Preprint Orthostatic Dysfunction and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2026, Wirth

[Chandelier]

Orthostatic Dysfunction and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Close Reciprocal Relationship Beyond Cardiac Preload Failure and Hypoperfusion

Klaus J. Wirth

Abstract
Orthostatic dysfunction, including postural orthostatic tachycardia syndrome (POTS) is highly prevalent in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Although cardiac preload failure and hypoperfusion provide plausible explanations for orthostatic symptoms, they may not fully account for the prolonged symptom exacerbation related to orthostatic stress.
A hypothesis is proposed in which orthostatic dysfunction and ME/CFS may interact through mechanisms extending beyond disturbed hemodynamics.
Orthostatic stress may markedly increase skeletal muscle sodium influx through sympathetic activation and α1-adrenergic stimulation of the sodium–proton exchanger NHE1, whereas the concomitant increase in sodium efflux mediated by Na+/K+-ATPase may be substantially attenuated by impaired β2-adrenergic receptor signaling resulting from receptor desensitization and autoantibodies, small fiber neuropathy, and reactive oxygen species.
This imbalance between sodium influx and efflux could promote intracellular sodium accumulation, potassium depletion, and membrane depolarization, ultimately favoring reverse mode operation of the sodium–calcium exchanger and consequent intracellular calcium overload.
Orthostatic stress may therefore lower the threshold for post-exertional malaise (PEM) and, with prolonged exposure or in severe ME/CFS, potentially trigger PEM even in the absence of physical exertion.
This hypothesis provides a potential mechanistic link between orthostatic dysfunction and the presumed core pathophysiology of ME/CFS, extending beyond hemodynamic factors to implicate disturbances in skeletal muscle ion homeostasis.

Web | DOI | Open Access

 

[Jonathan Edwards]

Why do they say 'reciprocal'. It seems to be direct.

 

[Hoopoe]

Despite my partial remission I still need to lie down during the day to feel well. Less than I used to, and the need is not as intense, but it brings relief.

I'm moderately fit in comparison to the average person so this cannot be attributed to a lack of physical activity.

The average relatively sedentary person seems to be less fit than me, but can do much more in terms of volume of activity. I still hit a wall after a certain volume of activity and pushing against it makes things worse.

 

[hummingbird95]

Would NHE1 inhibition drugs help orthostatic intokerance and pem? Are those drugs available off label, how high was the stroke risk or other adverse events?

 

[Utsikt]

The proposed explanation for mental stimuli triggering PEM is that «mental stress» somehow also affects skeletal muscles, and that this would be enough to trigger the cascade that causes PEM.

Is that in any way plausible?

 

[lethe]

What effects will Amiloride(NHE1 inhibitor) have? I haven't seen any related discussions on the forum.

 

[Dude]

The proposed explanation for mental stimuli triggering PEM is that «mental stress» somehow also affects skeletal muscles, and that this would be enough to trigger the cascade that causes PEM.

Is that in any way plausible?

The muscle is more the place where the mechanism in his model is particularly visible and can be studied. The underlying mechanism itself involves the mitochondria and cellular calcium homeostasis:

Excessive calcium uptake by the cell can become problematic, leading to mitochondrial calcium overload, increased ROS/oxidative stress, disruption of the electron transport chain, and reduced ATP production.

In principle, this mechanism could also affect other energy demanding cells, not just skeletal muscle cells.

Mitochondria and ATP production are central to brain function as well.

While his model identifies impaired microcirculation in skeletal muscle as the trigger, it is less clear what the initial trigger would be in the brain (cognitive pem). My hypothesis is that increased neuronal activity could lead to greater calcium influx through NMDA receptors and voltage gated calcium channels.

This could, for example, potentially explain how the Twitter user (sorry board rules, but if you know you know) managed to improve from very severe to mild ME/CFS using only lamotrigine and pregabalin. They both block calcium channels.

 

[duncan]

This imbalance between sodium influx and efflux could promote intracellular sodium accumulation, potassium depletion, and membrane depolarization, ultimately favoring reverse mode operation of the sodium–calcium exchanger and consequent intracellular calcium overload.

My science isn't so good these days. Are they proposing a channelopathy?

 

[duncan]

Sorry @Dude , we seemed to have posted similar thoughts at the same time.

