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

[Dakota15]

Sharing a screenshot that I wrote to NHLBI Director, and that others have started as well. Hoping others may follow suit, and that increased attention can only expedite urgency. I can provide a template for anyone that would also like to write to Gibbons and NHLBI.

 

[Violeta]

@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.

@mariovitali, how long does it take for the crash to hit after taking something that causes you to crash?

 

[SlamDancin]

He says it earlier in the thread but @mariovitali credits TUDCA to a large degree for his remission of symptoms. A reminder that TUDCA can lower/resolve ER stress and unfolded protein responses. Do you still take TUDCA @mariovitali?

 

[mariovitali]

@SlamDancin Yes, 4 months I take , 1 month i stop.

@Violeta The crash may happen within an hour

Some slides from a presentation I gave in 2018 regarding ER Stress which I think are quite interesting : Note also the mention on LXR (last slide) which Maureen Hanson has identified in her latest study (impaired LXR/RXR activation)

 

[Cipher]

@SlamDancin Yes, 4 months I take , 1 month i stop.

Have you done a write up somewhere about your TUDCA recovery story? Severity before & after, symptom profile, how long it took for you to improve, dosage, brand of TUDCA, etc?

 

[Violeta]

Thank you so much for all thr information from your slide presentation, @mariovitali!

Wow, crash within an hour! At least it makes it more obviously what the source of the problem was.

And thank you for having shared your journey here at Phoenix Rising!

You were definitely way ahead of the curve!

I had been wondering if you had any thoughts about zinc because it's turning up in so many places, and there it is! And then @datadragon had some information about copper and ER stress, so I was wondering if pyroluria is actually an ER stress condition.

 

[mariovitali]

Have you done a write up somewhere about your TUDCA recovery story? Severity before & after, symptom profile, how long it took for you to improve, dosage, brand of TUDCA, etc?

Unfortunately no and quite possibly I will not be able to do so in the foreseeable future.

 

[datadragon]

Some slides from a presentation I gave in 2018 regarding ER Stress which I think are quite interesting : Note also the mention on LXR (last slide) which Maureen Hanson has identified in her latest study (impaired LXR/RXR activation)

Yes and Retinoid X receptor (RXR) requires Vitamin A. LXRα and LXRβ form heterodimers with the obligate partner retinoid X receptor (RXR) also. Zinc is needed in Vitamin A metabolism. Covered earlier in this thread https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2442438

Bile Acids involve Vitamin A active metabolites as well covered here https://forums.phoenixrising.me/threads/could-and-upset-liver-be-a-clue-to-me-cfs.87544/post-2438568

Copper is dysregulated from low zinc and Vitamin A due to lowering of ceruloplasmin production that is needed to make copper and iron bioavailable (usable). Copper is shown to add to ER Stress in humans as mentioned earlier, as well as zinc deficiency which I mentioned (as well as @mariovitali) @Violeta

 

[Violeta]

I am glad you keep mentioning zinc, and along with that copper bioavailability. And now a B6 connection. Very helpful.

B6

The screenshot is from http://algogenomics.blogspot.com/2017/10/latest-network-analysis-results.html

 

[mariovitali]

@datadragon

Thank you for your posts, they seem to identify many associations ! I would be very careful with Vitamin A. Whenever I tried supplementing with it I had extremely negative reactions (even by ingestion of one carrot). Also , accutane is a medication that leads to ME/CFS like syndrome called Post-Accutane Syndrome. I don't know about others and how they felt, this would be interesting to know

 

[datadragon]

Thank you for your posts, they seem to identify many associations ! I would be very careful with Vitamin A. Whenever I tried supplementing with it I had extremely negative reactions (even by ingestion of one carrot). Also , accutane is a medication that leads to ME/CFS like syndrome called Post-Accutane Syndrome. I don't know about others and how they felt, this would be interesting to know

What I had found is that Vitamin A requires zinc and cytochrome P450 enzymes that use magnesium as a cofactor to convert Vitamin A to active metabolites and eliminate excess as covered a bit here in helping to prevent toxicity. https://forums.phoenixrising.me/thr...be-a-clue-to-me-cfs.87544/page-5#post-2438568

Cytochrome P450 enzymes also are impacted during inflammation. So you can get in trouble with vitamin A excessive intake while under chronic inflammation, zinc deficiency etc. It suggests to add that last as its more likely a inflammatory state or zinc deficiency may be why Vitamin A metabolism is dysregulated rather than always a true deficiency, although Vitamin A is lowered via infection and inflammation as covered here so that is always possible in some cases. https://forums.phoenixrising.me/thr...-fatigue-syndrome-patients.90588/post-2441323

Thanks also for your and everyones posts. It seems some of my posts were of high level and didnt get read or understood at the time.

