also spelled as methemoglobin.

https://en.wikipedia.org/wiki/Methemoglobin "An abnormal increase of methemoglobin will increase the oxygen binding affinity of normal hemoglobin, resulting in a decreased unloading of oxygen to the tissues. [2]"

=> So if we have a state of high ROS (oxidative stress) on top of a lack of 2,3-diphosphoglycerate (due to to few available ATP / energy) then both effects will add up and make oxygen release from the RBC to the tissues even more difficult!

=> This in effect makes oxygen availability to the tissue *very* poor when we have a burst in oxidative stress due to tissue (paradoxical, I know but that is how the body works) hypoxia.

Add potential hyperventilating as a reaction to this very severe lack of oxygen on top of it and we may be in a dire situation indeed.

But it gets worse! Too much oxidative stress for too long time does cause RBC to become inflexible and make blood more viscous, meaning it will reduce the speed at which blood flows with normal blood pressure. Cort has written on that research before. And the smaller the blood vessels, the more trouble these inflexible RBCs will have to flow through them. So the finest capillaries will take the largest hit in reduction of blood flow.

See also https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937982/ with title "Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging"

Now most of the tissue near these finest capillaries has the combined effect of (strongly) reduced blood flow and RBC clinging on to their oxygen a lot harder due to having less 2,3-diphosphoglycerate and more hydrogen peroxide bound to it. This tissue thus is very likely craving for oxygen.

Now with the RBC "clinging on" to their oxygen, another thing pops up: the tissue consumes less oxygen and hence produces less CO2. CO2 is a vassodilator. So less CO2 means the opposite: constriction or narrowing of the blood vessels. Together with already inflexible RBC that makes for even more reduced blood flow. Things are getting worse indeed.

So having a reduction in blood flow after exertion, as seen in several ME studies, makes sense here:
too high energy consumption (given the dire condition we are in) => energy production can't produce sufficient ATP plus more glucose is rapidly converted to pyruvate and lactate (reducing the speed of glycolysis as there is too much of the "waste" end product) => RBC have difficulty producing enough ATP => RBC produce less 2,3-diphosphoglycerate and even start to "eat" there buffer of the chemical => RBC start to cling on to their oxygen => tissue cells get oxygen starved and produce (contradictory, but it is a supposed defense mechanism) more hydrogen peroxide with the few remaining oxide they get their hands on => hydrogen peroxide transforms normal hemoglobin to methemoglobin that clings on even more to its remaining oxygen and methemoglobin has a long lifetime => with so few oxygen used CO2 production drops and initiate a quick vasoconstriction (as seen after exercise in multiple studies). Also blood (mainly from the lower limbs) will have a difficult time returning to the hart and we will get poor heart prefill. In order to compensate for that the heart has to pump quicker but with smaller stroke volume decreasing maximum blood flow output.

All of the above creates a prolongued and deep hypoxia but not yet complete ischemia. With complete ischemia, the ischemia is bad but the following reperfusion (if one survives that is) is even worse. There are plenty of links to it. It is very inflammatory. And with plenty of inflammation there comes also plenty of generation of hydrogen peroxide (to clean up the "junk" that this ischemia created). The generation of that hydrogen peroxide during that stage can be done by the cells themselves and by the immune system. Both will cost plenty of energy and oxygen and increase the inflammatory state of the body. Severe hypoxia is not identical to complete ischemia, but it is bordering close to it.

High chronic amounts of ROS and hydrogen peroxide also inhibit plenty of enzymes controlling both glycolysis (for both anaerobe and aerobe breathing) and the mitochondria themselves. So even if the mitochondria (under conditions of chronic strong oxidative stress) get oxygen they will produce less ATP. And the upregulated immune system will consume plenty of NADPH. That is a chemical that is used both by the immune system to produce oxidative stress in the first place and by the cells to recycle glutathione (needed to clean up the excess of oxidative stress). Many steps in the mitochondria can produce either NADH or NADPH. So a higher demand for NADPH means that less NADH is produced. AND it's NADH taht is used to produce ATP or "energy".