 

[duncan]

Orthostatic stress may markedly increase skeletal muscle sodium influx through sympathetic activation and α1-adrenergic stimulation of the sodium–proton exchanger NHE1, whereas the concomitant increase in sodium efflux mediated by Na+/K+-ATPase may be substantially attenuated by impaired β2-adrenergic receptor signaling resulting from receptor desensitization and autoantibodies, small fiber neuropathy, and reactive oxygen species.

Why? This part of the hypothesis hopefully is explained at length in the paper.

 

[EndME]

My science isn't so good these days. Are they proposing a channelopathy?

No. He proposes an acquired mitochondrial myopathy. The acquiring works via all the popular memes: microclots, GPCR aabs, inflammation...

 

[Jonathan Edwards]

Excessive calcium uptake by the cell can become problematic, leading to mitochondrial calcium overload, increased ROS/oxidative stress, disruption of the electron transport chain, and reduced ATP production.

But isn't this is just a string of vague fashionable buzzmemes, @Dude. A theory has to identify a reason for the overall shift in dynamics, together with specific mediators of change. And it needs to have something observed that needs explaining. There is nothing observed in people with ME/CFS that would be explained by this string of things as far as I can see. Calcium shifts in muscle tend to cause tetany or paralysis, neither of which are features of ME/CFS.

 

[Dude]

Calcium shifts in muscle tend to cause tetany or paralysis, neither of which are features of ME/CFS.

That is probably also the reason why it hasn’t been detected so far.
Total calcium levels in the muscle can be normal, while too much calcium can still accumulate in the mitochondria. This can damage the mitochondria and impair ATP production.
The consequence would be more likely to be exercise intolerance and rapid fatigability rather than classic tetany. But, this part of the hypothesis cannot currently be tested.

 

[Jonathan Edwards]

Total calcium levels in the muscle can be normal, while too much calcium can still accumulate in the mitochondria. This can damage the mitochondria and impair ATP production.

Is there actually any evidence for that? Why should calcium 'damage' mitochondria, whatever that means. If rapid fatiguability was the prediction why has this never been observed on CPET tests? Loads of people have done these CPET tests and we hear about VO2max and stuff but never about someone coming to a dead halt after 90 seconds. Never.

 

[Dude]

Is there actually any evidence for that? Why should calcium 'damage' mitochondria, whatever that means. If rapid fatiguability was the prediction why has this never been observed on CPET tests? Loads of people have done these CPET tests and we hear about VO2max and stuff but never about someone coming to a dead halt after 90 seconds. Never.

I’m thinking of the MRI study by Petter. The study actually found elevated sodium levels in muscle tissue.

If intracellular sodium becomes sufficiently elevated, the Ncx can reverse its normal direction and, instead of extruding calcium, bring calcium into the cell.

Normal total calcium levels in muscle would not necessarily rule out this mechanism, because the problem could be a misdistribution of calcium at the subcellular level.

The idea that excessive intracellular calcium can damage cells and mitochondria is also well established: https://pubmed.ncbi.nlm.nih.gov/15355853/

 

[Jonathan Edwards]

I’m thinking of the MRI study by Petter. The study actually found elevated sodium levels in muscle tissue.

Yes that is the study I could nto make much of. There seemed to be higher sodium content but I don't see how they could know it was intracellular. Most sodium is extracellular and a shift in compartment proportions could give a high Na level.

The idea that excessive intracellular calcium can damage cells and mitochondria is also well established: https://pubmed.ncbi.nlm.nih.gov/15355853/

That looks like a marketing review of the sort you get in these buzzmeme fields. The abstract does not say much other that nothing seems to be very sorted out yet...

 

[Utsikt]

The muscle is more the place where the mechanism in his model is particularly visible and can be studied. The underlying mechanism itself involves the mitochondria and cellular calcium homeostasis:

That’s not what chapter 4 says.

 

[Dude]

That’s not what chapter 4 says.

I see what you mean. I was probably putting too much emphasis on the downstream mitochondrial mechanism. Chapter 4 actually puts the disturbance of skeletal muscle ion homeostasis much more centrally in the proposed mechanism. My point was that the downstream consequences may involve cellular calcium handling and mitochondrial dysfunction.