 

[Murph]

It seems some of my posts were of high level and didnt get read or understood at the time.

Please, I'm begging you to include a line of context for every piece of research you share. You seem extremely smart and well-informed but your practice of dumping a huge pile of abstracts into a comment means I don't know what I'm looking at and why.

Every paper you share, please write a little line or two like, This paper shows why we should be paying attention to the endoplasmic reticulum, or This paper illustrates links between copper and vitamin A.
We can synthesise informtion so much easier when we understand why we're being shown it.

 

[datadragon]

From NIH earlier this year:
https://directorsblog.nih.gov/2023/02/14/more-clues-into-me-cfs-discovered-in-gut-microbiome/

Of particular note, Williams team found that people with ME/CFS had abnormally low levels of several bacterial species, including Faecalibacterium prausnitzii (F. prausnitzii) and Eubacterium rectale. Both bacteria ferment non-digestible dietary fiber in the GI tract to produce a nutrient called butyrate. Intriguingly, Oh’s team also uncovered changes in several butyrate-producing microbial species, including F. prausnitzii.

Further detailed analyses in the Williams lab confirmed that the observed reduction in these bacteria was associated with reduced butyrate production in people with ME/CFS. That’s of special interest because butyrate serves as a primary energy source for cells that line the gut. Butyrate provides those cells with up to 70 percent of the energy they need, while supporting gut immunity.

Butyrate and other metabolites detected in the blood are important for regulating immune, metabolic, and endocrine functions throughout the body. That includes the amino acid tryptophan. The Oh team also found all ME/CFS participants had a reduction in gut microbes associated with breaking down tryptophan.

While butyrate-producing bacteria were found in smaller numbers, other microbes with links to autoimmune and inflammatory bowel diseases were increased. Williams’ group also reported an abundance of F. prausnitzii was inversely associated with fatigue severity in ME/CFS, further suggesting a possible link between changes in these gut bacteria and disease symptoms.

---- This has been mentioned similarly before: in the fecal metabolome, the % butyrate was increased in the NoPEM group compared with both the PEM and control groups ... Importantly, histone deacetylase 2 (HDAC2) was ~four fold higher and HDAC3 was ~two-fold higher, in ME/CFS cases compared with controls https://www.mdpi.com/2075-4418/9/3/70/htm (Butyrate is a HDAC inhibitor)

So butyrate inhibits ER Stress as mentioned earlier in the thread which lowers WASF3, and is found low in ME/CFS. Inflammation and Infection can lead to both lower butyrate and zinc which also causes ER Stress as mentioned earlier. Butyrate as an HDAC inhibitor is involved with autoantibodies. By altering chromatin accessibility, HDAC inhibitors alter gene expression. HDAC inhibitors butyrate, and propionate epigenetic modifiers exert modulatory effects on intrinsic B cell functions even at moderate concentrations, thereby is what shapes normal and effective antibody and autoantibody responses. https://forums.phoenixrising.me/threads/bc007-what-are-your-thoughts.87520/post-2441668 as well as suppresses demyelination and enhances remyelination and involved with anxiety, learning and memory. https://forums.phoenixrising.me/threads/bc007-what-are-your-thoughts.87520/post-2442283

 

[Violeta]

Does anyone have raised AST and/or ALT liver enzymes or low alkaline phosphatase?

 

[SlamDancin]

Great find @datadragon. I remember that paper and there’s a lot going on that’s interesting.

One point from the study was a significant fall in hypoxanthine after exercise in pwME and staying low in PEM.

This paper describes how hypoxanthine normally responds to exercise and it is a marker of overall metabolic response. Low hypoxanthine means purine salvage and/or resynthesis is not happening after exercise in pwME. We’ve talked quite a bit about purines on here.

