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

[junkcrap50]

@godlovesatrier Wow, incredible to get to 90% from just adjusting your microbiome! Have you heard of Remission Biome on twitter? Look them up. A couple scientists with ME/CFS had remissions when taking antibiotics, so they created a crowdsource experiment with proper testing after a microbiome adjusting intervention. Might have some more info you may be interested in.

 

[godlovesatrier]

It's extremely hard to modulate the microbiome, that's my experience after 5 months of trying to get back to the Feb sample. Ken built his website microbiome prescription for that reason, it's primary purpose was to statistically comb scientific studies to find what food and supplements would alter the microbiome. However it's not perfect as even if you are the 90th percentile on a metric, you will still get that recommendation, which could send you the wrong way.

Biomesight offer broader recommendations, the issue here for me is that I am allergic to most of them.

As for remission biome, I've tried a lot of their recommended prep items, tributyrin, bpc-157, bacilus subtilis, but I react badly to all of these in different ways. Even so if I don't get anywhere the dysbiosis might not be possible to shift without antibiotics. In which case I'll have to take some but that will kill everything indiscriminetally.

In Feb bromii was very high too, which seemed to be statistically significant and no wonder considering what it produces.

Currently I am trying no inulin, no phgg, and taking longum bb536 with some shirota. Studies show shirota takes 6 months to normalise a microbiome (or at least make it healthier). Longum is recommended on kens site and biomesight.

I was at 90% for about 3.5 months btw so it was absolutely not a fluke. I've been invited to do remission biome a few times, but the side efects of doing it would render me unable to hold down a job so I can't right now. I'm super interested to see their study results! They spend thousands of testing, and have already produced a chart showing clear changes in cytokines, so it's scientifically quantifiable.

 

[Murph]

I've been thinking about whether PEM could be the unfolded protein response (UPR). If our ERs get overwhelmed doing their jobs, and have to start the UPR (where everything gets shut down while they try to get themselves in order), could that feel like PEM to us?

One clue: the endoplasmic reticulum is actually semi-shut-down by exercise. It isn't asked to do its normal job. During the high energy period of exercise it is asked to stand down, as this paper shows:
https://pubmed.ncbi.nlm.nih.gov/31487224/

Presumably after exercise is it asked to go back to folding proteins and other things. That got me wondering if it could explain the delayed onset of PEM. If PEM is UPR and the ER sometimes is turned on only after the exercise bout is finished, UPR could start well after exercise concludes.

I'm really struggling to find info on the timescales at which the UPR operates however. What's also important is whether it is something the whole body tends to do at once or just a subset of cells. If the latter, UPR probably can't be PEM, at least without some sort of signalling.

 

[Rufous McKinney]

PEM might be multi-faceted.

It might be several things occurring in combination, leading to the poisoned feeling.

 

[Mimicry]

I've been thinking about whether PEM could be the unfolded protein response (UPR). If our ERs get overwhelmed doing their jobs, and have to start the UPR (where everything gets shut down while they try to get themselves in order), could that feel like PEM to us?

One clue: the endoplasmic reticulum is actually semi-shut-down by exercise. It isn't asked to do its normal job. During the high energy period of exercise it is asked to stand down, as this paper shows:
https://pubmed.ncbi.nlm.nih.gov/31487224/

Presumably after exercise is it asked to go back to folding proteins and other things. That got me wondering if it could explain the delayed onset of PEM. If PEM is UPR and the ER sometimes is turned on only after the exercise bout is finished, UPR could start well after exercise concludes.

I'm really struggling to find info on the timescales at which the UPR operates however. What's also important is whether it is something the whole body tends to do at once or just a subset of cells. If the latter, UPR probably can't be PEM, at least without some sort of signalling.

According to a couple studies that were published this year, PEM is the combination of our immune systems not activating normally during exercise, hence they don't start clearing out the cellular waste that is produced during exertion, and then afterwards causing an inflammatory reaction because the immune system freaks out + impaired recovery. I think it makes sense that the ER is involved because the metabolic processes that heal the body after exertion require a lot of proteins.

