In 1905 a Swiss patent officer named Albert Einstein published four groundbreaking papers – one of which was on special relativity. Eleven years later, he added gravitation to the mix in his general relativity hypothesis.

high muscle sodium levels chronic fatigue syndrome

Could high muscle sodium levels be playing a core role in ME/CFS?

It wasn’t until 1919, though, that Einstein’s theory of general relativity was proved correct, and it wasn’t easy. British astronomers traveled halfway around the world to view an extended solar eclipse to determine if, as Einstein predicted, space-time gets curved by massive celestial bodies. When the position of stars appeared to move during the eclipse of the sun (it curved the light), an important part of Einstein’s theory was proved. (Other parts continued to be proved over the years).

Now, it’s hardly fair to compare anyone to Einstein, but a similar process recently took place in chronic fatigue syndrome (ME/CFS). In an April 2021 publication, “Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)”, Klaus Wirth and Carmen Scheibenbogen put on their thinking caps and proposed that the dysfunctional B2AdR receptors’ inability to effectively stimulate the Na+/K+-ATPase enzyme resulted in sodium overload in the muscles of people with ME/CFS.

The consequences of that were potentially vast. The high sodium levels turned the tables on the calcium pump, causing calcium to be imported into the cell instead of getting exported out of it. That calcium overload then impaired the mitochondria and other metabolic parts of the cell from working properly and with that – bam! – a new hypothesis (calcium overload) explaining the fatigue, post-exertional malaise, and inability to exercise, think well, etc. was born.

No Neuroinflammation Needed? An Epic ME/CFS Hypothesis Series Winds Up

It was all theory, though, until now. Thanks to funding from the Charite University Hospital in Berlin and researchers from Charite, the Center for Cardiovascular Research and the German Heart Center in Berlin teamed up together to have a go at Wirth and Scheibenbogen’s hypothesis.

The Study

In the introduction of the paper, the authors didn’t go through all findings regarding the muscles in ME/CFS, but they did enough to make one wonder once again why more researchers aren’t jumping at the opportunity to study this disease.

As has been noted many times in Health Rising blogs, in what is thus far a unique finding in all of medicine, repeat exercise studies have repeatedly shown that exercise one day impairs the ability to produce energy (e.g. exercise) the next in ME/CFS. Increased intramuscular acidosis, problems with muscle pH recovery, and reduced proton efflux (e.g. getting rid of the acids) from the muscles have been found as well. None of this is news at this point – some of those findings date back to 2010 – but they underscore how potentially impacted the muscles in ME/CFS are.

It’s not just ME/CFS. Something similar may be going on with the muscles in long COVID as well. A recent article from the Netherlands stated that the “similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study”, and invasive exercise tests in long COVID have produced similar results in that disease.

The Study

Handgrip test

The study used a hand grip test to assess muscle fatigue. Fatigue was higher at all points in ME/CFS.

The Petter/Kleim study, “Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome”, used an MRI to assess the sodium content of the participants’ (6 ME/CFS and 6 healthy controls) calf muscles before and after exertion.

First, the participants rested – and got a baseline MRI scan – and then did heel raises to exhaustion (30 secs) – and had their calves scanned again. Handgrip strength was also assessed at different times to assess the degree of muscle fatigue. Five different muscle compartments were tested. Factors like BMI, age, gender and salt intake did not differ between the ME/CFS patients and the healthy controls.


The study found significantly increased sodium levels in the ME/CFS patients’ muscles – both before and after exercise. With that one test, part of the Wirth/Scheibenbogen hypothesis was validated. Handgrip strength was also reduced and was associated with fatigue.

Importantly, the study also found a positive relationship between muscle fatigue (as demonstrated in the handgrip test) and muscle sodium levels; i.e. the higher the muscle sodium levels were, the greater the muscle fatigue. That made sense.

The sodium-proton exchanger subtype1 (NHE1) exchanges the acids (protons) produced during exercise for sodium ions. In low-energy states, though, proton production goes way up – causing sodium levels in the cell to climb. The sodium-potassium pump, Na+/K+- ATPase, is tasked with removing the sodium but – and here’s the clincher – note that ATPase – it takes a lot of ATP to make the pump work, and if ATP is scarce, it can’t function properly.

The B2 adrenergic receptors that Scheibenbogen and others have been studying in ME/CFS come into play as well. First of all, by hampering blood flows, they could be causing a multitude of problems including ATP production, but they also, interestingly enough, stimulate NA+/K+ ATPase to remove sodium.

industrial pump

The core problem – an essential cellular pump is not getting the stimulation it needs to work.

