Hypothesis: PEM caused by increase in pathogen levels

[forestglip]

The hypothesis is that PEM is when exertion causes pathogen levels to rise.

In more detail, the symptoms of ME/CFS are caused by a persistent active infection (maybe the infection that preceded the illness, or maybe reactivated latent viruses).

For some reason, exertion causes pathogen levels to rise. Maybe the body diverts resources to repair and away from the immune system. Or could be some other reason. Maybe the main mechanism of ME/CFS is exertion turning down the immune system.

A PEM "crash" is more or less simply a more intense viral (or other pathogen) illness.

Why does this make sense:

• This is the simplest explanation for why there is a delay in symptoms. As in acute infection, it takes some time for the pathogen to replicate. There are similar time frames in both cases:
  • Harvard Health on flu: "Symptoms usually appear from one to four days after exposure to the virus, and they last five to seven days."
• It's also a simple explanation because ME/CFS is already known to be very related to viral infection, as it is one of the most common triggers.
• The symptoms of ME/CFS are often described as "flu-like". In both ME/CFS and flu, people often experience symptoms such as malaise, muscle pain, and sore throat.

When I proposed this on S4ME, someone brought up that unlike viral illnesses, ME crashes can flip on like a light switch instead of having a gradual onset. From a quick search of Reddit, I found two people that reported symptoms of COVID appearing more-or-less like a light switch multiple days after infection:

Not instant, but this person on Reddit says after testing positive for COVID 1.5 days earlier, they went from a little sleepy to very sick in one hour, though no mention of fatigue as one of the after symptoms.

This person got intense fatigue and fever within an hour, after three days of muscle aches.

I am surprised that I haven't come across a single mention of this possible mechanism of PEM.

There might be various ways to test this, such as with viral detection in tissue before and after exercise, which will require sophisticated, expensive tools. Or maybe looking for similar changes in biological markers between ME/CFS pre/post exercise and healthy people pre/post infection.

I'm not sure what the implications would be, but for one, maybe antivirals could lessen PEM symptoms if, after exertion, a virus is spreading into an easier to reach location, like the blood.

Any thoughts?

 

[forestglip]

I emailed Nancy Klimas about this hypothesis. Here's her response:

Also in exercise the immune system activates, which could trigger viral expression as well. We all focus on herpes family viruses but not nearly enough on the rest. New technologies ( incredibly expensive technologies) allow a search for all know viruses. You can imagine we are pursuing that. But the tricky part of that is that some viruses are restricted to specific areas - muscle, gut etc So looking in the right place with a pre post exercise sample is the trick.

At this conference Dr Wust showed pre post exercise pictures of muscle after exercise that showed patchy breakdown and inflammation, Now he's digging deeper it's a recent Nature article with the long COVID group

 

[Treeman]

I've also often considered that running down the energy reserves could also effect the efficiency of the immune system and allow infections to reactive and flourish.

 

[Treeman]

This is the simplest explanation for why there is a delay in symptoms. As in acute infection, it takes some time for the pathogen to replicate. There are similar time frames in both cases:

This time delay is also known when inflammation hits its peak.

Here

 

[Dude]

Interesting approach. I, too, have thought a lot about viruses in connection with this disease. Over the course of the illness, I was convinced more than once that the solution lay in viruses. However, after reading countless of research Papers, and this is purely my amateur opinion, I don't believe that viruses play a role in the further course of the disease beyond being a trigger.

Of course, there are countless studies and scientists presenting arguments for and against this idea, making it extremely difficult to pinpoint arguments against it. For every point, there is likely at least one counterexample, even if it's only anecdotal.

I can only recommend this article from Riffreporter (Paywall + German) to everyone. It contains a hypothesis that, in my opinion, is the most convincing explanation for this disease and PEM that I've read so far. Moreover, there are already numerous studies supporting certain core aspects of this hypothesis. The mentioned studies by Dr. Wust would also align better with this hypothesis.

Regardless of what one believes or how one interprets the data, the great thing is that research is being conducted in all directions. We will surely soon have clarity about the mechanisms behind this disease.

 

[forestglip]

This time delay is also known when inflammation hits its peak.

Here

That's interesting. Timeline from that link:

The wound healing process is usually characterized as four sequential but overlapping phases: haemostasis (0–several hours after injury), inflammation (1–3 days), proliferation (4–21 days) and remodelling (21 days–1 year) [1].

 

[forestglip]

I can only recommend this article from Riffreporter (Paywall + German) to everyone. It contains a hypothesis that, in my opinion, is the most convincing explanation for this disease and PEM that I've read so far. Moreover, there are already numerous studies supporting certain core aspects of this hypothesis. The mentioned studies by Dr. Wust would also align better with this hypothesis.

Thanks for pointing me to that. Here's an English article.