Things are still getting worse. When the brains can produce too few ATP, the brain's neurons start to release glutamate into the space between the neurons. That creates a hyper excitation state (consuming plenty of energy we don't have) and when it gets worse can lead to neuronal death. That is one big potential source of brain inflammation! And of brain atrophy (reduction in brain volume) as is seen in several ME brain scan studies. All that damage in itself needs energy to clean it up too... ...likely going hand in hand with a lot of oxidative stress and immune triggering.

Issie and I are working around that topic in https://www.healthrising.org/forums/threads/potential-linking-fm-mast-cells-sleep-deprivation-food-intolerance-exercise-intolerance-and-me.6217/

=> All of this provides plenty of building blocks for both PEM and for a vicious circle keeping us in very poor health.

=> All of this also provides plenty of "paths" into getting ME: a strong infection like a bad flue or pneumonia, poor mitochondrial genes, glucose storage disseases, long time over exertion and (pshychological) stress, skeletal deformations squeezing main arteries, air polution and polution by heavy metals (producing plenty of ROS)...
 
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dejurgen

Well-Known Member
Forgot to mention: RBC / hemoglobin is only sort of a last line defense against excessive oxidative stress when all other defense mechanisms against oxidative stress like normal anti-oxidants, enzymes like catalase and "super anti -oxidant" glutathion fail (to be sufficient). If they are sufficient, few methemoglobin is formed.

So this helps understanding why the above proposed mechanism (especially the methemoglobin part of making it even worse) only comes into play when we are hit either by a strong single assault (like a strong infection) or a long lasting chronic infection or a problem with generating energy (for anti-oxidant production for example), an overly strong immune response (creating far more peroxide and consuming far more energy then it would with a "normal" person) or something similar throws some of us into this awful disease. The more of these factors and the stronger and longer lasting the assault, the higher the chances to get into ME according to this hypothesis. Just taking a bunch of anti-oxidants (when having a bad case of ME) will be nothing but a mere drop in the bucket IMO.
 

Issie

Well-Known Member
Good job dejurgen!!!! This does tie a lot of pieces together, doesn't it?

I can see so many possibilities here and potential explanation. Where this ties in for me is the "air hunger" thing and hyperventilating. So many times it can come with even slight exertion or even just upset. There had seemed to be a Co2 connection with this for me.

I do agree that we may all have issues with breathing properly. My sis and I and her son (all with ME/CFS, FMS and all with one form or another of dysautonomia), hold our breath with walking and climbing stairs. Maybe we unknowingly are trying to compensate here. Yet we render ourselves breathless by doing this. (That is in line with the Buteyko method of breathing. But normally that is done sitting in a chair, not exerting oneself. )

The other thing of note is the increase in Peroxide. My having such a progressive case of vitiligo and obvious too high levels of it. I had wondered if it was trying to clean up something as in pathogens (Lyme, fungus) but in this content it could be ROS but contributing to a vicious circle of destruction. Yet possibly a compensation, yet still with negative consequences if not tampered down and rendering us with even less needed oxygen. Catalase as mentioned is needed to tamper this down and maybe an enzyme that is deficient. (Also in one of the 3 types of enzymes I rotate between.)

Of interesting note is that Vit D may help the function of phosphorus. (Note the first link in dejurgen post here.) So many of us found to have very low levels of circulating Vit D. Is it used up trying to maintain this process? Or is it low to compensate for other issues? Vit D can also up calcium and there appears to be some dysfunction in calcium channels contributing to our issues. Calcium also ups glutamate and we are learning how this being in too high levels is neurotoxic and highly inflammatory. Vit D also required Vit K to keep calcium in the bones and not deposit it into soft tissue and form calcifications in places we don't want them. (There is one other possiblity that can affect phosphorus levels - magnesium. )

I however must note that adding phosphorus with kidney issues is dangerous and can give undesirable consequences. Causes edema and stresses kidneys even more. (I found out the hard way.) Other alternatives are much safer. The kidneys already have enough to process without us creating more work for them.
 
