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

[Violeta]

I think finasteride causes hypoxia. That's what cause mariovitali's ME/CFS.

 

[datadragon]

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

Yes if that wasnt clear from earlier posts, HIF1a induces expression of WASF3 under hypoxic conditions. I mentioned HIF1A is also upregulated with the itaconate shunt leading to increase in WASF3.

HIF1A induces expression of the WASF3 Metastasis Associated Gene under hypoxic conditions https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629704/​

Violeta- High glucose treatment, but not the osmotic control mannitol, induces csGRP78 expression through an ER stress–dependent mechanism. There are many 'roads' to increase NLRP3 and/or ER Stress. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514638/ GRP78 levels were positively correlated with HbA1c and AGEs. https://pubmed.ncbi.nlm.nih.gov/34591271/

 

[Violeta]

Yes if that wasnt clear from earlier posts, HIF1a induces expression of WASF3 under hypoxic conditions. I mentioned HIF1A is also upregulated with the itaconate shunt leading to increase in WASF3.

HIF1A induces expression of the WASF3 Metastasis Associated Gene under hypoxic conditions https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629704/​

Violeta- High glucose treatment, but not the osmotic control mannitol, induces csGRP78 expression through an ER stress–dependent mechanism. There are many 'roads' to increase NLRP3 and/or ER Stress. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514638/ GRP78 levels were positively correlated with HbA1c and AGEs. https://pubmed.ncbi.nlm.nih.gov/34591271/

Excellent. Yes, I remembered seeing HIF1A in one of your messages but didn't remember the specifics.

 

[datadragon]

I think finasteride causes hypoxia. That's what cause mariovitali's ME/CFS.

Maybe not - Finasteride administration in benign prostatic hyperplasia results in statistically significant suppression of MVD, VEGF, and HIF-1alpha in a time-dependent manner. https://pubmed.ncbi.nlm.nih.gov/16904480/

 

[Violeta]

Maybe not - Finasteride administration in benign prostatic hyperplasia results in statistically significant suppression of MVD, VEGF, and HIF-1alpha in a time-dependent manner. https://pubmed.ncbi.nlm.nih.gov/16904480/

HIF-1a helps a cell adapt to hypoxia. That might be good if you want apoptosis, but what if you don't want apoptosis?

Hypoxia-inducible factor-1 (HIF-1) is a key factor regulating cell adaptation to hypoxia [5]

"Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a central role in development and in adaptation to hypoxia by directing the expression of genes that promote angiogenesis, erythropoiesis, and vasodilation (1). The importance of HIF-1 in mammalian development is underscored by the finding that its absence is lethal during embryogenesis, in part because of defective vascularization (2). HIF-1 activation can have adaptive or maladaptive roles in a variety of pathological conditions. For example, HIF-1 allows revascularization after cardiac and cerebral ischemia, but it also allows tumor growth in hypoxic environments by promoting angiogenesis and metabolic adaptations to hypoxia."


But I don't know what that means with respect to finasteride. I'll have to keep looking.

 

[SWAlexander]

with respect to finasteride

Maybe this AI helps a little.

Apoptosis is a programmed cell death process that occurs naturally in the body to eliminate damaged or unnecessary cells. Hypoxia, on the other hand, refers to a condition where there is a reduced level of oxygen in the tissue or organ. When it comes to finasteride, it is important to understand how these two concepts are related, especially in the context of the drug's potential effects on the body.

Finasteride is a medication primarily used to treat conditions related to the prostate gland, such as benign prostatic hyperplasia (BPH) and male pattern baldness. It works by inhibiting an enzyme called 5-alpha-reductase, which converts testosterone into dihydrotestosterone (DHT). DHT is a hormone that can contribute to the enlargement of the prostate gland and male pattern baldness.

Now, let's discuss apoptosis and hypoxia in the context of finasteride:

1. Apoptosis and Finasteride:
   • Finasteride may have an impact on apoptosis in tissues where it reduces DHT levels. DHT is known to influence cell growth and proliferation in certain tissues, including the prostate and hair follicles.
   • By inhibiting 5-alpha-reductase and reducing DHT levels, finasteride may slow down cell proliferation in the prostate, which can be beneficial for conditions like BPH.
   • In some cases, finasteride may help promote apoptosis in prostate cells, leading to the shrinkage of the prostate gland, which can relieve symptoms associated with BPH.
2. Hypoxia and Finasteride:
   • Hypoxia, or reduced oxygen supply to tissues, can occur in various parts of the body, including the prostate. This can be due to factors like inflammation, obstruction, or inadequate blood supply.
   • In the context of BPH, the enlarged prostate can compress blood vessels, reducing oxygen delivery to the prostate tissue and causing localized hypoxia.
   • Finasteride's ability to reduce the size of the prostate can potentially improve blood flow to the area and alleviate hypoxia by relieving the compression on blood vessels.

