Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases, 2019, McGregor et al.

[Diwi9]

@percyval577 posted this article in the McGregor's Hypothesis of ME/CFS thread, but it deserves its own thread. It is available in full-text.

https://www.mdpi.com/2075-4418/9/3/70/htm

Abstract
:
Post-exertional malaise (PEM) is a cardinal predictive symptom in the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). If the cases overexert themselves they have what is termed “payback” resulting in a worsening of symptoms or relapse which can last for days, weeks or even months. The aim was to assess the changes in biochemistry associated with the cases self-reported PEM scores over a 7-day period and the frequency of reporting over a 12-month period. Forty-seven ME/CFS cases and age/sex-matched controls had a clinical examination, completed questionnaires; were subjected to standard serum biochemistry; had their serum and urine metabolomes analyzed in an observational study. Thirty-five of the 46 ME/CFS cases reported PEM in the last 7-days and these were allocated to the PEM group. The principal biochemical change related to the 7-day severity of PEM was the fall in the purine metabolite, hypoxanthine. This decrease correlated with alterations in the glucose:lactate ratio highly suggestive of a glycolytic anomaly. Increased excretion of urine metabolites within the 7-day response period indicated a hypermetabolic event was occurring. Increases in urine excretion of methylhistidine (muscle protein degradation), mannitol (intestinal barrier deregulation) and acetate were noted with the hypermetabolic event. These data indicate hypoacetylation was occurring, which may also be related to deregulation of multiple cytoplasmic enzymes and DNA histone regulation. These findings suggest the primary events associated with PEM were due to hypoacetylation and metabolite loss during the acute PEM response.

 

[Seven7]

What?

 

[Rufous McKinney]

Just started reading thru this in a full state of PEM from: 3 hours of going in little shops, being with the grandchild and having lunch. (after any number of days of NOT doing anything).

All of this feels like its exactly what is occuring here. Within the last year, all these metabolic things have worsened here to a great degree.

Can we see how Doctors just cannot stay on top of this level of whole -body complicated? I took biochemistry and got an "A". This stuff is HARD. and that was 45 years ago.

I'm on Day 4 of taking BCAAs. I think it is DOING SOMETHING good. I did not expect to even make it thru the 3 hour field trip yesterday. But I did.

Today there are boulders in my eye balls; my spine is arrested in several locations and I am covered in Magnets (they are helping).

But I'm tremendously excited WE ARE FINDING THESE THINGS OUT NOW.

Permission to NOT FULLY UNDERSTAND this level of metabolically complicated/ cut yourselves some slack.

Its more bread crumbs for us to follow!

 

[Murph]

Terrific study by McGregor, probably the last one he will do with Chris Armstrong who has now moved to OMF.

Also worth noting the terrific contribution by Donald Lewis, whose clinic supplied all these patients, and who recently retired (leaving me with no doctor!!). His retirement is a blow not only to local patients but to the global me/cfs community.

I hope that "melbourne bioanalytics" continues after the departure of Armstrong and the retirement of Lewis. I fear instead we will see that pattern where an isolated researcher or group of researchers makes good progress and then stops, only to be rediscovered years later with people asking " how come we knew this twenty years ago and did nothing?"

The great hope is OMF. If Armstrong can act as a vector conveying these ideas to OMF and money flows in sufficient volume for the ideas to be explored further, there's a chance we avoid repeating the pattern.

 

[kangaSue]

Can't say I have a good grasp of this but I wonder if allopurinol might be beneficial here. It has protective properties in intestinal/ischemia reperfusion injury and intestinal mucosal ischemia is one way to alter the gastrointestinal barrier function and allopurinol also enhances purine salvage.

 

[pattismith]

Can't say I have a good grasp of this but I wonder if allopurinol might be beneficial here. It has protective properties in intestinal/ischemia reperfusion injury and intestinal mucosal ischemia is one way to alter the gastrointestinal barrier function and allopurinol also enhances purine salvage.

I had the same idea to enhance IMP and the purine salvage pathway from Hypoxanthine.