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Merida

Well-Known Member
@dejurgen @Issie
So glad you two are still working on this. I will add my 2 cents. I think the family history is important - my Mom and her maternal line, me, my son - all affected. Years ago I kept testing low for lactate dehydrogenase. 60-70 % of normal. I found 2 research articles confirming this in fibro patients.

LDH controls the inter conversion of pyuvate and lactate. Since enzyme quantity is strictly genetic controlled, it is not likely that lack of LDH is a secondary compensation for another problem. In fact, I learned that lack of LDH is considered glycogen storage disorder #11. Almost no research , except a few Japanese studies where there is almost no enzyme.

The other point concerns RhD neg individuals. At one fibro/ CFS support group meeting of 17 women, 55 % were RhD neg. Weird, as the highest % in the world is with the Basque people, at 35%. Amazing that research has not revealed exactly what the Rh proteins on the RBC surface do - but thoughts are that they serve as CO2 releasing channels.

Flegr et. al. Published research that RhD neg individuals are superior in reaction times over RhD positive folks. But after Toxoplasma infection, the RhD negs perform worse than RhD positives.

It is interesting that at least one of the Lyme coinfections ( Bartonella) target and reproduce in the red blood cells.

So, I think the cascade of biochemical issues ( glutathione, etc etc) May all be compensatory for a big, basic inherited issue and / or a stealth organism.

Also, appreciate our common structural differences - scoliosis, large bunions/hammer toes, lack of neck/ lumbar curves, high- arched palate, deviated septum, spina bifida occulta, connective tissue differences, structure/ attachment of colon, kidney differences ( polycystic, one kidney) , and more.

Thanks again, you two.
 

Issie

Well-Known Member
@dejurgen @Issie
So glad you two are still working on this. I will add my 2 cents. I think the family history is important - my Mom and her maternal line, me, my son - all affected. Years ago I kept testing low for lactate dehydrogenase. 60-70 % of normal. I found 2 research articles confirming this in fibro patients.

LDH controls the inter conversion of pyuvate and lactate. Since enzyme quantity is strictly genetic controlled, it is not likely that lack of LDH is a secondary compensation for another problem. In fact, I learned that lack of LDH is considered glycogen storage disorder #11. Almost no research , except a few Japanese studies where there is almost no enzyme.

The other point concerns RhD neg individuals. At one fibro/ CFS support group meeting of 17 women, 55 % were RhD neg. Weird, as the highest % in the world is with the Basque people, at 35%. Amazing that research has not revealed exactly what the Rh proteins on the RBC surface do - but thoughts are that they serve as CO2 releasing channels.

Flegr et. al. Published research that RhD neg individuals are superior in reaction times over RhD positive folks. But after Toxoplasma infection, the RhD negs perform worse than RhD positives.

It is interesting that at least one of the Lyme coinfections ( Bartonella) target and reproduce in the red blood cells.

So, I think the cascade of biochemical issues ( glutathione, etc etc) May all be compensatory for a big, basic inherited issue and / or a stealth organism.

Also, appreciate our common structural differences - scoliosis, large bunions/hammer toes, lack of neck/ lumbar curves, high- arched palate, deviated septum, spina bifida occulta, connective tissue differences, structure/ attachment of colon, kidney differences ( polycystic, one kidney) , and more.

Thanks again, you two.
Thanks @Merida, we both are trying.
Will be more coming as we keep digging for more WHYS and trying new things.
 