I had an AI summarize the article's explanation for PEM so my tired brain could understand:

1. Exercise/Exertion Trigger:
When a person with ME/CFS engages in physical or mental exertion, it triggers increased demand for blood flow to muscles and/or the brain.

2. Vasoconstriction-Vasodilation Imbalance:
- The sympathetic nervous system activates, causing vasoconstriction in arteries.
- However, due to dysfunction in the β2-adrenergic receptors (β2AdR), the small blood vessels can't dilate properly to accommodate increased blood flow needs.

3. Overproduction of Vasodilators:
- In response to this imbalance, the body produces an excess of vasodilating substances (like adenosine, ATP, prostaglandins, bradykinin, etc.) in an attempt to force open the blood vessels.

4. Vascular Leakage:
- The overproduction of vasodilators, particularly bradykinin, increases the permeability of small blood vessels.
- This causes these substances to leak into surrounding tissues and the general circulation.

5. Widespread Effects:
- The spillover of these vasodilatory substances can affect multiple systems, leading to:
- Pain (due to sensitization of pain receptors)
- Fatigue (possibly due to effects on energy metabolism and cellular function)
- Flu-like symptoms (potentially through immune system activation)
- Cognitive issues (possibly due to effects on cerebral blood flow and blood-brain barrier)

6. Prolonged Recovery:
- The dysregulation of the cardiovascular system and the spillover effects may take time to resolve, explaining the prolonged nature of PEM.
- Chronic activation of this process could lead to further desensitization of β2AdR receptors, potentially worsening the condition over time.

This hypothesis provides a mechanistic explanation for why even minor exertion can trigger a cascade of symptoms that persist long after the initial activity. It also explains why both physical and mental exertion can trigger PEM, as both types of activity increase demand on the cardiovascular system.

The model is particularly intriguing because it connects several observed phenomena in ME/CFS, including cardiovascular abnormalities, energy metabolism issues, and the diverse array of symptoms experienced during PEM. However, it's important to note that while this hypothesis is compelling, it still requires further research and validation.

When I asked the AI if the article explains the delay in symptoms:

You raise an excellent point about the delay in PEM onset, which is indeed a key characteristic of ME/CFS that any comprehensive hypothesis should address. The paper doesn't explicitly discuss this delay, but we can consider how this model might potentially account for it:

1. Gradual Accumulation of Vasodilators:
The overproduction and spillover of vasodilators like bradykinin might not cause immediate symptoms. It could take time for these substances to accumulate in the interstitial spaces and general circulation to levels that trigger symptoms.

2. Delayed Inflammatory Response:
The leaked vasodilators might trigger a secondary inflammatory response that takes time to develop. This could involve the activation of immune cells and the production of pro-inflammatory cytokines, which often have delayed effects.

3. Metabolic Derangement:
The cardiovascular dysfunction might lead to a gradual buildup of metabolic byproducts or a progressive depletion of energy reserves. The full impact on cellular metabolism may not be immediate but could worsen over hours or days.

4. Autonomic Nervous System Dysregulation:
The prolonged stress on the cardiovascular system might lead to a delayed dysregulation of the autonomic nervous system, potentially explaining the onset of symptoms like orthostatic intolerance some time after the initial exertion.

5. Blood Volume and RAAS Effects:
Changes in blood volume and the renin-angiotensin-aldosterone system (RAAS) described in the hypothesis might take time to manifest, potentially contributing to the delayed onset of symptoms.

6. Receptor Desensitization:
Chronic activation of the β2-adrenergic receptors could lead to their gradual desensitization or downregulation, which might not be immediate but could contribute to worsening symptoms over time.

7. Tissue-Specific Responses:
Different tissues (muscles, brain, immune system) might respond to the vascular changes and metabolic disturbances at different rates, leading to a staggered onset of various symptoms.

While these potential explanations align with the overall hypothesis, it's important to note that the paper doesn't specifically address the delay in PEM onset. This is an area where the hypothesis could be expanded or refined in future research. The delay in PEM is a crucial aspect of ME/CFS, and any comprehensive model should ideally provide a clear mechanism for this characteristic feature.

This gap in explaining the delay highlights the complexity of ME/CFS and the need for continued research to fully understand the intricate mechanisms at play. It also underscores the importance of considering multiple factors and their interactions over time when developing hypotheses about this condition.

The published paper itself doesn't seem to discuss the delayed nature of PEM specifically, either.

 

[Dude]

The article I mentioned is somewhat more recent and introduces a new factor that is not included in your article: the sodium-calcium exchanger, which, according to the hypothesis, is responsible for PEM.

