What is the biomechanics of the damage from overexertion

[Aerose91]

This is for those here with true ME. Do we know what physically happens to our mitochindria when we overexert? I mean severely, in cases where someone never recovers from the damage. I over exerted in the beginning a couple years ago and my brain has never recovered from it even 1%. I've heard many places that this may change the course of the disease but I'm wondering why. What's the difference between the disease progressing on its own and damage from overdoing it

 

[Jonathan Edwards]

This is for those here with true ME. Do we know what physically happens to our mitochindria when we overexert? I mean severely, in cases where someone never recovers from the damage. I over exerted in the beginning a couple years ago and my brain has never recovered from it even 1%. I've heard many places that this may change the course of the disease but I'm wondering why. What's the difference between the disease progressing on its own and damage from overdoing it

That is a very interesting and difficult question. I must admit to being baffled but I wonder if others have theories? Especially the issue of thinking function - I find it hard to see what would change in terms of metabolism.

 

[Marco]

I'll have a shot.

My theory is that the key mechanism in ME/CFS pathology is microglial activation/neuroinflammation of the brain whereby normal physiological levels of metabolites etc function as 'alarmins' which activate already primed microglia. I don't rule out some peripheral physiological mechanism which may be driving this on an ongoing basis but I don't feel there is sufficient evidence to suggest there are any primary mitochondrial abnormalities per se or that exertion impacts directly on mitochondria.

You don't state whether you mean physical, mental overexertion or both. I'll assume physical but it doesn't really matter that much. Physical exertion results in various physiological changes including microtrauma to tissues and various metabolic/physiological signals (ATP, heat shock proteins, high mobility group box proteins etc) are mobilised to assist in damage repair but also to act as 'alarmins' to signal damage/physiological stress. Where the brain is already oversensitised I would suggest that what would normally be tolerated results in over-activation of microglia or increased recruitment of activated microglia in a 'kindling' like process. Once activated microglia express a range of proinflammatory cytokines which initiate and sustain ' sickness behaviour' - a key feature of which is cognitive impairment (over-activated microglia being constantly being bombarded by sensory signals would also be likely to impair cognition due to 'sensory overload'/impaired attentional processes).

In a nutshell overexertion in vulnerable individuals doesn't cause any immediate physiological damage (to the body) but may cause lasting microstructural changes to the brain and how it subsequently interprets 'effort'.

Various 'stressors' could have the same impact from over-exertion to psychological stress to even a single instance of 'binge-drinking'.

In the words of Monty Python - 'That is my theory, etc'.

 

[Snow Leopard]

Overexertion depletes the regular energy stores and further energy relies on the break down of energy stores (eg fats), which need to be delivered to the cell first and then into the mitochondria.

As to what damage, it depends on what is happening to the muscles, what disease you have etc.

The half life of mitochondria is 2-4 days, depending on their location. Simply put, direct damage to mitochondria does not stay for very long. If there is damage, then there must be an ongoing process either cellular (eg cancer, or genetic diseases), or is a consequence of something interfering with extracellular signalling (that causes downstream dysfunction in the cell) that causes this damage. Deconditioning and other diseases can also lead to lower mitochondrial numbers in cells.
http://www.jbc.org/content/256/16/8652.full.pdf

There is no direct evidence for dysfunction within the mitochondria in ME/CFS patients, there is however some evidence for dysfunction of fatty acid metabolism (which seems reasonable given the time periods of the PEM), perhaps something is limiting the proceeding metabolic process of fatty acids getting into the cell, or the mitochondria in the right form to be metabolised.

 

[Aerose91]

Overexertion depletes the regular energy stores and further energy relies on the break down of energy stores (eg fats), which need to be delivered to the cell first and then into the mitochondria.

As to what damage, it depends on what is happening to the muscles, what disease you have etc.

The half life of mitochondria is 2-4 days, depending on their location. Simply put, direct damage to mitochondria does not stay for very long. If there is damage, then there must be an ongoing process either cellular (eg cancer, or genetic diseases), or is a consequence of something interfering with extracellular signalling (that causes downstream dysfunction in the cell) that causes this damage. Deconditioning and other diseases can also lead to lower mitochondrial numbers in cells.
http://www.jbc.org/content/256/16/8652.full.pdf

There is no direct evidence for dysfunction within the mitochondria in ME/CFS patients, there is however some evidence for dysfunction of fatty acid metabolism (which seems reasonable given the time periods of the PEM), perhaps something is limiting the proceeding metabolic process of fatty acids getting into the cell, or the mitochondria in the right form to be metabolised.