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Merida

Well-Known Member
@Issie Sending big Hugs in the form of electromagnetic waves. I am in a crazy place. Big cardiovascular stuff - low oxygen at nite, and low blood pressure. High blood pressure in the am. Normal rest of day unless at doctor’s appt. ( same doc 15 years - high BP only last 4 years), breathlessness that is discussed on the forum. Anyway . . . Will eagerly read your next installment!
 

Issie

Well-Known Member
@Issie Sending big Hugs in the form of electromagnetic waves. I am in a crazy place. Big cardiovascular stuff - low oxygen at nite, and low blood pressure. High blood pressure in the am. Normal rest of day unless at doctor’s appt. ( same doc 15 years - high BP only last 4 years), breathlessness that is discussed on the forum. Anyway . . . Will eagerly read your next installment!
So sorry!
I have an idea though. Raising my bed up has helped with this. I have to have my head up to sleep. Best if whole bed can be angled without bending body. But if not possible, lots of pillows. We got bed risers and put just at top of bed. Helps hubby too, and he doesn't have our issues.
 
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dejurgen

Well-Known Member
Copy from https://www.healthrising.org/blog/2019/11/30/tompkins-harvard-chronic-fatigue-collaboration/ ,words my thoughts better then the original posts in this thread.

If any researcher reads this, I believe it would be very very interesting to try and zoom in on the role of 2,3-Bisphosphoglycerate https://en.wikipedia.org/wiki/2,3-Bisphosphoglyceric_acid in the RBC themselves.

This little known chemical can be formed from https://en.wikipedia.org/wiki/1,3-Bisphosphoglyceric_acid.

1,3-Bisphosphoglyceric acid is an intermediate in the glycolysis process. https://en.wikipedia.org/wiki/Glycolysis is the process in which glucose converts into pyruvate and produces a modest amount of ATP in the process.
As such, glycolysis is vital to convert glucose to pyruvate for the mitochondria to use and hence for the bodies energy production. But most cells do have mitochondria. RBC need to be small enough to flow easily enough trough small blood vessels. Therefore they don’t have mitochondria. As such, they depend vitally on glycolysis to produce enough ATP for their functioning and their very own survival.
Yet, it are those RBC (and the placenta of pregnant women) that can produce this 2,3-Bisphosphoglycerate intermediate in the glycolysis chain. In such, they divert some of the very much needed energy production. That asks for a clear why.
It appears that this 2,3-Bisphosphoglycerate chemical very strongly modulates how much affinity RBC show for oxygen or in other words how willing they are to release their oxygen. Low amounts of 2,3-Bisphosphoglycerate mean that the RBC will cling very hard on to their oxygen, while high amounts of 2,3-Bisphosphoglycerate mean that they will release it easily.

This 2,3-Bisphosphoglycerate chemical however can be either stored in the RBC, helping to better release oxygen, or converted to https://en.wikipedia.org/wiki/3-Phosphoglyceric_acid. 3-Phosphoglyceric acid is another intermediate of the glycolysis chain. So converting some of the “stash” of 2,3-Bisphosphoglycerate that the RBC have to 3-Phosphoglyceric acid will produce extra ATP for the RBC but it will decrease the ability for the RBC to release its oxygen as there is less 2,3-Bisphosphoglycerate left in the RBC and that makes RBC cling on more tight to their oxygen.

So when somehow RBC are depleted of energy, they have to make a choice to use their “stash” of 2,3-Bisphosphoglycerate as a sort of private emergency fuel and convert it into ATP for their very own survival BUT lose much of their ability to release oxygen and thereby hurt almost all other cells in the process OR prioritize oxygenation of the other cells by keeping enough 2,3-Bisphosphoglycerate in store to do this but risk the chance to cause themselves extensive damage or die quickly.
So basically when the speed of glycolysis falls down body wide, as is more then once observed in ME/CFS, then the speed at which RBC can generate energy for their own survival falls down. If that gets too low, they have to scale back on releasing oxygen in favor of their own survival. But that leaves much of the other tissue deprived from oxygen. In the absence of enough oxygen, the flow of pyruvate to the mitochondria must be reduced in order to not create copious amounts of ROS. That can be done by further slowing down glycolysis. We have a clear potential for a vicious circle here.
 

dejurgen

Well-Known Member
Another copy from Cort's Blog:

The idea of the importance of 2,3-Bisphosphoglycerate also could explain why ME cells dump part of their very hard won ATP into the bloodstream.