Here are the studies I mentioned:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9916639/
https://pubmed.ncbi.nlm.nih.gov/36835097/

 

[SWAlexander]

hypothesis about how bc007 works

BC007 would only be an option for those with positive GPCR antibodies, which not everyone has - and of course it may be that the study is negative - but we need arrows in our quiver. Also for ME/CFS.
According to Austrian Neurologist

https://twitter.com/i/web/status/1708717276302651648

 

[datadragon]

To better understand WASF3 related to PEM, the researchers engineered mice to produce excess WASF3. They found that muscles in these mice were slow to recover after exercise which is similar to people with post-exertional malaise. Those mice showed a 50% reduction in their ability to run on a treadmill, even though their muscle strength was comparable to mice without the excess WASF3. In a small sample, they found substantially higher levels of WASF3 in those with ME/CFS.

The protein WASF3 is boosted in response to ER Stress as one reason, and this disrupts the cells energy production when WASF3 was increased, while blocking the WASF3 increase through blocking ER Stress allowed mitochondria to produce energy at normal levels. The researchers showed that extra WASF3 in the cells interfered with formation of the structures that mitochondria use to produce energy and are looking further into the mechanisms. Here I mentioned some prior research that may be potentially related to the mechanisms and have been discussing the others like GRP78, HIF1a, IFN-y, viral infections, intensive exercise, zinc deficiency, b1 deficiency, High Glucose etc that also can induce increased expression of WASF3. https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2444227

Zinc and Butyrate are both known to lower ER Stress; butyrate is found low in ME/CFS as confirmed by the NIH, and an increase in butyrate is shown to be helpful for the PEM. There are several inhibitors of ER Stress mentioned earlier from Ivermectin to 4-PhenylButyric acid (4-PBA) and Sodium Butyrate, Tauroursodeoxycholic acid (TUDCA), Proanthocyanidins and others that can be potentially tested alone or with zinc glycinate which seem to be helpful to some people while they work on the mechanisms and then potential have drugs as treatments targeting these pathways as more is learned about what helps with the PEM and other symptoms of ME/CFS. The drug Relyvrio is a combination of 3g sodium phenylbutyrate (butyrate) and 1g TUDCA for example. https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2443526 Salubrinal which they used to show improvement reduces ER Stress but also has some other features I found https://pubmed.ncbi.nlm.nih.gov/25619567/ so it is good to know when other things that mainly work on the ER Stress alone show similar benefits.

 

[SWAlexander]

Zinc and Butyrate

Evaluation of the protective effects of zinc butyrate in IPEC-J2 cells and grower pigs under heat stress1​

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200505/​

"In conclusion, results presented here demonstrate that E-ZnB supplementation during HS improves ADG and G:F in grower pigs. Although we could not measure any differences, the mode of action of butyric acid and zinc suggests that the performance improvements are related to improved intestinal health."

 

[BNQG2RDU]

So I was undergoing a muscle biopsy a few weeks ago for elevated AST, ALT and CK with mildly elevated anti-jo-1 antibodies to rule out myositis. I reached out to Dr. Hwang to see if my biopsy could be tested for the WASF3 malfunction but unfortunately he said it was only available at the NIH. I got my results back which show no myositis (yay) but that I have mitochondrial malfunction. The pathology could not determine if the mitochondrial defects were secondary to an acquired or genetic state. My doctor told me to take CoQ10, l-carnitine and creatine and would refer me to a medical geneticist. I wonder if it's worthwhile to try TUDCA and butyrate as well while waiting or if it would be adding to many things at once.

 

[Osaca]

I got my results back which show no myositis (yay) but that I have mitochondrial malfunction. The pathology could not determine if the mitochondrial defects were secondary to an acquired or genetic state.

Do you know how and on what basis they detected the mitochondrial dysfunction? (Rob Wüst has also been looking at muscle tissue of LC patients and finds some alterations in the Krebs cycle enzymes expressed post exercise, perhaps your data is comparable?)

 

[Alvin2]

I wonder if it's worthwhile to try TUDCA and butyrate as well while waiting or if it would be adding to many things at once.

I would not try anything right now, let them do their tests without anything new they don't understand involved.

 

[BNQG2RDU]

Do you know how and on what basis they detected the mitochondrial dysfunction? (Rob Wüst has also been looking at muscle tissue of LC patients and finds some alterations in the Krebs cycle enzymes expressed post exercise, perhaps your data is comparable?)

