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

[Alvin2]

Lots of good info, worth the read:

WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome
https://medicalnewsbulletin.com/jou...c-encephalomyelitis-chronic-fatigue-syndrome/

 

[mitoMAN]

So how many of you guys have taken naPB according to Dr Hwang at sufficient dosages for a few months?
(ALS Dosage regiment)
https://www.relyvrio.com/RELYVRIO-Directions-For-Use.pdf
Its easy to access, so I assume there have been dozen of PR members taking it so far?

 

[Rufous McKinney]

like Enlarged Brain Stems

thats news to me.

thats what this illness has felt like for over 35 years now: my brain stem is swollen and thats the center of discomfort and inflammation radiating everywhere else. That is also why I wanted that 20/20 operation. I saw on the TV one Friday night. Long Long ago.

 

[bob800]

Its easy to access, so I assume there have been dozen of PR members taking it so far?

Easy to access? It's a specialty drug in the US, not available at normal pharmacies. So I think the only routes to get it are (a) via insurance approval form to the manufacturer, which is not possible for our usage, or (b) buying from a compounding pharmacy off-label (no insurance coverage). I got a quote for $831 for a 30-day supply from Hopewell Pharmacy. That's a pretty big gamble for a drug whose effect on CFS is largely speculative at this point.

 

[Shanti1]

So how many of you guys have taken naPB according to Dr Hwang at sufficient dosages for a few months?
(ALS Dosage regiment)
https://www.relyvrio.com/RELYVRIO-Directions-For-Use.pdf
Its easy to access, so I assume there have been dozen of PR members taking it so far?

I would like to try it but the cost is prohibitive. I tried a different compound, sodium benzoate, which also targets urea cycle dysfunction and felt significantly better with it. Unfortunately, it made my kidneys ache even though I have no known kidney issues, so I discontinued it after a few days.

 

[mitoMAN]

Easy to access? It's a specialty drug in the US, not available at normal pharmacies. So I think the only routes to get it are (a) via insurance approval form to the manufacturer, which is not possible for our usage, or (b) buying from a compounding pharmacy off-label (no insurance coverage). I got a quote for $831 for a 30-day supply from Hopewell Pharmacy. That's a pretty big gamble for a drug whose effect on CFS is largely speculative at this point.

It is a simple combination of two compounds which are easily available.
Tudca which is easily accessible in raw powder form via bodybuilding shops or Amazon in pills but beware of fake vendors (supplements are sadly often faked).
Alternatively you can take UDCA which gets converted to TUDCA to a certain degree and is a licenced medication with good safety data.

So TUDCA/UDCA is often as easy as amazon depending on your country.

The second ingredient is NaPB also called sodium 4-phenylbutyrate and it can be bought at 98%-99% Purity for affordable prices in USA/Canada/EU or even cheaper from China obviously.

Common Source most patient communities use - as this was also used as supplier for a few studies.
https://www.canchema.com/product/sodium-phenylbutyrate-4-pba/

Sodium Phenylbutyrat (4-PBA) Powder​

€ 173.00 – € 681.00

• Sodium Phenylbutyrat powder
• 50, 100 and 250 gram bottles

The patent is a combination of the two to enable an ultra high markup.

European Safety Report of naPB (not FDA)

EMA assessment of NaPB Safety Data: 21 February 2013 EMA/212039/2012 Committee for Medicinal Products for Human Use (CHMP) Assessment report Pheburane International non-proprietary name: sodium phenylbutyrate https://www.ema.europa.eu/en/docume...heburane-epar-public-assessment-report_en.pdf

 

[Shanti1]

@mitoMAN
At 3g bid of sodium phenylbutyrate from the source you post, that would be 681 euros ($750) for a 41 day supply.
Is this something you have tried, and if so, did you have positive results?

I'm interested in trying it because I felt so much better with sodium benzoate, but the price is too steep for me ongoing use. I would have to look for a cheaper source. It doesn't seem like it would be expensive to produce.

I already take TUDCA and think it has some benefit. I noticed it when I first started it, but not sure if it is still helping.

 

[bob800]

It is a simple combination of two compounds which are easily available.