**The Hypothesis of Wirth and Scheibenbogen:**

**ME/CFS is caused by a disturbed ion exchange in muscle cells, damaging the mitochondria. This leads to a negative spiral where mitochondria are further destroyed, explaining the symptoms of ME/CFS and Post-Exertional Malaise (PEM).**

1. **Circulatory Disturbance & Ion Exchange**

* Infections can damage the endothelium (cell layer on the inside of blood vessels), disrupting blood flow through the capillaries,
* leading to oxygen deficiency in muscles and organs.

2. **Response to Strain**

* During activity, muscles require more oxygen and nutrients, but due to circulatory disturbances, this need is not met.
* The body responds by increasing the pulse, further lowering blood pressure in the capillaries.

3. **Disturbance of the Sodium-Calcium Exchanger (NCX)**

* Normally, the NCX transports calcium out of the muscle cells and brings sodium in.
* In ME/CFS, sodium levels rise significantly due to circulatory disturbances and oxygen deficiency.
* If the sodium content exceeds a certain threshold, the NCX reverses its function, transporting calcium into the cells instead of pumping it out.

4. **Consequences**

* The overload of muscle cells with calcium damages the mitochondria, which are responsible for energy production in the cells.
* Damaged mitochondria release aggressive oxygen radicals, further lowering ATP levels (important for cellular energy) and additionally inhibiting the sodium-potassium ATPase (an ion pump).

5. **PEM & Vicious Circle**

* Upon renewed strain, the weakened mitochondria suffer further damage.
* This gradually reduces the number of functional mitochondria.
* When intracellular sodium reaches a critical level, the NCX switches and causes another calcium overload,
* leading to a marked worsening of symptoms (PEM).
* This endless spiral continuously worsens the health condition.

Mitodicure plans to begin the Phase 1 study for the ME/CFS drug candidate in autumn 2025, depending on securing investors/funding!

Article: [RiffReporter](https://www.riffreporter.de/de/wissen/mecfs-long-covid-corona-pathomechanismus-mitochondrien-wirth-scheibenbogen-mitodicure)


The article is behind a paywall, but for those interested in detailed information, including studies, it is well worth the cost.

 

[Dysfunkion]

The article I mentioned is somewhat more recent and introduces a new factor that is not included in your article: the sodium-calcium exchanger, which, according to the hypothesis, is responsible for PEM.

What does it say on the sodium-calcium exchanger, like you said the article is behind a paywall. Looking this up I completely missed this thing and I can see why dysfunction of it would be a huge problem.

 

[southwestforests]

This looks like a thread to watch.

 

[Dude]

What does it say on the sodium-calcium exchanger, like you said the article is behind a paywall. Looking this up I completely missed this thing and I can see why dysfunction of it would be a huge problem.

There is an informative article from Healthrising that discusses this topic:Healthrising article on Chronic Fatigue Syndrome and Calcium in Muscles.

Essentially, the NCX pump consumes ATP (produced by mitochondria) as fuel. However, in CFS, there is insufficient ATP available, causing the pump to malfunction. In the worst case, this leads to an overload of calcium in the cell. According to Wirth's theory, this excess calcium causes mitochondrial damage. Consequently, oxygen radicals are released, which further reduce ATP levels, thereby impairing the pump even more. These oxygen radicals also attack the endothelium, disrupting blood flow. This creates a vicious cycle that perpetuates itself. The idea now would be to interrupt this process at some point to stabilize the system.

In my opinion, this makes sense: the less ATP one has, the more severe the disease becomes. This is probably also the reason why a bedridden patient has almost no chance of improving to a milder level.

The initial process that triggers the whole cycle is explained as a blood flow disorder following an infection. This leads to mitochondrial damage due to a lack of oxygen, thereby starting the vicious cycle.

This might also explain why ME/CFS often occurs in the context of COVID-19. The virus directly attacks the ACE2 receptors present in the endothelium, undermining the body's defense mechanisms. This allows the virus to spread, leading to generalized inflammation in the endothelium and compromising its protective function. As a result, severe microcirculation disorders arise, which can damage the heart, cause lung embolisms, and lead to vascular blockages.

 

[Dysfunkion]

There is an informative article from Healthrising that discusses this topic:Healthrising article on Chronic Fatigue Syndrome and Calcium in Muscles.

Essentially, the NCX pump consumes ATP (produced by mitochondria) as fuel. However, in CFS, there is insufficient ATP available, causing the pump to malfunction. In the worst case, this leads to an overload of calcium in the cell. According to Wirth's theory, this excess calcium causes mitochondrial damage. Consequently, oxygen radicals are released, which further reduce ATP levels, thereby impairing the pump even more. These oxygen radicals also attack the endothelium, disrupting blood flow. This creates a vicious cycle that perpetuates itself. The idea now would be to interrupt this process at some point to stabilize the system.

In my opinion, this makes sense: the less ATP one has, the more severe the disease becomes. This is probably also the reason why a bedridden patient has almost no chance of improving to a milder level.