I read in a medical journal once that exertion causes damage to the mitochondrial DNA and once the DNA is damaged, it reproduces more damaged mitochindria. That would make sense why once damage is done, if bad enough, it's permenant. I guess the trick would be to figure out how to have your body recycle the bad mitochondria and reproduce the good ones

 

[Aerose91]

I'll have a shot.

My theory is that the key mechanism in ME/CFS pathology is microglial activation/neuroinflammation of the brain whereby normal physiological levels of metabolites etc function as 'alarmins' which activate already primed microglia. I don't rule out some peripheral physiological mechanism which may be driving this on an ongoing basis but I don't feel there is sufficient evidence to suggest there are any primary mitochondrial abnormalities per se or that exertion impacts directly on mitochondria.

You don't state whether you mean physical, mental overexertion or both. I'll assume physical but it doesn't really matter that much. Physical exertion results in various physiological changes including microtrauma to tissues and various metabolic/physiological signals (ATP, heat shock proteins, high mobility group box proteins etc) are mobilised to assist in damage repair but also to act as 'alarmins' to signal damage/physiological stress. Where the brain is already oversensitised I would suggest that what would normally be tolerated results in over-activation of microglia or increased recruitment of activated microglia in a 'kindling' like process. Once activated microglia express a range of proinflammatory cytokines which initiate and sustain ' sickness behaviour' - a key feature of which is cognitive impairment (over-activated microglia being constantly being bombarded by sensory signals would also be likely to impair cognition due to 'sensory overload'/impaired attentional processes).

In a nutshell overexertion in vulnerable individuals doesn't cause any immediate physiological damage (to the body) but may cause lasting microstructural changes to the brain and how it subsequently interprets 'effort'.

Various 'stressors' could have the same impact from over-exertion to psychological stress to even a single instance of 'binge-drinking'.

In the words of Monty Python - 'That is my theory, etc'.

Sounds just, and I'm up for all theories. The really bad ones which have been permenant so far have been from physical exertion. They have left almost no reprocussions on my body, but tons of damage in my brain. My SPECT clean shows 9 lobes of hhypoperfusion

 

[Jonathan Edwards]

I read in a medical journal once that exertion causes damage to the mitochondrial DNA and once the DNA is damaged, it reproduces more damaged mitochindria. That would make sense why once damage is done, if bad enough, it's permenant. I guess the trick would be to figure out how to have your body recycle the bad mitochondria and reproduce the good ones

I forget the details of this but I think it refers to the classical progressive mitochondrial diseases, which include progressive muscle weakness syndromes. As I understand it in these conditions you are born with a mixture or mozaic of cells some with good and some with bad mitochondria. To start with you have plenty of good cells but for some reason when there is death and regeneration of muscle cells (which happens to us all every day) the cells with bad mitochondria outcompete with good ones and gradually you are left with muscles with only cells with bad mitochondria. This sort of mozaic situation is very rare, at least in terms of causing disease. In cases of ME that are slowly progressive over years without any clear onset then this would seem to be a possible mechanism. But it does not seem to make sense for sudden onset ME. Nor does it seem to make much sense for brain fog because neurons are not continually replaced like muscle cells. Maybe some form of glial cell might be affected but I doubt it.

My guess is that it is very unlikely that exertion damages mitochondria in ME and I agree wit htose who tend to place the problem somewhere else.

 

[chipmunk1]

To answer that question you would have to know what causes fatigue in the first place. What can cause fatigue?

 

[Aerose91]

I forget the details of this but I think it refers to the classical progressive mitochondrial diseases, which include progressive muscle weakness syndromes. As I understand it in these conditions you are born with a mixture or mozaic of cells some with good and some with bad mitochondria. To start with you have plenty of good cells but for some reason when there is death and regeneration of muscle cells (which happens to us all every day) the cells with bad mitochondria outcompete with good ones and gradually you are left with muscles with only cells with bad mitochondria. This sort of mozaic situation is very rare, at least in terms of causing disease. In cases of ME that are slowly progressive over years without any clear onset then this would seem to be a possible mechanism. But it does not seem to make sense for sudden onset ME. Nor does it seem to make much sense for brain fog because neurons are not continually replaced like muscle cells. Maybe some form of glial cell might be affected but I doubt it.

My guess is that it is very unlikely that exertion damages mitochondria in ME and I agree wit htose who tend to place the problem somewhere else.