It's worth noting that the relationship between finasteride, apoptosis, and hypoxia is complex and not fully understood. Finasteride's mechanisms of action are primarily related to hormonal changes, and any effects on apoptosis or hypoxia are secondary and may vary among individuals.

 

[Violeta]

Maybe this AI helps a little.

Apoptosis is a programmed cell death process that occurs naturally in the body to eliminate damaged or unnecessary cells. Hypoxia, on the other hand, refers to a condition where there is a reduced level of oxygen in the tissue or organ. When it comes to finasteride, it is important to understand how these two concepts are related, especially in the context of the drug's potential effects on the body.

Finasteride is a medication primarily used to treat conditions related to the prostate gland, such as benign prostatic hyperplasia (BPH) and male pattern baldness. It works by inhibiting an enzyme called 5-alpha-reductase, which converts testosterone into dihydrotestosterone (DHT). DHT is a hormone that can contribute to the enlargement of the prostate gland and male pattern baldness.

Now, let's discuss apoptosis and hypoxia in the context of finasteride:

1. Apoptosis and Finasteride:
   • Finasteride may have an impact on apoptosis in tissues where it reduces DHT levels. DHT is known to influence cell growth and proliferation in certain tissues, including the prostate and hair follicles.
   • By inhibiting 5-alpha-reductase and reducing DHT levels, finasteride may slow down cell proliferation in the prostate, which can be beneficial for conditions like BPH.
   • In some cases, finasteride may help promote apoptosis in prostate cells, leading to the shrinkage of the prostate gland, which can relieve symptoms associated with BPH.
2. Hypoxia and Finasteride:
   • Hypoxia, or reduced oxygen supply to tissues, can occur in various parts of the body, including the prostate. This can be due to factors like inflammation, obstruction, or inadequate blood supply.
   • In the context of BPH, the enlarged prostate can compress blood vessels, reducing oxygen delivery to the prostate tissue and causing localized hypoxia.
   • Finasteride's ability to reduce the size of the prostate can potentially improve blood flow to the area and alleviate hypoxia by relieving the compression on blood vessels.

It's worth noting that the relationship between finasteride, apoptosis, and hypoxia is complex and not fully understood. Finasteride's mechanisms of action are primarily related to hormonal changes, and any effects on apoptosis or hypoxia are secondary and may vary among individuals.

I was just looking at finasteride's side effects. Yikes.

Here's just the first 4.

1. Chills
2. cold sweats
3. confusion
4. dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position

I think #4 might indicate it causes hypoxia. That is helpful for killing cancer cells but then there are the unwanted side effects elsewhere.

 

[SWAlexander]

finasteride's side effects

Here 10 more - no fun at all:
Common side effects of finasteride can include:

1. Sexual Side Effects: These are among the most commonly reported side effects and can include reduced libido (sex drive), erectile dysfunction, and reduced ejaculate volume. In some cases, these side effects may persist even after discontinuing the medication.
2. Breast Tenderness and Enlargement: Some individuals may experience breast tenderness, enlargement, or breast lumps while taking finasteride.
3. Allergic Reactions: Although rare, some people may experience allergic reactions to finasteride, such as itching, rash, hives, swelling of the lips, tongue, or face, and difficulty breathing.
4. Depression and Mood Changes: Some users have reported mood changes, including feelings of depression or anxiety while taking finasteride. However, more research is needed to establish a clear link between finasteride and mood changes.
5. Testicular Pain: A small percentage of users may experience testicular pain while taking finasteride.
6. Gynecomastia: Rarely, men taking finasteride may develop gynecomastia, which is the growth of breast tissue.
7. Decreased Semen Volume: Finasteride may reduce the volume of semen ejaculated during sexual activity.
8. Skin Reactions: Some users have reported skin reactions such as rashes and itching.
9. Liver Enzyme Changes: In rare cases, finasteride may lead to changes in liver enzyme levels. Regular monitoring of liver function may be recommended during treatment.
10. Orthostatic Hypotension: A drop in blood pressure upon standing up, resulting in dizziness or fainting, has been reported by some individuals.