“These results suggest that plasma Hx (hypoxanthine) concentration and erythrocyte HGPRT activity may be used as training status indicators in consecutive training phases in athletes of different specializations and ages (28–32). A lower purine concentration in the competition period indicates that the administered training resulted in an adaptation to high-intensity exercise expressed as reduced purine efflux from the skeletal muscle. It represents a more economical energy distribution from ATP catabolism consisting of the posttraining decrease in resting muscle adenine nucleotide pool and exercise-induced ATP degradation (24).”

Hypoxanthine: A Universal Metabolic Indicator of Training Status in Competitive Sports

Im pretty sure that what the quoted section is talking about is normal physiology. These athletes quickly recovered and after the actual exercise phases the hypoxanthine quickly recovered and stays high in the normal athletic recovery. In pwME, after the above happens and hypoxanthine drops, the level does not recover.

 

[SlamDancin]

https://pubmed.ncbi.nlm.nih.gov/21763752/

This paper looking at rat livers established an inverse relationship where HDAC3 over activation caused LXR (and PPARgamma) repression

 

[datadragon]

Still, there has to be a reason why the cells are pumping out wasf3. Is it high levels of endoplasmic reticulum stress? And could that be caused by lingering infection? These papers, shared by @Forummember9922 hint that enteroviruses could cause Er stress.

https://pubmed.ncbi.nlm.nih.gov/36366584/

Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway​

https://pubmed.ncbi.nlm.nih.gov/20070307/

Endoplasmic reticulum stress is induced and modulated by enterovirus 71​

https://www.nature.com/articles/4401833

Viruses, endoplasmic reticulum stress, and interferon responses​

So a plausible model of the disease that looks more likely now than it did before this research is this: lingering enteroviruses create chronic ER stress that creates exercise limitations. when we exercise our ERs start the "unfolded protein reponse" (an emergency repsonse when the endoplasmic retticulum starts failing) and our cells pump out wasf3. the wasf3 gets in the mitochondria and prevents us from doing glycolysis properly. we conk out.

So these studies below mention that Viral Infections are well known to cause ER Stress (which increases WASF3 levels), including also SARS-Cov-2, MERS-CoV and Dengue below as further examples that activate NLRP3 inflammasome and cause ER Stress so that can explain now why some people have similar experience of the symptoms of ME/CFS added although its not only just the ME/CFS symptoms they would be dealing with, and should not be considered identical conditions to ME/CFS.

Viral infection has been widely known to cause ER stress and activate the unfolded protein response (UPR). As an essential ER chaperone and master regulator of the UPR, GRP78 is upregulated during ER stress and generally accepted as a canonical marker of ER stress induction and UPR activation. Here we have documented the temporal increase of both GRP78 mRNA and protein levels as SARS-CoV-2 infection intensifies, and that GRP78 knockdown or inhibition of its activity suppresses SARS-CoV-2 replication and infectivity in vitro and in vivo, implying that GRP78 could be a valuable stable host target to combat COVID-19. https://www.nature.com/articles/s41467-022-34065-3

Sars-Cov-2 spike protein activates NLRP3 inflammasome

https://www.nature.com/articles/s41380-022-01831-0
https://www.biorxiv.org/content/10.1101/2020.10.27.357731v1.full https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472716/

Dengue virus NS1 secretion is regulated via importin-subunit β1 controlling expression of the chaperone GRp78 and targeted by the clinical drug ivermectin. We show that ivermectin impairs folding and secretion of endoplasmic reticulum-luminal glycoproteins, including NS1. Proteomic analysis identified chaperones interacting with NS1, including GRp78 (78-kDa glucose-regulated protein, also known as HSPA5 or BIP). This chaperone increased in abundance on DENV infection via activation of the unfolded protein response (UPR). Ivermectin blocked the nuclear transport of transcription factors required for UPR, thus impairing GRp78 upregulation and NS1 secretion. Reduction of GRp78 and NS1 secretion was also observed in patients treated with ivermectin. https://journals.asm.org/doi/10.1128/mbio.01441-23

the Dengue virus membrane protein (M) interacts with the host NLRP3 protein to promote NLRP3 inflammasome activation, which leads to the activation and release of a proinflammatory cytokine, interleukin-1 beta (IL-1β) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803285/