I definitely agree with this sentiment but this article was specifically referring to ME and how the damage to mitochindria from overexertion can be permenant. It described DNA damage as the pathway. I'll try to find it again

 

[Aerose91]

To answer that question you would have to know what causes fatigue in the first place. What can cause fatigue?

As my doctor explains it, all fatigue is inflammation.

 

[Snow Leopard]

As my doctor explains it, all fatigue is inflammation.

Sounds like a tautology at best.

 

[Aerose91]

Sounds like a tautology at best.

Doesn't really do much for me on the PEM front though. My PEM is never fatigue, just more parts of my brain shutting down

 

[cmt12]

I would say there is a difference between discussing the root cause and discussing why some experience symptoms differently. The difference is factoring in beliefs is unproductive when trying to zero in on the root cause but is essential to factor in when attempting to analyze symptoms.

In chronic illnesses with chronic pain, psychology cannot be dismissed in how symptoms are experienced.

Take the example of someone enduring through a tough workout. After the first exercise, there is probably very little psychological activity. But at the end of a long, grueling workout, there is that voice in your head that gets louder and louder saying that you are too tired to continue. This is common knowledge.

Why does this happen? It is the product of a survival mechanism that seeks to avoid pain. This mechanism gets louder the more pain you are in. Once the workout is finished, then the mechanism will gradually go silent, but what if you are in a chronic, even if subtle pain state in which that mechanism never fully goes silent.

If you have some understanding of how beliefs work, it should not be too much of a leap to consider the impact this ongoing pain avoidance mechanism is going to have on the formation or molding of beliefs at a subconscious level and how that may effect symptoms.

This is completely different than saying that beliefs are involved in root causes of chronic illnesses.

 

[gregf]

The question has two parts :

1) What happens to our mitochindria when we overexert?

2) Over exertion, brain recovery and damage from overdoing it.

The two are not necessarilly directly linked.

We have a problem in the mitochondria and our body cuts off oxygen to protect us from this being fatal.

Two ways I can remember off hand are a PFO (heart) and blood pH.

Under aerobic stress (exercise) Oxygenated blood to the brain is reduced, unlike a healthy person where it increases.

The result is chronic Cerebral Hypoxia and brain injury. The number of people (including myself) who say they were made worse after exercise tends to support this.

Current thinking on brain plasticcicy is that given time, our brain will repair around the damaged parts.

That has certainly been my experience since going full-blown M.E. over 10 years ago. There is no sudden improvement in brain functioning, just a very slow, almost imperceptible improvement.

Non aerobic exercise helps. Do not do aerobic exercise.

The interesting development is that the Apple watch may measure blood-oxygen saturation
and this will be very relevant to us.

http://appadvice.com/appnn/2015/05/could-current-apple-watches-also-measure-blood-oxygen-saturation

http://www.idownloadblog.com/2015/05/25/apple-watch-blood-oxygen-saturation-hardware/

In the future we may have to wear an Apple watch during exercise or other exertion, to monitor blood oxygen levels. When it alerts to danger, we reduce exertion.

 

[heapsreal]

Rhabdomyolysis is something that comes to mind which happens to athletes and people in general who exercise excessively when sick and severe heat exhaustion where muscle tissue breaks down, can have damage to heart, kidneys, brain.

Im not saying this is the case but maybe varying degrees of ? ?

 

[nandixon]

One possibility for PEM being related to mitochondrial impairment is raised by the theory being proposed by Fluge & Mella in conjunction with their rituximab work, namely that a large subset of ME/CFS may be due to impaired endothelial nitric oxide (NO) signaling.

Importantly, NO, via its receptor enzyme known as soluble guanylate cyclase (sGC), stimulates mitochondrial biogenesis. (sGC converts GTP into cGMP.)

A scenario can be envisioned then in which the defect in NO signaling, which is currently unknown but which might involve, e.g., interfering autoantibodies, is worsened with exercise/stressors. There would then be a delayed exacerbation of symptoms - a hallmark of PEM - as mitochondrial biogenesis requirements are not met in the days following the stressor event.

