WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome

[Forummember9922]

Since I did not see it mentioned here yet, another thread on phoenix rising has a wealth of information on possibly related topics
https://forums.phoenixrising.me/thr...ponse-and-a-possible-treatment-for-cfs.37244/

with @mariovitali perhaps appearing quite ahead of his time, and taking a data-driven approach.

I see his mentions of TUDCA but also separate Jarrow Bile Acid products. I hope that you are doing well if you see this Mario.

 

[mariovitali]

Since I did not see it mentioned here yet, another thread on phoenix rising has a wealth of information on possibly related topics
https://forums.phoenixrising.me/thr...ponse-and-a-possible-treatment-for-cfs.37244/

with @mariovitali perhaps appearing quite ahead of his time, and taking a data-driven approach.

I see his mentions of TUDCA but also separate Jarrow Bile Acid products. I hope that you are doing well if you see this Mario.

Hi, all is well Thanks! I also wrote to Dr Hwang explaining to him that a key intervention for my remission was TUDCA. He was out of office but he replied and said that he will get back to me with any questions.

Also I would suggest to stay away from supplemental Bile acids

 

[Forummember9922]

Hi, all is well Thanks! I also wrote to Dr Hwang explaining to him that a key intervention for my remission was TUDCA. He was out of office but he replied and said that he will get back to me with any questions.

Also I would suggest to stay away from supplemental Bile acids

It is nice to hear you are doing well. I was skimming the linked thread to find progress reports but imagined that question might get old to you!

Even if Tudca is not a source of improvement, it is empowering that new research can pave the way for discussions about possible treatments, and also validate previous discussions. cheers

 

[mariovitali]

Thank you @Forummember9922 ! Unfortunately, no patient organisation or researchers agreed to fully use this technology to better understand ME/CFS, to this day.

Regarding TUDCA : I believe that it is not just about lowering ER Stress. Oxidative stress must also be managed (quite possibly on a personalized level) and any other underlying conditions must be addressed. Essentially we create the best environment for the body to get out of a vicious cycle.

 

[hapl808]

Regarding TUDCA : I believe that it is not just about lowering ER Stress. Oxidative stress must also be managed (quite possibly on a personalized level) and any other underlying conditions must be addressed. Essentially we create the best environment for the body to get out of a vicious cycle.

That's really interesting - I think that thread is from before I joined.

Would you say that the info in there is still your best understanding of your situation what led to your remission, or are there aspects you would modify with further experience? Do you continue your supplement regimen, or did you no longer need certain elements once you achieved better health?

Also, how severe were you when you started, and what's your current health if you don't mind my asking.

Really fascinating post - sorry for all the questions!

 

[mariovitali]

@hapl808

I am currently writing a paper about this work where I will put some new concepts that have been found but I am giving here the greater idea : Both oxidative and endoplasmic nreticulum stress should be dealt with.

I continue to supplement. Any attempt to stop, results in certain symptoms come in with the more pronounced being tinnitus. For me, tinnitus signifies the beginning of a crash and the beginning of yet another vicious cycle. I have purposely crashed myself hundreds of times.

The last on purpose crash I tried (but I havent crashed!) was when I deliberately stayed in a room with visible mold. No problems !

I think that I was about to go quite severe and luckily I managed to delay it -this was done probably with Choline- and methylation support. But I did have energy issues if I would go out and walk for 15-20 minutes. I would have substantial PEM for many hours after that.

In my opinion, the conversation about "Post-viral" syndromes is not productive because it assumes that ME/CFS originates from a virus. This of course, is not always the case.

I can say that I am doing better than before I got ME/CFS. I am down to ideal weight, no issues with energy, sleeping through the night for 6-7 hours. But, if I begin eating glutamate sources, whey protein, drinking alcohol hell will break loose. So I am still in remission but also still a patient I suppose.

 

[hapl808]

Some of your 'avoid' category seems unusual to me. Green tea and quercetin seem to help me. But then I see you had symptoms like bradycardia, where I've had constant tachycardia for years.

Choline also seems a mixed bag. I've tried CDP Choline, eggs, Alpha GPC, etc - eggs don't really agree with me, not sure what CDP Choline does for me, and maybe Alpha GPC is slightly helpful along with SAMe and methyl B vitamins.