I tried allopurinol, but had a very bad reaction on the very first day (eye scleritis), so had to stop it.
Inositol is an alternative option to allopurinol (Febuxostat is another)

I tested Inosine (with or without inositol) with caffeine (with the idea to make Inosine entering cells to fuel hypoxanthine ) and it worked fine initially.

https://forums.phoenixrising.me/thr...ance-cellular-atp-in-two-mito-diseases.62929/

https://forums.phoenixrising.me/threads/instant-relief-with-inosine-caffeine.62649/#post-1020649

 

[kangaSue]

(Febuxostat is another)

I don't think febuxostat will be effective here as it is only an inhibitor of xanthine oxidase and doesn't influence the activity of other enzymes involved in purine or pyrimidine synthesis or metabolism.
https://www.ebmconsult.com/articles/allopurinol-febuxostat-zyloprim-uloric-uric-acid-gout-mechanism

 

[Learner1]

It's interesting how hypicanthine is so intertwined with ATP production and NAD/NADH. This diagram is helpful.

Hypoxanthine is a breakdown product of ATP. Cells try to maintain a high energy charge even if ATP concentration falls and the energy level decreases. The energy charge can be kept high during ATP deficiency by reducing the concentration of AMP, which can become a problem...

Hypoxanthine moves forward and interacts with NAD and oxugen and creates uric acid to be flushed out of the body.

 

[bertiedog]

This looks particularly interesting to me because I am 5 days into Imunovir which is basically inosine. It has already helped my immune system to get over a very nasty 2 week virus which hit my throat, sinuses and muscles to the degree my back went into spasms and I was unable to walk. I had nil energy and my legs were like lead.

I felt like death but within 3 days of taking the Imunovir I had no sign I ever had a virus and my muscles returned to their normal level of functioning which can be pretty good as long as I don't overdo things.

I actually feel happy and well which is unbelievable the way I was just so ill for 14 days.

Thanks for the above diagram @Learner1.

Pam

 

[bread.]

me/cfs is mitochondrial damage caused by reperfusion injury (that is PEM) - the thing is, what is causing the the low oxygen state in the first place - that is were we will be stuck for a long time because it will be different for everyone and not a „one fits all explanation“ with one solution.

(it seems clear that people with EDS will struggle more and are more prone to get into the me/cfs state because of this hypoxic process)

 

[Learner1]

me/cfs is mitochondrial damage caused by reperfusion injury (that is PEM) - the thing is, what is causing the the low oxygen state i

Hmmm...do you have any evidence to back this up?High hypoxanthine seems to relate to hypoxia, not low.

https://www.nature.com/articles/pr1988227

I HBOT regularly and have not found it to reduce PEM. I have found glutathione does, though. Your mitochondrial damage statement is helpful, but it seems to be, not from reperfusion (how do you reperfuse a mitochondria??) ,from peroxynitrite damage as several researchers (Maes and Morris, Martin Pall, Garth Nicolson, among others) have discussed and as Ron Tompkins made sure to include in his summary at the recent NIH Conference. I believe this is why the glutathione is so helpful - it can reduce the damage to cell membranes from peroxynitrites and minimize impairment of complex I that has been attributed to peroxynitrites.

However, this wasn't discussed much in this article.

It seems the ATP/NAD susyem was disturbed. @bertiedog was there some test that caused you to try inosine or what caused you to try it?

I'm also wondering if helping acetylation. Or manipulating lysine may be helpful. I found the attached - wondering which set of supps one might try, though I already take curcumin...

And what might one do about a glycolysis problem? How would you know if you had one?

I take NMN regularly and glutathione and BCAAs before and after exercise and can see why they all help, but I just experienced the biggest PEM I've had in a long time after 2 days of too much activity, and all my usual tricks weren't enough. They worked enough so I wasn't bedbound but really had to lay low...

 

[bertiedog]

t seems the ATP/NAD susyem was disturbed. @bertiedog was there some test that caused you to try inosine or what caused you to try it?

I have awful problems with picking up so many viruses or possibly viruses recurring. I had many high IgG results on 5 of the herpes type viruses including CMV and also Coxsackie was extremely high. I do pretty well on many days with 9000 steps daily but when this virus comes along everything changes and i feel dreadful. It has been happening at least twice a month all this year following an extremely stressful time in 2018 when I was doing a bit of voluntary work.

Breakspear is a private hospital here in the UK and they did the tests for me in 2011 and when I got the results they recommended Imunovir. I don't remember what happened when I originally took it but it might well have been it was expensive to keep getting from them so I stopped taking it. Probably I didn't ever get more than one script from them.

This time after reading about the Polish version of it on PR I ordered it through eBay and when I was so ill with probably one virus on top of another and couldn't get better I remembered it was in the cupboard and now I am on Day 5 so will be stopping it after tomorrow to have the 2 days off. My throat is still not quite right but my energy has come back really well and I feel so much better.