The initial process that triggers the whole cycle is explained as a blood flow disorder following an infection. This leads to mitochondrial damage due to a lack of oxygen, thereby starting the vicious cycle.

This might also explain why ME/CFS often occurs in the context of COVID-19. The virus directly attacks the ACE2 receptors present in the endothelium, undermining the body's defense mechanisms. This allows the virus to spread, leading to generalized inflammation in the endothelium and compromising its protective function. As a result, severe microcirculation disorders arise, which can damage the heart, cause lung embolisms, and lead to vascular blockages.

Oh wow very nice article! It also in there answers my question of what happens if we lower sodium intake (I've tried before, it actually also makes me feel worse). I don't consume large amounts of calcium as calcium also makes me feel terrible along with other members here so this definitely makes sense. Lowering the already small amount I'm consuming probably won't do anything for me. I wonder if there is a drug that can be developed to specifically target this system and cause the reverse to happen while stopping a mechanism that causes it safely. I feel like mine is virally or other pathogen backed considering mine starts in the brain and spreads outwards to the point of being physically disabling is telling. When mental exertion comes into play or repetitive muscle movements for long enough that's when I get hit. the faster the movement the faster the PEM hits without any relation to strength of them. I can only think there is something in the nerves themselves that the more activation there is, the more of some kind of byproduct that causes the problem gets produced leading to that signature poisoned feeling when it hits.

The fastest way for me to trigger my PEM is quickly playing a game with repetitive movements. Like I can if I'm playing at a very slow speed play video poker online play longer before it hits but if I play very quickly than in less than half an hour I will get hit like a tidal wave. The sudden PEM strikes like that by fast movements + rapid fire thinking are the most hellish. Large surges of intense emotions are up next in the most damage.

"Plus, desensitization of the alpha2-adrenergic receptors – which inhibit norepinephrine release – allows the noradrenergic neurons to release more and more norepinephrine, resulting in hypervigilance (a “wired” state), blood vessel constriction, and reduced blood flows to the muscles."

This likely explains why after these PEM crashes happen I will also be ironically full of anxiety! I get hypersensitive emotionally and physically to everything. Normally this wouldn't make any sense, things in PEM should get more dull completely but something specific ramps up and contributes to the overload. I don't think it's histamine, glutamate, or dopamine (though its the real dopamine releasing activities that hit the hardest and I'm a sucker for all of them). I also noticed in these PEM states that stimulants will do nothing. I can drink all of the coffee in the world but it will be like drinking dirty water until I'm out of at least the main part of the episode and then I'll increasingly be able to feel it normally again for my tolerance level.

 

[alcasa]

Oh wow very nice article! It also in there answers my question of what happens if we lower sodium intake (I've tried before, it actually also makes me feel worse). I don't consume large amounts of calcium as calcium also makes me feel terrible along with other members here so this definitely makes sense. Lowering the already small amount I'm consuming probably won't do anything for me. I wonder if there is a drug that can be developed to specifically target this system and cause the reverse to happen while stopping a mechanism that causes it safely. I feel like mine is virally or other pathogen backed considering mine starts in the brain and spreads outwards to the point of being physically disabling is telling. When mental exertion comes into play or repetitive muscle movements for long enough that's when I get hit. the faster the movement the faster the PEM hits without any relation to strength of them. I can only think there is something in the nerves themselves that the more activation there is, the more of some kind of byproduct that causes the problem gets produced leading to that signature poisoned feeling when it hits.

The fastest way for me to trigger my PEM is quickly playing a game with repetitive movements. Like I can if I'm playing at a very slow speed play video poker online play longer before it hits but if I play very quickly than in less than half an hour I will get hit like a tidal wave. The sudden PEM strikes like that by fast movements + rapid fire thinking are the most hellish. Large surges of intense emotions are up next in the most damage.

"Plus, desensitization of the alpha2-adrenergic receptors – which inhibit norepinephrine release – allows the noradrenergic neurons to release more and more norepinephrine, resulting in hypervigilance (a “wired” state), blood vessel constriction, and reduced blood flows to the muscles."

This likely explains why after these PEM crashes happen I will also be ironically full of anxiety! I get hypersensitive emotionally and physically to everything. Normally this wouldn't make any sense, things in PEM should get more dull completely but something specific ramps up and contributes to the overload. I don't think it's histamine, glutamate, or dopamine (though its the real dopamine releasing activities that hit the hardest and I'm a sucker for all of them). I also noticed in these PEM states that stimulants will do nothing. I can drink all of the coffee in the world but it will be like drinking dirty water until I'm out of at least the main part of the episode and then I'll increasingly be able to feel it normally again for my tolerance level.

Why do you thin it is not glutamate? I do think that what you describe could be…