Beyond the SNPs, seems like a lot of potential trouble spots.

I do take magnesium (helps more than calcium), vitamin D3, resveratrol, TUDCA at times (just finished a bottle of 250mg capsules), turmeric (curcumin doesn't seem to do anything for me), methyl B vitamins, taurine, NAC, selenium, 5-HTP, and a few other things.

That seems somewhat similar, but I haven't gotten much results - maybe slight improvements, but less than 5% overall I think. Have tried NAG but didn't notice anything. Used mucuna in the past but ran out.

Other things I've tried recently - milk thistle, chlorella, bee propolis, theanine, allicin, natto-serra, skullcap, PEA, lactoferrin, cromolyn sodium, and so forth.

 

[mariovitali]

@hapl808

There are many supplements that I would like to call "love or hate" supplements and this is because whatever supplement one patient finds extremely beneficial another patient does not find beneficial at all. Some examples are NAC and taking any supplement that increases Methyl Groups.

Regarding eggs : They are a source of misfolded protein because when you boil them or fry them, the egg white essentially turns to denatured protein and I think this is not what we want.

Egg whites and whey protein have been always a problem for me. I just ordered undenatured whey protein -which I had no idea that it existed- to try it out.

What is required is a very detailed patient history. I've heard that many patients who were not aware that had hemochromatosis or Wilson's disease.

Again, I am not suggesting that this is THE solution for ME/CFS, I described what I did and that within months I got my life back.

 

[pattismith]

interestingly MBL deficiency seems to affect intracellular ER, I will add TUDCA to m regimen...

Mannan-binding lectin deficiency augments hepatic endoplasmic reticulum stress through IP3R-controlled calcium release​

Yu Chen 1, 2021

• DOI: 10.1016/j.ceca.2021.102477

Abstract​

The aberrant release of endoplasmic reticulum (ER) calcium leads to the disruption of intracellular calcium homeostasis, which is associated with the occurrence of ER stress and closely related to the pathogenesis of liver damage.
Mannan-binding lectin (MBL) is a soluble calcium-dependent protein synthesized primarily in hepatocytes and is a pattern recognition molecule in the innate immune system.

MBL deficiency is highly prevalent in the population and has been reported to be associated with susceptibility to several liver diseases.

We here showed that genetic MBL ablation strongly sensitized mice to ER stress-induced liver injury.

Mechanistic studies established that MBL directly interacted with ER-resident chaperone immunoglobulin heavy chain binding protein (BiP), and MBL deficiency accelerated the separation of PKR-like ER kinase (PERK) from BiP during hepatic ER stress.

Moreover, MBL deficiency led to enhanced activation of the PERK-C/EBP-homologous protein (CHOP) pathway and initiates an inositol 1,4,5-trisphosphate receptor (IP3R)-mediated calcium release from the ER, thereby aggravating the hepatic ER stress response.

Our results demonstrate an unexpected function of MBL in ER calcium homeostasis and ER stress response, thus providing new insight into the liver injury related to ER stress in patients with MBL deficiency.

 

[mariovitali]

@pattismith do you have MBL deficiency?

 

[hapl808]

Again, I am not suggesting that this is THE solution for ME/CFS, I described what I did and that within months I got my life back.

Yeah, I'm definitely a believer that there's unlikely to be any 'one' solution to this type of illness.

Just trying to see if with my symptoms (relatively severe, unable to walk, etc), there's any aspects that might be worth adding (or subtracting).

Would some people having hemochromatosis be a likely explanation for the varied responses to methylene blue?

There are so many things that seem promising in theory, but end up being unremarkable in practice. Just for my brain fog and crashes after mental exertion, it frustrates me immensely that all the things that should help don't seem to do anything, so I continue to trial things.

 

[mariovitali]

@hapl808

May I ask how much TUDCA you were taking ? I was taking up to 1 gram per day

 

[pattismith]

@pattismith do you have MBL deficiency?

yes I have severe deficiency (undetectable). This lead to a constant proinflammatory state.

 

[hapl808]

May I ask how much TUDCA you were taking ? I was taking up to 1 gram per day

I was only taking 250mg-500mg per day. (I don't have a ton of food, so I was taking it with my main meal, then sometimes a second capsule with a snack.)

 

[mariovitali]

What is required is a very detailed patient history. I've heard that many patients who were not aware that had hemochromatosis or Wilson's disease.