I know, and I agree with you on the TUDCA, but not with the sodium phenylbutyrate. My post regarding the $831 quote from Hopewell was only for sodium phenylbutyrate itself, not for the patented combo.

The fact remains that the only legit source for off-label 4PBA in the US is a compounding pharmacy such as Hopewell.

it can be bought at 98%-99% Purity for affordable prices in USA/Canada/EU

The CanChema link you posted ships from Lithuania, and it is worth noting this is essentially being sold as a research chemical. Sure, it's spec'd at 99% purity, but you're still taking a gamble with that 1% impurity and also the accountability of this random chemical supplier.

I'm in favor of people making their own risk-benefit analysis, but if you're going to post a supplier like that, please make it clear there is a risk involved. This risk is significantly greater than purchasing supplements marketed for human consumption, since supplement companies can be held liable in case of egregious contamination by toxins.

this was also used as supplier for a few studies.

I would be very interested if you could post the links to these studies. I wasn't able to find any with any mention of CanChema in a quick Google Scholar search.

I already take TUDCA and think it has some benefit. I noticed it when I first started it, but not sure if it is still helping.

I noticed the same thing - a significant initial boost, but then nothing after that. Similar effect as I get from a lot of things.

 

[Mimicry]

I was reading the Health Rising post about the itaconate shunt research yesterday and was wondering if the high ammonia levels produced when cells use amino acids for energy could cause endoplasmic reticulum stress. Turns out it can, at least if you ask marine biologists. I didn't find any research on humans but I guess our cells are not so different from shrimps and other creatures.

 

[SlamDancin]

Was it this thread we were talking about NLRP3 inflammasome activation?

Check out this 2023 paper from China finding a mechanistic link between Itaconate and NLRP3 activation.

The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function

Abstract​

The NLRP3 inflammasome is a supramolecular complex that is linked to sterile and pathogen-dependent inflammation, and its excessive activation underlies many diseases. Ion flux disturbance and cell volume regulation are both reported to mediate NLRP3 inflammasome activation, but the underlying orchestrating signaling remains not fully elucidated. The volume-regulated anion channel (VRAC), formed by LRRC8 proteins, is an important constituent that controls cell volume by permeating chloride and organic osmolytes in response to cell swelling. We now demonstrate that Lrrc8a, the essential component of VRAC, plays a central and specific role in canonical NLRP3 inflammasome activation. Moreover, VRAC acts downstream of K+ efflux for NLRP3 stimuli that require K+ efflux. Mechanically, our data demonstrate that VRAC modulates itaconate efflux and damaged mitochondria production for NLRP3 inflammasome activation. Further in vivo experiments show mice with Lrrc8a deficiency in myeloid cells were protected from lipopolysaccharides (LPS)-induced endotoxic shock. Taken together, this work identifies VRAC as a key regulator of NLRP3 inflammasome and innate immunity by regulating mitochondrial adaption for macrophage activation and highlights VRAC as a prospective drug target for the treatment of NLRP3 inflammasome and itaconate related diseases.

I found this part from the full paper interesting but don’t know exactly how to decipher it;

Besides, Lrrc8a deficient macrophages did not exhibit detectable morphological and developmental abnormalities under resting conditions (Fig. S1G, H). The populations of T cells and B cells in the spleen were comparable between Lrrc8afl/fl and Lrrc8amKO mice (Fig. S1I, J), implying that VRAC was dispensable for the development and functionality of macrophage in steady state. Besides, deficiency of Lrrc8a did not affect general exploratory and locomotor behavior in mice, as assessed by the open field test, including total distance, vertical episode counts, and the time mice spent in the open center area

 

[SlamDancin]

Not to derail the thread too much but VRAC checks a lot of theoretical boxes. Sustained activation would drive constant glutamate efflux and presumably might cause the wired but tired feeling. It’s involved in mitochondrial function, glutathione homeostasis, GABA/glutamate, itaconate production and skeletal muscle metabolism and function. Other Chloride channels cause skeletal muscle conditions like myotonia and cystic fibrosis when their activation becomes sustained.