I was a bit surprised they didn't mention this possibility in their recently published patent application that's the subject of this thread:

Soluble Guanylate Cyclase [activators or stimulators] for use in treatment of CFS with B-cell depletion

 

[Eeyore]

I agree with Dr. @Jonathan Edwards here. I do not believe there is good evidence for mitochondrial damage in ME. There is much focus on mitochondria because we perceive an energy deficit on a macro clinical level, but I think extrapolating this to a micro cellular level and the mechanisms of cellular energy production is not supportable. We know of MANY diseases that cause fatigue - arguably most do - and they do not reflect any problems with cellular energy production or mitochondrial damage. Relatively few diseases do result from mitochondrial dysfunction, and they don't generally look like ME.

The best piece of evidence I can think of is the studies done by Dr. Hokama which showed elevated levels of cardiolipin (which is found only in the membranes of mitochondria) in ME patients - as well as antibodies to it in many patients. http://www.ncbi.nlm.nih.gov/pubmed/18348309

I was actually a patient in some of his published studies, although I have not met him personally.

However I'm not convinced that this is a result of mitochondrial damage or inability to produce energy - I think rather that there may be some defect in the extrinsic apoptotic pathways, which may lead to compensatory upregulation of intrinsic apoptotic pathways mediated via cardiolipin and cytochrome c, ultimately triggering the various caspases and resulting in cell death. There is definitely evidence of increased apoptosis in ME.

As for why exercise has such a negative effect on ME patients and causes exacerbations, it's not really clear. One study in fibro patients showed that they do not have a normal response to exercise. Certain hormones should increase in response to exercise, but seem to show a blunted response in ME, including both cortisol and hgh. ME patients have blunted response to TRH, CRH, and ACTH. The problem is more functional, so static measurements may not capture it - it's more that the system doesn't respond appropriately to stress. Curiously, this opens up 2 distinct possibilities in my mind - that this lack of a normal sensitivity to stress creates susceptibility to ME, so that when a stressor occurs (e.g. acute illness), ME develops because the body doesn't release the proper stress hormones (e.g. cortisol) OR ME causes the inability to respond normally to stress and this deficit is absent in the premorbid state.

 

[Kyla]

I would say there is a difference between discussing the root cause and discussing why some experience symptoms differently. The difference is factoring in beliefs is unproductive when trying to zero in on the root cause but is essential to factor in when attempting to analyze symptoms.

In chronic illnesses with chronic pain, psychology cannot be dismissed in how symptoms are experienced.

Take the example of someone enduring through a tough workout. After the first exercise, there is probably very little psychological activity. But at the end of a long, grueling workout, there is that voice in your head that gets louder and louder saying that you are too tired to continue. This is common knowledge.

Why does this happen? It is the product of a survival mechanism that seeks to avoid pain. This mechanism gets louder the more pain you are in. Once the workout is finished, then the mechanism will gradually go silent, but what if you are in a chronic, even if subtle pain state in which that mechanism never fully goes silent.

If you have some understanding of how beliefs work, it should not be too much of a leap to consider the impact this ongoing pain avoidance mechanism is going to have on the formation or molding of beliefs at a subconscious level and how that may effect symptoms.

This is completely different than saying that beliefs are involved in root causes of chronic illnesses.

What you are talking about is exercise intolerance. Which happens immediately after exercise.
How does this possibly apply to PEM, where symptom onset is delayed by 24-48 hours?
And where symptoms are often not pain but things like swollen glands, flu-like feeling, problems with temperature regulation etc?

 

[cmt12]

What you are talking about is exercise intolerance. Which happens immediately after exercise.
How does this possibly apply to PEM, where symptom onset is delayed by 24-48 hours?
And where symptoms are often not pain but things like swollen glands, flu-like feeling, problems with temperature regulation etc?

I was attempting to more address the issue of why long term "damage" from over exertion is occurring (symptoms worsening) even after prolonged rest and pacing and absent evidence of physical deterioration. There needs to be consideration that there are additional factor(s) involved beyond physical damage to get to the truth of it.

The physical symptoms are at the heart of it but when over exertion occurs and pain flares up, then psychology comes into play making us susceptible to a back-and-forth downward spiral. When we are in a pain state (over exertion), we are more sensitive to stress and at the same time we are more stressed; when you combine the two like that you can get prolonged worsening of symptoms. Then you beat yourself up for over exerting, making yourself even more fearful and sensitive to stress and the downward spiral continues.

All of this I have observed in myself. I would've certainly claimed that this condition is progressive or there must be long term physical damage at one time also. It's more complicated than that I've realized.

 

[Eeyore]

You can't ignore the interrelatedness of the mind and body. Chemicals that affect any part of the body can also affect the mind, and psychological states are very obviously strongly affected by biochemistry.