Others may be dealing with ME/CFS from other causes such as from a downstream effect of NLRP3 over activation that leads to zinc deficiency/unavailability which induces ER Stress and involved with B6 ( required for the conversion of methionine to SAMe and for the conversion of homocysteine to methionine as just two of its functions), a cofactor for glutathione, a cofactor for methionine synthase, which is needed to convert homocysteine to methionine. Zinc is involved with Vitamin A metabolism that leads to ceruloplasmin production that makes copper and iron bioavailable (usable) among other functions. Zinc is involved with the itaconate shunt that will inhibit B12, zinc deficiency leads to a leaky gut and low butyrate levels in the gut which also has numerous functions mentioned. Many HDACs are zinc-dependent enzymes which require the zinc ion for the catalytic reaction, PPARs need zinc etc so there are quite a lot of downstream effects is what I've been trying to explain from inflammation/infection in general beyond just 'ER Stress' or 'Itaconate Shunt'. That is why there was a lot of posts looking at some of the effects of zinc, ,vitamin A, butyrate etc.

ER Stress induces NLRP3 inflammasome so ER Stress can set it off, but even intensive exercise can induce NLRP3 activation unlike light exercise as well as many other factors can induce NLRP3 inflammasome activation that may also become chronic so it doesnt seem to require a viral onset. On page 3 I mentioned only a few other things that can induce NLRP3. https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2442005

 

[Violeta]

It's a vicious circle.

WASF3 and UPR are just there to save the day, just like mast cells degranulate to save the day. So we just have to figure out what they are trying to save us from.

 

[SlamDancin]

It's a vicious circle.

WASF3 and UPR are just there to save the day, just like mast cells degranulate to save the day. So we just have to figure out what they are trying to save us from.

Indeed check this out yall;

“Neonatal rat ventricular myocyte cultures subjected to hypoxia (16 hours) exhibited increased XBP1 mRNA splicing, XBP1 protein expression, GRP78 promoter activation, and GRP78 protein levels; however, the levels of these UPR markers declined during reoxygenation, suggesting that the UPR is activated during hypoxia but not during reoxygenation. When cells were infected with a recombinant adenovirus (AdV) encoding dominant-negative XBP1 (AdV-XBP1dn), UPR markers were reduced; however, hypoxia/reoxygenation-induced apoptosis increased. Confocal immunocytofluorescence demonstrated that hypoxia induced GRP78 in neonatal rat and isolated adult mouse ventricular myocytes. Moreover, mouse hearts subjected to in vivo myocardial infarction exhibited increased GRP78 expression in cardiac myocytes near the infarct, but not in healthy cells distal to the infarct. These results indicate that hypoxia activates the UPR in cardiac myocytes and that XBP1-inducible proteins may contribute to protecting the myocardium during hypoxic stress.”

My guess is hypoxemia is involved as a root cause in a lot of cases. It’s a direct cause of ER stress

 

[Violeta]

Indeed check this out yall;

“Neonatal rat ventricular myocyte cultures subjected to hypoxia (16 hours) exhibited increased XBP1 mRNA splicing, XBP1 protein expression, GRP78 promoter activation, and GRP78 protein levels; however, the levels of these UPR markers declined during reoxygenation, suggesting that the UPR is activated during hypoxia but not during reoxygenation. When cells were infected with a recombinant adenovirus (AdV) encoding dominant-negative XBP1 (AdV-XBP1dn), UPR markers were reduced; however, hypoxia/reoxygenation-induced apoptosis increased. Confocal immunocytofluorescence demonstrated that hypoxia induced GRP78 in neonatal rat and isolated adult mouse ventricular myocytes. Moreover, mouse hearts subjected to in vivo myocardial infarction exhibited increased GRP78 expression in cardiac myocytes near the infarct, but not in healthy cells distal to the infarct. These results indicate that hypoxia activates the UPR in cardiac myocytes and that XBP1-inducible proteins may contribute to protecting the myocardium during hypoxic stress.”

My guess is hypoxemia is involved as a root cause in a lot of cases. It’s a direct cause of ER stress

Wow, geez. Thank you!

Rereading that is my homework for today!

I see high blood glucose can cause hypoxia, I looked at one study so far. I have a headache and my brain is frayed from having someone working in the house yesterday and my puppy's reaction to it, so I am having difficulty being sure that I don't jump to incorrect conclusions. If you see something on high glucose plus ER stress that makes sense, let me know.