 

[Violeta]

Zinc is also needed for metalloprotease like MMP9 and these metalloprotease may lower MBL levels..;

Hypothyroidism also lower MBL levels.

Otherwise, genetic is the main factor for low MBL and it's the reason for my low level.

Mannose-binding lectin (MBL) mutants are susceptible to matrix metalloproteinase proteolysis: potential role in human MBL deficiency​

@pattismith , do you know if this causes fatigue, and if so, how?

 

[gbells]

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

Doesn't make sense to me. People are perfectly healthy then develop a viral illness and become disabled.

If it were a genetic defect then they would have fatigue their whole life.

 

[hapl808]

Doesn't make sense to me. People are perfectly healthy then develop a viral illness and become disabled.

If it were a genetic defect then they would have fatigue their whole life.

I don't remember what this refers to (I keep forgetting details of this thread), but can't a genetic defect just mean you're susceptible or more likely to develop a condition, rather than meaning it is single Mendelian disorder?

 

[gbells]

I don't remember what this refers to (I keep forgetting details of this thread), but can't a genetic defect just mean you're susceptible or more likely to develop a condition, rather than meaning it is single Mendelian disorder?

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

 

[Murph]

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

Doesn't make sense to me. People are perfectly healthy then develop a viral illness and become disabled.

If it were a genetic defect then they would have fatigue their whole life.

wasf3 is a protein. it is made by a gene of the same name, sure. But its increased production is the problem and that is due to a signal. Something (a virus, a cytokine, er stress, something else) could be encouraging its overproduction. Nobody is saying mecfs is due to a mutation in the wasf3 gene.

edited to add: I re-read the original paper just to double check my claim here and it really is a tour de force. https://www.pnas.org/doi/10.1073/pnas.2302738120 some of the most impressive, detailed and insightful science I've ever seen on this illness. Hard to believe they're not onto something and if you're not adding tudca to your supplement stack you probably should!

 

[Murph]

A side-observation here. They find the me/cfs patient uses up her phosphocreatine quickly and struggles to get it back. s1 is the patient with mecfs, she was tested twice. her recovery constant is found to be 80 seconds compared to 30 seconds in her brother.

as the next picture shows, phosphocreatine is the reserve of energy in the cell that people use before we really get cracking on creating energy with regular metabolism.

I find this intriguing. Because I know that if I go for a walk I need to start out ultra slow. Racing out the gate means I'm not even going to last 5 minutes and guarantees PEM later. If I want to do a decent walk I need to amble, shuffle and saunter at the start. Later I can probably go quicker. But not in the first couple of minutes. In fact, i'm usually best off starting any walk by heading downhill so the effort is less.

It makes me wonder if preservign some of that phosphocreatine store is vital for me, and whether actually my normal aerobic metabolism is working, if not perfectly then at least better than the systems that have to top up the phosphocreatine.

I wonder if anyone else has noticed the same thing? Do you get into extra trouble if you start out any exercise by going hard vs starting out easy?

 

[BrightCandle]

Hard to believe they're not onto something and if you're not adding tudca to your supplement stack you probably should!

The odd thing is I have tried quite high does of Tudca daily and it does nothing for me. I don't doubt the WASF3 finding but I can't say TUDCA has been in any way beneficial.

 

[Violeta]

wasf3 is a protein. it is made by a gene of the same name, sure. But its increased production is the problem and that is due to a signal. Something (a virus, a cytokine, er stress, something else) could be encouraging its overproduction. Nobody is saying mecfs is due to a mutation in the wasf3 gene.

edited to add: I re-read the original paper just to double check my claim here and it really is a tour de force. https://www.pnas.org/doi/10.1073/pnas.2302738120 some of the most impressive, detailed and insightful science I've ever seen on this illness. Hard to believe they're not onto something and if you're not adding tudca to your supplement stack you probably should!

That is a good paper.

I wonder why we are so prone to endoplasmic reticulum stress.

 

[SlamDancin]

That is a good paper.

I wonder why we are so prone to endoplasmic reticulum stress.

My guess is that there is at least a significant portion of pwME that have undiagnosed neuromuscular conditions