If Scheibenbogen and Wirth are correct, balky B2 adrenergic receptors are not only causing problems with the blood vessels but they’re also messing up the transport of sodium out of the cell. Two other studies which found low intracellular potassium levels suggest this may be happening in ME/CFS.

Plus, other factors could be in play: the small fiber neuropathy found in ME/CFS could lower the levels of another sodium-potassium pump stimulator – CGRP.

Plus,  people with ME/CFS appear to have low levels of several other sodium-potassium pump stimulators (cortisol, aldosterone, and T3/triiodothyronine). Finally, the mitochondrial dysfunction found in ME/CFS could be affecting ATPase – a key feature of the sodium-potassium pump. All told, a multitude of factors could be affecting this critical intracellular pump in ME/CFS.

Because the authors believe those high pre- and post-exercise sodium cellular levels they found in ME/CFS are probably much lower than those which occur during the exercise itself, the current findings may be understating the problem. (It’s impossible to directly measure sodium levels during exercise.)

The authors believe the crux of the matter in the muscles is that high sodium levels can cause the cell to import instead of export calcium. The impaired blood flows are making the situation worse by reducing ATP production in the muscles, but it’s the calcium overload that really takes a hammer to the mitochondria and, as it’s doing so, it also damages (the already damaged) blood vessels. (Nice!)

The model

The authors state:

Changes in intracellular and mitochondrial calcium via NCX induced by the rise in intramuscular sodium are considered the key pathomechanism in the energetic and mitochondrial disturbance in ME/CFS”.

They believe this mix of mitochondrial and endothelial (blood vessel) damage produce a vicious circle in ME/CFS.

This entire mitochondrial and blood vessel mix vicious circle … can explain post-exertional malaise, exercise intolerance and chronifcation (chronic illness state).”

The finding of high sodium levels in the muscles before and after exercise doesn’t prove that calcium loading is occurring – they weren’t able to measure intracellular calcium levels – but they do demonstrate that the conditions are ripe for that to occur. They’re also enough for Wirth to move forward (see below).

The Gist

  • Wirth and Scheibenbogen have produced a series of hypothesis papers on chronic fatigue syndrome (ME/CFS). Like a Russian nested egg, each has built on the past. Their ability to keep churning out complicated hypothesis papers that build on and agree with each other has been unique in ME/CFS. 
  • Their latest hypothesis paper implicated the B2aDR receptors in the mitochondrial dysfunction in ME/CFS. They proposed that balky B2aDR receptors in ME/CFS are causing the sodium-potassium pump to fail to remove sodium out of the cell – resulting in high intracellular sodium levels. 
  • This, in turn, causes calcium levels to rise and disrupt mitochondrial output. It’s this calcium overload that they believe is predominantly responsible for low energy levels in ME/CFS. 
  • This small German study (12 people) put their sodium loading hypothesis to the test. During rest and after exercise (heel raises to exhaustion), an MRI assessed muscle sodium levels. A separate handgrip test assessed muscle fatigue. 
  • The results vindicated their hypothesis: muscle sodium levels were greatly increased both at rest and after exercise. Plus, the handgrip test found that muscle fatigue was correlated with muscle sodium levels as well. 
  • They believe this may be happening for a number of reasons. For one, poorly functioning B2aDR receptors are failing to stimulate the sodium-potassium pump to remove sodium from the cell. At the same time they’re doing that, by constricting blood flows, they’re reducing ATP production and the sodium-potassium pump (Na+K+ATPase) requires a lot of ATP.  
  • Other factors in ME/CFS (low CGRP, cortisol, aldosterone, and T3/triiodothyronine levels) that stimulate the sodium-potassium pump may also come into play. 
  • Note that there’s a back-up sodium pump that can function when calcium levels are high and should jump in to prevent this situation. That may not be happening in ME/CFS, though, because of another factor – the Epstein-Barr virus (EBV).  Not only does EBV shares a common genetic sequence with this pump, but a recent study found elevated levels of an EBV antibody that could be causing the body to attack this back-up pump – leaving the cells of people with ME/CFS possibly helpless against sodium and calcium influxes. 
  • The crux of the matter, though, is that high intracellular sodium levels can cause the cell to import instead of export calcium, and it’s this calcium overload that they believe is causing the energy production problems in this disease:
  • Changes in intracellular and mitochondrial calcium via NCX induced by the rise in intramuscular sodium are considered the key pathomechanism in the energetic and mitochondrial disturbance in ME/CFS”.
  • They believe that the situation found in ME/CFS – reduced blood flows (B2ADr issues) and calcium overload – produces a vicious circle that is hard to break out of:
  • This entire mitochondrial and blood vessel mix vicious circle … can explain post-exertional malaise, exercise intolerance and chronification (chronic illness state).”
  • Note that the way to fix this problem is to go to the source – and get the sodium-potassium pump working again. 
  • When asked if the high sodium dietary intake often seen in ME/CFS could be exacerbating this problem, the answer was an emphatic “no”. In fact, if the high sodium intake was helping with orthostatic intolerance (problems sitting up or standing), then it’s probably helping the situation. 
  • Wirth wrote to me that the hypothesis and the study results are getting us closer to a good “therapeutic strategy” for ME/CFS. When I asked him about that, he reported that he believes that drugs are available that could get at the core of this situation and has formed a company to facilitate that. That company is now looking for seed funding. 