There is some excellent information about Sue Jackson's 10 year's experience on Imunovir on her Living with ME/CFS blog...Her 2 sons have also been taking it for a long time together with LDN and they have all done well but crashed badly when they came off it.

I did try LDN but it was a horrid drug for me making me extremely dizzy and panicky whereas the Imunovir at 1 x 3 daily suits me fine. I am hoping I won't have to go higher than 2 x 3 day on some weeks before going back down to 1 x 3 day though Dr Cheney reckoned you can go higher if necessary.

Sue Jackson now just takes the supplement inosine and says she gets the same response and as I have an unopened bottle of this in the cupboard I will move onto that once the Imunovir is finished just to see.

Pam

 

[Mary]

I'm on Day 4 of taking BCAAs. I think it is DOING SOMETHING good. I did not expect to even make it thru the 3 hour field trip yesterday. But I did.

Very glad to hear this! I remember you were debating awhile ago whether or not to try BCAAs - I wouldn't be without them!

I have found glutathione does, though.

Hi @Learner1 - I know I've asked you this before but can't remember the answer . . . what form or brand of glutathione do you take? Do you take it with or without food? I've started it a couple of times and can't remember now why I stopped. I think it did cause a herx reaction and perhaps I wasn't able to spend the down time the herx was causing -- but, am thinking I should probably give it another go --

@bertiedog - several years ago I took inosine for several months. I liked it, it initially boosted my energy a bit, but after awhile I felt no different so eventually stopped it. I am prone to infections which lay me low and have found andrographis to be very effective in quelling them rather quickly. Sometimes I combine it with echinacea. And lately I have been using cordyceps, it helps as well - just a couple more suggestions in case the inosine or immunovir stops working --

 

[wigglethemouse]

Tweet from Dr. John Whiting who I believe is closely connected with the researchers of this paper

https://twitter.com/i/web/status/1146762215254401024

This is the real deal ! It not only demonstrates that adenosine recovery by cells is inadequate, and gets metabolised to depletion, but purine signalling throughout the body AND the brain are going through issues. Adenosine and normal sleep are intertwined.

@Learner1 Would this tie in with you diagram above where hypoxia causes a blockage of Hypoxathine to IMP to recycle? Do you have a reference for that diagram that I could share with John Whiting......

https://twitter.com/i/web/status/1146783659380240384

The adenosine salvage system will need this speculation to be studied carefully to make it real.

https://twitter.com/i/web/status/1146783384414216192

There is likely to be an cell membrane adenosine salvage transporter system failure here. The loss of body adenosine means it has to be re-synthesised to novo, an energy dependent system. Without sufficient adenosine, then less available to make ATP. I’m not sure if ribose helps.

https://twitter.com/i/web/status/1146791311103668224

If I search for this, I find papers that say trypanosomes salvage purines from their host. That might explain the reported similarity between sleeping sickness and this illness.

 

[bread.]

Hmmm...do you have any evidence to back this up?High hypoxanthine seems to relate to hypoxia, not low.

https://www.nature.com/articles/pr1988227

I HBOT regularly and have not found it to reduce PEM. I have found glutathione does, though. Your mitochondrial damage statement is helpful, but it seems to be, not from reperfusion (how do you reperfuse a mitochondria??) ,from peroxynitrite damage as several researchers (Maes and Morris, Martin Pall, Garth Nicolson, among others) have discussed and as Ron Tompkins made sure to include in his summary at the recent NIH Conference. I believe this is why the glutathione is so helpful - it can reduce the damage to cell membranes from peroxynitrites and minimize impairment of complex I that has been attributed to peroxynitrites.

However, this wasn't discussed much in this article.

It seems the ATP/NAD susyem was disturbed. @bertiedog was there some test that caused you to try inosine or what caused you to try it?

I'm also wondering if helping acetylation. Or manipulating lysine may be helpful. I found the attached - wondering which set of supps one might try, though I already take curcumin...

And what might one do about a glycolysis problem? How would you know if you had one?

I take NMN regularly and glutathione and BCAAs before and after exercise and can see why they all help, but I just experienced the biggest PEM I've had in a long time after 2 days of too much activity, and all my usual tricks weren't enough. They worked enough so I wasn't bedbound but really had to lay low...

—

NO, which your cells will „produce“ in the emergency state of being hypoxic will do damage to your mitochondria via some of the mechanisms you mentioned, when cells and tissues are reoxygenated your oxidative stress (again, that is PEM) will rise and do further damage.