 

[SlamDancin]

My guess about Finasteride is that by depleting Dihydrotestosterone, allopregnanolone, and other 5-AR reduced steroids, you are left exposed to hypoxic stress much more easily, especially everywhere in the body but the prostate. I found one study that DHT reduces HIF-1a under hypoxic stress.

https://pubmed.ncbi.nlm.nih.gov/26365557/
“Elevated levels of neurosteroids during late gestation protect the fetal brain from hypoxia/ischaemia and promote neurodevelopment.”

 

[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

LXR has been in the conversation lately. HIF1-a is involved.

 

[SlamDancin]

@Violeta yeah I remember studying LXR a few years ago and it’s a double edge sword. It’s involved in the immune response to viruses and helps to kick off inflammatory responses.

I found a super interesting paper that just was published about AMPK, master metabolic regulator, being involved in kicking off the UPR response to high dose saturated fatty acid (SFA) Palmitate in muscles.

https://www.imrpress.com/journal/FBL/28/8/10.31083/j.fbl2808159/htm#S4

“In summary, we have provided evidence of bidirectional crosstalk between AMPK signaling and early activation of the UPR in muscle cells exposed to SFAs (Fig. 6). We also showed that pharmacologic activation of AMPK was sufficient to induce mild UPR in skeletal muscle cells. These findings demonstrate an essential role for the AMPK pathway in restoring ER homeostasis via activation of the UPR in response to metabolic stress. Furthermore, they may guide the development of new strategies for the treatment of diseases such as obesity and diabetes through improvements in skeletal muscle metabolism.”

They tested an AMPK agonist, a closely related drug to Metformin (also an AMPK agonist) and depending on dose timing it increased the UPR and made ER stress worse. I would be careful with Metformin if anyone was thinking of taking it

 

[Violeta]

@Violeta yeah I remember studying LXR a few years ago and it’s a double edge sword. It’s involved in the immune response to viruses and helps to kick off inflammatory responses.

I found a super interesting paper that just was published about AMPK, master metabolic regulator, being involved in kicking off the UPR response to high dose saturated fatty acid (SFA) Palmitate in muscles.

https://www.imrpress.com/journal/FBL/28/8/10.31083/j.fbl2808159/htm#S4

“In summary, we have provided evidence of bidirectional crosstalk between AMPK signaling and early activation of the UPR in muscle cells exposed to SFAs (Fig. 6). We also showed that pharmacologic activation of AMPK was sufficient to induce mild UPR in skeletal muscle cells. These findings demonstrate an essential role for the AMPK pathway in restoring ER homeostasis via activation of the UPR in response to metabolic stress. Furthermore, they may guide the development of new strategies for the treatment of diseases such as obesity and diabetes through improvements in skeletal muscle metabolism.”

They tested an AMPK agonist, a closely related drug to Metformin (also an AMPK agonist) and depending on dose timing it increased the UPR and made ER stress worse. I would be careful with Metformin if anyone was thinking of taking it

It will take me a while to understand this, but a quick question, it looks as if this is saying saturated fatty acids are detrimental to muscle cells. Is that what is means?

And I found this study about taurine being good for hypoxia and glutamate induced ER stress. I realize most people already know taurine is good for ER stress, but I link papers that I find interesting so I can find them again later.

Beneficial effect of taurine on hypoxia- and glutamate-induced endoplasmic reticulum stress pathways in primary neuronal culture​

https://pubmed.ncbi.nlm.nih.gov/220... taurine suppresses,by reducing the ER stress.

 

[Violeta]

From @mariovitali's slide presentation.

From the paper:
These findings suggest that ER stress may underlie TD-induced damage to the CNS. To date, the mechanisms underlying TD-induced ER stress is unclear. It has been well documented that oxidative stress and disruption of calcium homeostasis can cause ER stress. TD is shown to cause oxidative stress and the disruption of intracellular calcium concentration. Therefore, it is likely TD may induce ER stress through these mechanisms.


From another source:
Insufficient thiamine intake creates a state of cell level hypoxia. Although it is called pseudo-hypoxia, because no obstruction is evident, deficiency-induced hypoxia elicits all of the same molecular changes one might expect with obstructive hypoxia.

So maybe it's actually also the hypoxia that is contributing to the ER stress.

 

[mariovitali]

Thanks for all of your posts and this is correct. I ended up having ME/CFS after taking finasteride. Please note that the crash happened AFTER I stopped Finasteride.

 

[SWAlexander]

it looks as if this is saying saturated fatty acids

This is what I understand.