That is according to Ron Davis something that is unique to ME. Why would our cells do this if they already lack energy so much?

One explanation could be that the cells studied that show this behavior are all cells with mitochondria as far as I know. They can, when having enough oxygen, produce far more ATP out of one molecule glucose then can be produced by the RBC through glycolysis. The difference is about a factor of 10.

So if the (non RBC) cells starving from oxygen somehow “know” that the RBC still have plenty of oxygen but wont release it, then they could “know” that the RBC are starved for energy and can’t release oxygen therefore.

So they send some of the ATP they produce in the bloodstream for the RBC to pick up. Then the RBC can release more oxygen. And the cells receiving that oxygen can produce much more ATP per molecule of glucose then the RBC can, so they can “afford” to dump a reasonable amount of ATP in the bloodstream as that will increase the release of oxygen more then enough to compensate for the lost ATP.

It would be sort of a trade of the cells to dump some ATP in the bloodstream: we’ll give the RBC some of our ATP if they give us more oxygen.
 

dejurgen

Well-Known Member
Another copy from Cort's blog:

This chemical also could help explain why so much pregnant women have a strong temporary reduction in ME symptoms. The only other known human cells that can produce this 2,3-Bisphosphoglyceric acid molecule are in the placenta. Pregnant women produce up to 30% more of it, making oxygen release from the RBC so much easier.

https://en.wikipedia.org/wiki/2,3-Bisphosphoglyceric_acid: “In pregnant women, there is a 30% increase in intracellular 2,3-BPG.”

It is a complex method to help get the fetus more oxygen. I wrote more about this and the other mentioned topics in https://www.healthrising.org/forums/threads/potential-linking-rbc-glycolysis-air-hunger-thyroid-atp-dumping-pregnancy-improvement-and.6236/. It gets (more then) a bit technical however.
 

dejurgen

Well-Known Member
Another copy from Cort's blog:

There is more to this chemical. Thyroid hormone supplementation has been a subject of debate for decades in ME.

Many (but far from all) patients with “in range” thyroid values seem to benefit from thyroid hormone supplementation. Many of us know people who benefit, sometimes to very large and obvious degree.

On the one hand there is a group of patients and their doctors willing to stand strongly by it. They say that “in range” is not specific enough taking diverse patients into account and that the difference between active and non-active thyroid hormone should be more taken into account.

On the other hand there is a large group of highly trained medical experts say that it is total nonsense and dangerous to supply these patients with thyroid hormones.
Well, maybe BOTH could be right. https://en.wikipedia.org/wiki/2,3-Bisphosphoglyceric_acid:

” Hyperthyroidism
A 2004 study checked the effects of thyroid hormone on 2,3-BPG levels. The result was that the hyperthyroidism modulates in vivo 2,3-BPG content in erythrocytes by changes in the expression of phosphoglycerate mutase (PGM) and 2,3-BPG synthase. This result shows that the increase in the 2,3-BPG content of erythrocytes observed in hyperthyroidism doesn’t depend on any variation in the rate of circulating hemoglobin, but seems to be a direct consequence of the stimulating effect of thyroid hormones on erythrocyte glycolytic activity.[3] ”

Maybe the specialist are right that it risks getting “in range” patients to a (near) hyperthyroid situation. And patients and their doctors are right that it improves many of their patients a lot.

Both can go hand in hand as a slight form of hyperthyroidism increases this so important 2,3-BPG chemical in the RBC and helps to alleviate the so very important oxygen release bottleneck in ME by increasing the production of the chemical that helps release oxygen from the RBC.