 

[Learner1]

Hi @Learner1 - I know I've asked you this before but can't remember the answer . . . what form or brand of glutathione do you take? Do you take it with or without food? I've started it a couple of times and can't remember now why I stopped. I think it did cause a herx reaction and perhaps I wasn't able to spend the down time the herx was causing -- but, am thinking I should probably give it another go --

I have used Seeking Health and Core Med Science but likely any Setria will do. I take a teaspoon 10 min before coffee and light breakfast. After exercise, I take a couple Thorne SR glutathione capsules - easier to keep eiyh me on the go, no refrigeration needed where liposomal has to be refrigerated.

If you dont have enough B1 or molybdenum, you could have trouble, or if you have dome toxin that you can't fully get rid of, it csn get reabsorbed... Either way, you could have some unpleasant symptoms. I take 500mg benfotiamine and 2mg molybdenum, which helps my transsulfuration pathway so bad stuff leaves my system.

@Learner1 Would this tie in with you diagram above where hypoxia causes a blockage of Hypoxathine to IMP to recycle? Do you have a reference for that diagram that I could share with John Whiting......

I'm not sure about that. See attached for original doc. Please let us know what John Whiting says.

NO, which your cells will „produce“ in the emergency state of being hypoxic will do damage to your mitochondria via some of the mechanisms you mentioned, when cells and tissues are reoxygenated your oxidative stress (again, that is PEM) will rise and do further damage.

There are a lot of reasons for oxidative and nitrosative stress. Reducing these stresses and finding balance is important. They can cause mitochondrial damage. But tgats a different level of granularity than tissues or cells, where your reperfusion pronlem happens...yes?

 

[bread.]

I have used Seeking Health and Core Med Science but likely any Setria will do. I take a teaspoon 10 min before coffee and light breakfast. After exercise, I take a couple Thorne SR glutathione capsules - easier to keep eiyh me on the go, no refrigeration needed where liposomal has to be refrigerated.

If you dont have enough B1 or molybdenum, you could have trouble, or if you have dome toxin that you can't fully get rid of, it csn get reabsorbed... Either way, you could have some unpleasant symptoms. I take 500mg benfotiamine and 2mg molybdenum, which helps my transsulfuration pathway so bad stuff leaves my system.


I'm not sure about that. See attached for original doc. Please let us know what John Whiting says.

There are a lot of reasons for oxidative and nitrosative stress. Reducing these stresses and finding balance is important. They can cause mitochondrial damage. But tgats a different level of granularity than tissues or cells, where your reperfusion pronlem happens...yes?

—

I don‘t think so - one is dependent on the other - but also, maybe that is above my paygrade. It could be (and I am quite sure it is) a chronic mechanical issue with your blood circulatory system, hence the high numbers of EDS patients.

It is a vicious cycle that gets worse with age (and then stops when people stop moving) because of accruing damage to your blood vessels which are highly (!) dependent on mitochondrial function - arteries get whacked (Systrom findings), your body reacts with POTS and a higher catecholamine output (wired) to come up with more oxygen for your brain and tissues (people feel stronger and better when on „adrenaline“) - at some point the damage hits a certain point where your body is just struggling to come up with energy demands. It is also not difficult to see how a constant sympathetic state would fuck up your immune system, thats the point where people got „suddenly“ sick with an infection, which for most/many people is not the truth, they simply tell that everyone and themselves for varying reasons.

I do believe that me/cfs in many (30%?!) patients is exactly just that:

Some form of EDS (we know so little about it) + secondary mitochondrial damage in cells (with the highest oxygen turnover) due to many (potentially hundreds) physical stressors that happen to human beings, that is why there are so many triggers, and why so many patients had a continous deteoriation.

Best case scenario for these patients (like myself) that I could see would be if it was „only“ an Enterovirus that fucks up Collagen Synthesis with reversible damage, but it is unlikely.

One of the biggest problems I see is that the main people looking into this disease still believe that it is exactly just that: ONE disease. It is completely obvious that this is NOT the case.

They mix people together with different diseases and the same symptoms and are surprised when they find nothing significant. Its like saying cancer is ONE disease, it is NOT.


@Hip @Jonathan Edwards

 

[Learner1]

@bread. It is not necessary to quote the entire input of another member. It is simpler if you use the QUOTE function to break it into chunks. Just select the text you wish to respond to, choose Quote, then, below the Reply box, choose "insert quotes,"

I don‘t think so - one is dependent on the other - but also, maybe that is above my paygrade.

Maybe so?

I am quite sure it is) a chronic mechanical issue with your blood circulatory system, hence the high numbers of EDS patients.