So here is an example on what @pattismith mentioned about MBL. And we see that MBL affects liver function (the paper that @pattismith linked mentions liver injury) In much the same way we must screen for other conditions that impair liver function : Hemochromatosis, Wilson's disease, Antitrypsin deficiency, Gilberts syndrome...unfortunately the list has many entries :

Alpha-1 Antitrypsin Deficiency

Autoimmune Hepatitis

Budd-Chiary Syndrome

Cholecystitis

Choledochal Cysts

Cholestasis

Cystic Fibrosis

Drug-Induced Liver Injury (DILI)

Gallstones

Gaucher's Disease

Gilbert's Syndrome

Glycogen Storage Disease

Granulomatous Liver Disease

Hemochromatosis

Hereditary Tyrosinemia

Hyperammonemic Syndromes

Liver Fibrosis

Niemann-Pick Disease

Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-Alcoholic Steatohepatitis (NASH)

Porphyria

Portal vein Thrombosis

Primary Biliary Cirrhosis

Primary Sclerosing Cholangitis

Pyogenic Cholangitis

Sinusoidal Obstruction Syndrome

Wilson Disease and Copper Metabolism

 

[mariovitali]

I was only taking 250mg-500mg per day. (I don't have a ton of food, so I was taking it with my main meal, then sometimes a second capsule with a snack.)

Thank you and I forgot to ask for how much time were you taking it? I do have some questions as to how one should be taking TUDCA :

-Is it better to take one single dose?
-Should it be taken across the day (say every 8 hours)
-Should it be taken with food?
Note that for a medication called UDCA (Ursodeoxycholic acid) there is evidence suggesting that one single dose at bedtime has the best effect.

https://pubmed.ncbi.nlm.nih.gov/9864972/

A significant in difference decreased SI was observed during UDCA bedtime administration, but not during mealtime administration, compared to the SI before administration. This suggests a decreased cholesterol excretion into the bile. Based on these findings and from the point of view of compliance, bedtime administration of UDCA appears to be an effective method.

So, many factors we still do not know yet. And that is for a single supplement !

 

[Violeta]

Thank you @Forummember9922 ! Unfortunately, no patient organisation or researchers agreed to fully use this technology to better understand ME/CFS, to this day.

Regarding TUDCA : I believe that it is not just about lowering ER Stress. Oxidative stress must also be managed (quite possibly on a personalized level) and any other underlying conditions must be addressed. Essentially we create the best environment for the body to get out of a vicious cycle.

​

Very interesting, @mariovitali.

And the thing I appreciate most about your research is that you provide remedial advice, too.

​

Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?​

The ER provides a unique oxidizing folding-environment that favors the formation of the disulfide bonds. Accumulating evidence suggests that protein folding and generation of reactive oxygen species (ROS) as a byproduct of protein oxidation in the ER are closely linked events. It has also become apparent that activation of the UPR on exposure to oxidative stress is an adaptive mechanism to preserve cell function and survival. Persistent oxidative stress and protein misfolding initiate apoptotic cascades and are now known to play predominant roles in the pathogenesis of multiple human diseases including diabetes, atherosclerosis, and neurodegenerative diseases.

https://pubmed.ncbi.nlm.nih.gov/17979528/

 

[Violeta]

I wish it wasn't true but I am seeing that fructose does cause ER stress.

I am trying to find out if PUFA also causes ER stress.

 

[mariovitali]

I wish it wasn't true but I am seeing that fructose does cause ER stress.

I am trying to find out if PUFA also causes ER stress.

Fructose ingestion is one of the worst things you can do if you have liver issues

 

[Violeta]

I was wondering if the ER and oxidative stress relationship was related to the mitochondria and found this.

https://www.frontiersin.org/article... (ER) and,dynamics and other related cellular

The endoplasmic reticulum (ER) and mitochondria are physically connected to form dedicated structural domains known as mitochondria-associated ER membranes (MAMs), which participate in fundamental biological processes, including lipid and calcium (Ca2+) homeostasis, mitochondrial dynamics and other related cellular ..

Mitochondria-Associated Endoplasmic Reticulum Membranes in Cardiovascular Diseases​

https://www.frontiersin.org/article... (ER) and,dynamics and other related cellular