I don’t understand a lot of the report (lots of different sections) but here is a copied sectioned from the pathology report which mentions the mitochondria:

Ultrastructural findings: Fibers show an increase in exocytosis, with the vesicles containing myelin material or hydroxylated lipid. Lipofuscin is noted in subsarcolemmal spaces. Mitochondria show thickened cristae with increased matrix material, electron-dense granules, and focally disordered cristae, but no cystalline arrays. There is loose glycogen present around mitochondria but no membrane-bound glycogen is seen. Myofiber nuclei demonstrate no pathologic inclusion filaments or aggregates. Capillaries show focal endothelial reaction and mild basal laminar expansion. No tubuloreticular inclusions are seen. No amyloid is identified. Mature collagen is noted in the stroma.
Impression: Increased exocytosis of lipid; mitochondrial morphologic changes.

 

[BNQG2RDU]

I would not try anything right now, let them do their tests without anything new they don't understand involved.

That makes sense. I haven’t called for the genetics appointment yet but appointments take around 6 - 12 months which is a long time to wait. But you are right - I don’t want to interfere with the diagnostic work up that is undergoing. I have been fortunate to have a team who believes me and orders all these diagnostic tests.

 

[Mimicry]

For what it's worth, inspired by this very thread I've been taking sodium butyrate 600 mg (brand Body Bio, got it from iHerb) for three weeks and during the last two weeks my condition has improved from moderate to mild. I have much more energy, am able to be upright for several hours a day without getting my usual awful lightheadedness, my PEM isn't that bad and I recover from it quicker. And my mental health is amazing. It also feels like I keep improving every day.

Last Saturday I was able to do some cleaning and yard work for 1.5 hours, go to sauna (I'm Finnish so sauna is pretty much part of my "religion" and we have a beautiful 100-year old wood-heated sauna in our yard, but I wasn't able to go to sauna for two months because the heat made me so nauseous and dizzy) and watch a movie. On Sunday I visited my grandma, it was a 5 hour trip and I didn't need to lie down even once and had the energy to talk to my relatives and be my usual cheerful self, no brain fog whatsoever. I was exhausted afterwards but the PEM hasn't hit me yet. I feel like I'm reborn, even though I know it's too early to celebrate yet and I need to take it easy so I don't crash again. I've been practically housebound for a year and unable to be upright for more than two hours a day, and haven't had actual good days in what feels like forever, so this has been a huge step up in my quality of life!

I also take zinc, benfotiamine, vit C and D and several other supplements and I feel like I was already slowly improving on them before butyrate, but after starting it my energy levels have shot up. I'm planning to increase the butyrate dose to two capsules (1.2 g in total). I started on that, but it was clearly too much because I became restless and anxious and had to halve the dose + lower the dose of my antidepressant mirtazapine because I suspect that together they raise my noradrenaline levels too high (I got a similar anxiety spike for a week after every dose increase when I was tapering up the mirtazapine). I also bought TUDCA but haven't started it yet, because I first wanted to see what the butyrate does.

I know I'm still far from healthy and I don't want to jinx it, but these improvements make me really happy and for the first time in over two years I actually have hope for the future! I still have a migraine every day and it's triggered by activity, but that doesn't feel nearly as bad now that the ME symptoms are a bit better!

 

[SWAlexander]

sodium butyrate

Sounds very promising. Congratulations on your progress.
Sodium butyrate has many benefits because it is a short-chain fatty acid (SCFA) and so do the other supplements you take.

I wish I could use the sauna again. I also experience dizziness among other symptoms.
Nauseous or dizzy after using a sauna is not uncommon, and there are several potential explanations for this:

1. Dehydration: One of the most common reasons for feeling dizzy or nauseous after using a sauna is dehydration. Saunas can lead to excessive sweating, which can cause your body to lose a significant amount of fluids and electrolytes. Dehydration can lead to symptoms like dizziness, nausea, headache, and even fainting.
2. Overheating: Your body works hard to regulate its internal temperature. In a sauna, your core body temperature can rise, which can lead to symptoms of overheating. Overheating or heat exhaustion symptoms include dizziness, nausea, heavy sweating, headache, and muscle cramps.
3. Drop in Blood Pressure: The heat in the sauna can cause blood vessels to dilate (vasodilation). This can lead to a drop in blood pressure, which can result in dizziness or lightheadedness, especially when standing up quickly after a long stay in the sauna.
4. Low Blood Sugar: If you haven't eaten for a while before using the sauna or if you're on certain medications, you might experience a drop in blood sugar levels. Low blood sugar can cause symptoms like dizziness, nausea, and even fainting.
5. Toxins and Metabolic Waste: One of the benefits of using a sauna is that it can help the body rid itself of toxins and metabolic waste through sweating. However, the rapid release of these substances can sometimes cause temporary feelings of nausea or dizziness.
6. Underlying Health Conditions: If you have certain medical conditions, such as heart conditions, respiratory issues, or others, you might be more susceptible to the adverse effects of the heat in a sauna.
7. Lack of Acclimatization: If you're not used to the heat of a sauna, your body might have a more robust reaction to it initially. As you use the sauna more frequently, your body might adjust and become more tolerant to the heat.
8. Extended Duration: Staying in a sauna for too long without breaks can increase the risk of dehydration, overheating, and other adverse effects.