The clear risk here is that RBC then could starve from ATP because if they produce more 2,3-BPG and keep a higher buffer of it, then they can (temporarily) produce less ATP for themselves. But the cells can produce more ATP and release more of it in the bloodstream to support the RBC if needed. And over time this *could* (in some patients) help break the vicious circle through better cell oxygenation.
 

dejurgen

Well-Known Member
Another copy from Cort's blog:

Now this is very early and I do hesitate to post it, but I feel it is important if researchers would read this and doubt to include researching this idea.

Issie and I are for some time trying to alleviate this bottleneck. So far, based on this very idea, we identified a way to improve our breathing quite a bit. We feel we have more oxygen available to our tissues, have less air hunger, must breath less deep yet still feel like we are breathing well.

Then why do I hesitate to write about it yet? It is unfortunately not easy to avoid side effects at all and we first wish to try and improve our knowledge about what we are doing and how we can get it more stable. For if not, we’ll only get patients sicker as it’s pretty damn difficult to get it right.

But our attempts demonstrate that this (the problem with this 2,3-BPG chemical in the RBC ) *could* be indeed an important or even core part of ME. But we all know how much can go wrong.

And please do not try and fix this problem yourself!!! You’ll risk for example bad reperfusion damage or extensive damage to the RBC if you don’t get it right. And getting it right is though!!!

Note also that we believe this is not the cause of ME, but a “locking in mechanism”. We believe many many patients have ongoing issues requiring this *!*protective*!* mechanism to be active so identifying and reducing those is of vital importance before trying to unlock this security mechanism.

That also holds for viral onset patients who see nothing else but a viral onset being the cause of their disease. Most very likely had hidden weaknesses before getting ill that are triggered now and need to be target before unlocking the safety mechanism.
In the eventual case professional researchers were interested, ask Cort to forward a mail to me.
 

dejurgen

Well-Known Member
Another copy from Cort's blog:

https://en.wikipedia.org/wiki/Myoglobin, an important carrier of oxygen in muscle tissue is not affected by https://en.wikipedia.org/wiki/2,3-Bisphosphoglyceric_acid:

“In contrast, 2,3-BPG has no effect on the related compound myoglobin.”
But myoglobin gets its oxygen transferred to it by hemoglobin. So if hemoglobin releases its oxygen slower (or in other words hemoglobin clings on to its oxygen) then different options can arise:

A) Blood flows at a normal rate in and near muscle tissue. The amount of time hemoglobin and myoglobin (the main oxygen carrier for muscles) “spent” together is the same in these patients as it is in healthy people. But the transfer from oxygen from hemoglobin to myoglobin is a lot slower.
That in practice will make that few oxygen molecules “have the time” to “hop” from hemoglobin to myoglobin. As a result the hemoglobin will return to the heart and lungs packed with oxygen but the muscles will be left with few oxygenated myoglobin and hence be low on oxygen supply.
=> This resembles Corts “High-Flow (Low Oxygen)” model a lot.

B) Blood flow goes at a slow rate in the “main” blood circulation. The time any amount of blood spends in or near the muscle tissue is a lot longer due to the slow flow now. Even if hemoglobine binds to oxygen a lot more then in healthy people, enough oxygen will make the “hop” from hemoglobine to myoglobine allowing a greater part of hemoglobines oxygen to be given to the muscle tissue.
This in practice will make that the RBC will return to the heart and lungs with lower (normal for healthy people) amounts of oxygen left. But, if flow of blood is low enough then the capacity of distributing oxygen throughout the body including to the muscles is limited just because fewer RBC per minute pass by the heart and lungs. So its not an ideal situation either.
=> This resembles a lot Corts “Low Flow (Normal Oxygen)” model