Thiamine, also known as vitamin B1,

Energy Production: Thiamine is a cofactor for several enzymes involved in the metabolism of carbohydrates, such as pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. These enzymes are crucial for converting glucose into energy (ATP) through aerobic respiration in the mitochondria. When thiamine is deficient, energy production is impaired, leading to reduced ATP synthesis. This energy deficit can cause cells to switch to anaerobic metabolism, leading to the production of more ROS.
Against Oxidative Stress: Thiamine also has a role in protecting cells against oxidative stress.

More on Thiamine responsive megaloblastic anemia
Sideroblastic anemias - Divide + conquer Inherited -X-liked sideroblastic -Pearson -Thiamine responsive megaloblastic anemia Clonal = MDS -RARS -RARS-T Metabolic -Copper deficiency -Zinc tox Drugs/toxin -Chloramphenicol -INH -Linezolid -EtOH
See:

https://twitter.com/i/web/status/1705319354169164092

 

[Violeta]

Thanks for all of your posts and this is correct. I ended up having ME/CFS after taking finasteride. Please note that the crash happened AFTER I stopped Finasteride.

Do you have a theory about why the crash happened after you stopped Finasteride?

 

[SWAlexander]

Here is more on mitochondria. Are we going in circles?
"The tissue samples from human patients allowed us to look at how mitochondrial gene expression was affected at the onset and end of disease progression, while animal models allowed us to fill in the blanks and look at the progression of gene expression differences over time."

SARS-CoV-2 can damage mitochondrion in heart, other organs, study finds​

https://www.cidrap.umn.edu/covid-19...-mitochondrion-heart-other-organs-study-finds

 

[datadragon]

Exercise and WASF3 levels:

IFN-y is also induced by intense exercise, (and also strongly induces IDO1). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849644/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484649/

Here, we report that IFN-γ rapidly increases protein synthesis and causes the unfolded protein response (UPR), as evidenced by the increased expression of glucose-regulated protein 78, activating transcription factor-4, and c/EBP homologous protein (CHOP) in cells treated with IFN-γ. The JAK1/2-STAT1 and AKT-mTOR signaling pathways are required for IFN-γ-induced UPR. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366549/ So this is the same GRP78 that increases WASF3 levels. The 24 hr delay for PEM correlates with IFN-y levels that are known to rise ~24 hrs after exertion.

Glucose deprivation strongly inhibited IFN-gamma gene expression (increased by ifn-a, heavy exercise), whereas IL-2 production was little affected. Inhibition correlated with diminished phosphorylation of p70S6 kinase and eIF4E binding protein 1 and a requirement for de novo protein synthesis, whereas other signaling pathways known to regulate IFN-gamma expression were unaffected. Together, our data reveal that optimal induction of IFN-gamma transcription is a glucose-dependent process https://pubmed.ncbi.nlm.nih.gov/15814691/ High glucose increase GRP78 (which increases WASF3 levels) https://forums.phoenixrising.me/thr...s-chronic-fatigue-syndrome.90582/post-2443763

So Intensive exercise, interferon gamma (IFN-y) and high glucose also increase ER Stress and WASF3 which is currently shown to cause exercise intolerance/fatigue. Blocking WASF3 allowed mitochondria to produce energy at normal levels. The team then showed that extra WASF3 in the cells interfered with formation of the structures that mitochondria use to produce energy. To better understand the role of WASF3, the team engineered mice to produce excess WASF3. They found that, similar to people with post-exertional malaise, muscles in these mice were slow to recover after exercise. The mice also showed a 50% reduction in their ability to run on a treadmill, even though their muscle strength was comparable to mice without extra WASF3.

 

[SWAlexander]

datadragon​

Is it not amazing that we, the patients, understand the content of these papers while doctors don´t?​

 

[SlamDancin]

@datadragon I think we can add Nitric Oxide to the list of suspected players;

NO derived from lipopolysaccharide (LPS) -activated macrophages or a NO donor (NOR5) treatment, suppressed Ppara mRNA expression in 10T1/2 adipocytes. In addition, Ppara transcript levels were reduced in the white adipose tissue (WAT) in both acute and chronic inflammation mouse models; however, such suppressive effects were attenuated via a nitric oxide synthase 2 (NOS2) inhibitor. Endoplasmic reticulum (ER) stress inhibitors attenuated the NO-induced repressive effects on Ppara gene expression in 10T1/2 adipocytes.
https://pubmed.ncbi.nlm.nih.gov/37739218/