 

[Judee]

I'm planning to increase the butyrate dose to two capsules (1.2 g in total).

 

[BNQG2RDU]

For what it's worth, inspired by this very thread I've been taking sodium butyrate 600 mg (brand Body Bio, got it from iHerb) for three weeks and during the last two weeks my condition has improved from moderate to mild. I have much more energy, am able to be upright for several hours a day without getting my usual awful lightheadedness, my PEM isn't that bad and I recover from it quicker. And my mental health is amazing. It also feels like I keep improving every day.

Last Saturday I was able to do some cleaning and yard work for 1.5 hours, go to sauna (I'm Finnish so sauna is pretty much part of my "religion" and we have a beautiful 100-year old wood-heated sauna in our yard, but I wasn't able to go to sauna for two months because the heat made me so nauseous and dizzy) and watch a movie. On Sunday I visited my grandma, it was a 5 hour trip and I didn't need to lie down even once and had the energy to talk to my relatives and be my usual cheerful self, no brain fog whatsoever. I was exhausted afterwards but the PEM hasn't hit me yet. I feel like I'm reborn, even though I know it's too early to celebrate yet and I need to take it easy so I don't crash again. I've been practically housebound for a year and unable to be upright for more than two hours a day, and haven't had actual good days in what feels like forever, so this has been a huge step up in my quality of life!

I also take zinc, benfotiamine, vit C and D and several other supplements and I feel like I was already slowly improving on them before butyrate, but after starting it my energy levels have shot up. I'm planning to increase the butyrate dose to two capsules (1.2 g in total). I started on that, but it was clearly too much because I became restless and anxious and had to halve the dose + lower the dose of my antidepressant mirtazapine because I suspect that together they raise my noradrenaline levels too high (I got a similar anxiety spike for a week after every dose increase when I was tapering up the mirtazapine). I also bought TUDCA but haven't started it yet, because I first wanted to see what the butyrate does.

I know I'm still far from healthy and I don't want to jinx it, but these improvements make me really happy and for the first time in over two years I actually have hope for the future! I still have a migraine every day and it's triggered by activity, but that doesn't feel nearly as bad now that the ME symptoms are a bit better!

That is awesome that you are seeing so many improvements!

It makes me want to try it. I am on the waiting list to make the genetics appointment but they told me once I’m accepted off of it that the average wait time to an appointment is about 12 - 18 months!

Making me reconsider a trial of these medications prior to that appointment…

 

[Dakota15]

Was just curious, did anyone catch Dr. Hwang's talk in Berlin, online anywhere?

'The World Mitochondria Society will host Targeting Mitochondria 2023 with challenging visions in Berlin'

Date: October 11-13

Highlighted WMS Speakers 2023: Paul Hwang, National Heart, Lung and Blood Institute, USA'

"Dr. Hwang's talk will be titled: "WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in ME/CFS".

"He will share his latest findings reported in the Proceedings of the National Academy of Sciences. Increased expression of WASF3 in transgenic mice decreased their treadmill running capacity and specific respiratory complexes. Expanding on our findings in a single patient, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels associated with aberrant ER stress activation. Pharmacologic inhibition of ER stress decreased WASF3 and improved mitochondrial function in the cells of the patient with chronic fatigue, suggesting a therapeutic strategy for ME/CFS treatment."

 

[Alvin2]

I keep seeing sodium butyrate mentioned, would this work or does it have to be sodium butyrate?
https://villagevitaminstore.ca/products/genestra-sunbutyrate-liquid-280ml

 

[Rufous McKinney]

Lack of Acclimatization: If you're not used to the heat of a sauna, your body might have a more robust reaction to it initially. As you use the sauna more frequently, your body might adjust and become more tolerant to the heat.

I think this is a particularly important aspect...