C) Anything in between it.
Note 1:
This division between A) and B) *may* be part of how patients get divided between FM and ME if my intuition is right. Very preliminary however. Reason to think so: brains don’t have myoglobin so optimizing for better transfer to myoglobin could go at the cost of decreasing blood flow to the brain.
Note 2:
This slow transfer of oxygen from hemoglobin to myoglobin (in both cases A) and B)) due to 2,3-BPG problems could also help explain why many of us have a very short buffer of muscle energy: if we rest long enough the muscles have time to “recharge” their myoglobin. When we start to exercise however this “battery” gets depleted very quickly and we have a very poor “provision to the main lines”.
One could compare it a bit with having a lawn mower that can operate both on battery power and mains power. With it having a good quality large battery but only a very poor mains cable able to provide it with a low current. As long as the battery is full enough, the mower will work fine. When it has to draw power from the mains cable, it falls flat. But recharging it with an appropriate battery loader over night and continuing work tomorrow will work with that tiny cable.
Here, the limited cable is the slow transfer from oxygen from hemoglobine to myoglobine.
 

dejurgen

Well-Known Member
Another copy from Cort's blog:

“I wish there could also be summaries for the comments of members who have very complicated theories.”

That could fit me. For now:
Issie and I may have found a chemical typical to Red Blood Cells that helps a whole lot with the RBC giving their oxygen to the rest of the body. But when the RBC can’t produce enough energy, they can’t produce enough of this chemical.

If the production of this chemical goes wrong, it can create or strengthen a nasty vicious circle. We have seen an option to try and break that part of the vicious circle. We now both can breath better and have *at times* clearly more energy. But it still is kind of a minefield. One wrong step and we are worse off for several days.
We also need to learn if it is safe to break open that vicious circle. It could be a safety measure protecting us.

So it’s not stable or ready to be released. We have to be very careful not to set ourselves months back. We can’t risk that other patients go in head first with far less precautions then we take now. But we are tying to see if we can get it more safe, stable and reliable.

Then and only then we can tell what we do and how we try to make it more reliable and tell so in plain words. Having some professional researchers helping us to get it work better and safer would help too.

Hang on Birdie. For now we only can offer some hope.
 

Issie

Well-Known Member
I had found that hyperventilating has been an issue for me and posted this elsewhere. Thought it may fit here, as something to consider.

Where this ties in for me is the "air hunger" thing and hyperventilating. So many times it can come with even slight exertion or even just upset. There had seemed to be a Co2 connection with this for me. Not a need for more Co2 but possibly less. I figured this out while having this happen while swimming in the ocean and my snorkel possibly causing a buildup of Co2 and my rebreathing it. Not only was the salt water causing issues but the pressure on my body was causing more constriction. The exercise contributing to issues with swimming and then a build up, apparently, of Co2 - causing massive hyperventilating, POTS, dizziness and near fainting. Breathing into a bag would have been the wrong thing as it would up Co2 more and cause more vasoconstriction and render blood flow and therefore oxygen flow even more impaired. So many of us have talked of this "air hunger" with POTS too, so not just ME/CFS connected.
 

Not dead yet!

Well-Known Member
=> It's a bit technical but basically IMO it says: you need enough of it in order to get the RBC to release the majority of their oxygen. With too few of this "2,3-Bisphosphoglycerate" much of the oxygen "keeps sticking" onto the RBC "for another tour of the body". In ME language: blood oxygenation is high but it seems as if cells can't use the oxygen; that is a *very* common observation in ME.
Doctors have observed this effect in me. I'm tempted to call my previous pulmonologist who was perplexed by this and show him. He had me doing all sorts of tests to figure out why I could have 100% oxygenation but still be out of breath. ER doctors have seen it too. There may be a concentration thing going on here because if I got an IV of just fluids and electrolytes, this went away. ER doctors don't often agree to that as a therapy though, not anymore, not since IV clinics became a thing. But it worked.

Thank you both for looking into this!
 

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