Not sure how one can have a mechanical issue with chemistry - this doesn't make sense...

because of accruing damage to your blood vessels which are highly (!) dependent on mitochondrial function - arteries get whacked (Systrom findings), your body reacts with POTS

These antibodies are what causes POTS for many of us, confirmed by research:

https://www.celltrend.de/en/pots-cfs-me-crps.html

and a higher catecholamine output

My catecholamines are low, as are many patients', likely due to the increased amino acid consumption found by Fluge and Mella. Some folks with hyperadrenergic POTS may have high norepinephrine, but their other catecholamines may still be low.

to come up with more oxygen for your brain and tissues (people feel stronger and better when on „adrenaline“) -

Catecholamines don't create oxygen for the brain. Many of us are hypoxic snd have found help from strategies of increasing oxygen from external sources like inhaling oxygen or HBOT.

the damage hits a certain point where your body is just struggling to come up with energy demands.

There are many reasons for increased energy demand. This article describes why ATP production may be decreased. There are other rrasons for decreased ATP production, like arsenic toxicity which can impair ATP production, or peroxynitrite damage to mitochondrial membranes causing inefficiency or impaired complex I or lack of cofactors.

It is also not difficult to see how a constant sympathetic state would fuck up your immune system, thats the point where people got „suddenly“ sick with an infection, which for most/many people is not the truth, they simply tell that everyone and themselves for varying reasons.

The psychiatrists would like us to believe that. For most of us, this is a medical disease,.

I do believe that me/cfs in many (30%?!) patients is exactly just that:

That might be high...but there definitely are multiple subsets of patients.

One of the biggest problems I see is that the main people looking into this disease still believe that it is exactly just that: ONE disease. It is completely obvious that this is NOT the case.

Agreed.

One of the biggest problems I see is that the main people looking into this disease still believe that it is exactly just that: ONE disease. It is completely obvious that this is NOT the case.

They mix people together with different diseases and the same symptoms and are surprised when they find nothing significant. Its like saying cancer is ONE disease, it is NOT.

That is a problem. But researchers are more aware of this now, and for instance, the current NIH study only is looking at viral onset patients, so this will improve.

 

[bread.]

@bread. It is not necessary to quote the entire input of another member. It is simpler if you use the QUOTE function to break it into chunks. Just select the text you wish to respond to, choose Quote, then, below the Reply box, choose "insert quotes,"

Maybe so?

Not sure how one can have a mechanical issue with chemistry - this doesn't make sense...

These antibodies are what causes POTS for many of us, confirmed by research:

https://www.celltrend.de/en/pots-cfs-me-crps.html

My catecholamines are low, as are many patients', likely due to the increased amino acid consumption found by Fluge and Mella. Some folks with hyperadrenergic POTS may have high norepinephrine, but their other catecholamines may still be low.

Catecholamines don't create oxygen for the brain. Many of us are hypoxic snd have found help from strategies of increasing oxygen from external sources like inhaling oxygen or HBOT.
There are many reasons for increased energy demand. This article describes why ATP production may be decreased. There are other rrasons for decreased ATP production, like arsenic toxicity which can impair ATP production, or peroxynitrite damage to mitochondrial membranes causing inefficiency or impaired complex I or lack of cofactors.

The psychiatrists would like us to believe that. For most of us, this is a medical disease,.

That might be high...but there definitely are multiple subsets of patients.
Agreed.

That is a problem. But researchers are more aware of this now, and for instance, the current NIH study only is looking at viral onset patients, so this will improve.

——

„not sure how one can have a mechanical issue with chemistry“

—>

if I close your mouth and nose mechanically, what will happen to your chemistry?

„catecholamines are not producing oxygen“

—>

really?


„.... celltrend“

—>

not even celltrend believes they have anything that comes even close to a biomarker for POTS, there are at least a dozen of mechanisms of how you could end up with POTS (yes, really)

lets conserve energy.

 

[Rufous McKinney]

Very glad to hear this! I remember you were debating awhile ago whether or not to try BCAAs

I've continued to take the BCAAs. The main "recent new symptom" they seem to be reducing is: tachycardia...my heart beating away and flopping about: I am far too run down.

I get about one hour of: function a bit after the BCAAs: before I am again STARVING. I feel like all I do is eat every two hours, in order to not feel HORRIFIC. Yet I'm still losing weight.

Been unable to adequately PACE myself on this visit to my new grandaughter, being around other people all day long. GOT to Pace better.