An Epstein-Barr Virus Connection? 

Wirth reported that another possible mechanism may be in play involving something called the NCKX3 (potassium-dependent sodium-calcium exchanger). NCKX3 is a kind of back-up or reserve sodium-calcium exchanger that jumps into action when intracellular sodium levels are high. Unlike the sodium-calcium exchanger the authors focused on in the paper, though, the NCKX3 still removes calcium from the cell during times of high sodium levels. Thus it should be protecting ME/CFS patients’ muscle cells from calcium overload

People with ME/CFS, though, may have a complicating factor – the Epstein-Barr virus. It turns out that genetic sequences found in NCKX3 share a close resemblance to those found in an EBV antigen called EBNA6_0070. (An antigen is anything – a part of a pathogen, a toxin, etc. that provokes an immune response in the body. In this case, the antigen is found on an EBV protein.)

This protein is produced during one of EBV’s latency stages. Latency means that the virus is not replicating – it does not mean that the virus is not active. The virus can actually be quite active during latency.

The really interesting thing about this EBV antigen and ME/CFS is that just last year, Sepulveda et. Al found high levels of antibodies in two EBV antibodies – one of which just happened to be EBNA6_007. Sepulveda proposed that molecular mimicry – a state in which the immune system mistakenly directs an attack against human tissues that have similar genetic sequences as a foreign substance or antigen – might be occurring in ME/CFS and urged further study.

Wirth pointed out that if these antibodies were indeed harming NCXK3’s functioning, “one of the last protective mechanisms against calcium overload would be abolished and would fail.”  He warned that this is still speculative and wrote that cellular studies are now needed to determine if this antibody is actually affecting the functioning of this sodium-calcium exchanger. He noted, though, that is just one of the possible scenarios that could be producing calcium overload in the muscle cells of ME/CFS patients.


Given that this is about sodium, and that many people with ME/CFS have high sodium intake, I thought it made sense to if high salt intake could have an effect on the high intracellular sodium levels he saw in this study?

It turned out it couldn’t. This is partly because the orthostatic stress (eg. difficulties sitting up or standing) issues may be making the calcium loading problems in ME/CFS worse. This is because chronic stress reduces (blood) perfusion to the brain and muscles and can desensitize ß2AdR and alpha2-adrenergic receptors. Since the “ß2AdR receptors are the most potent activators of the Na-K-ATPase in skeletal muscle”, any desensitization of these receptors can make the situation worse. Thus anything that helps with orthostatic intolerance such as increased salt and fluid intake could be helpful.

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.

In other words, reducing sodium uptake could make the situation worse. Plus, Wirth explained that:

“sodium uptake in the hypovolemic situation of ME/CFS causes water retention and volume expansion of the blood, but does not lead to a rise in plasma sodium.” In fact, “you cannot lower intracellular sodium in skeletal muscle by lowering sodium intake because high intramuscular sodium is due to insufficient Na-K-ATPase mainly.”

The way to reduce the high intramuscular sodium in ME/CFS is to find a drug that stimulates Na-K-ATPase to get sodium out of the cell.

Given the important role the B2AdR receptors play in their hypothesis I asked if problems with the receptors were showing up in long COVID?

“Autoantibodies against B2AdR have also been found in long Covid (Szewczykowski et al, Wallukat et Al.). Autoantibodies as well as desensitization by chronic stress are the main presumed disturbances in our hypothesis. In long COVID, orthostatic intolerance occurs early on. Orthostatic stress is the biggest stressor in our hypothesis.”

drug startup ME/CFS

Wirth has created a startup company to bring a drug to market that he believes could help resolve the core issues in ME/CFS.

Finally, I asked about next steps.

“You told me that the hypothesis and the study results are getting us closer to a good “therapeutic strategy” for ME/CFS. Are there drugs or treatments that could help? What are your next steps?”

“ME/CFS is one of the most complicated diseases. Although according to our unifying hypothesis, the pathophysiology may be understood, it remains complex. Such complex disease hypotheses are usually not proven or refuted by a single biomarker, patient or other experimental findings. The final proof of a disease hypothesis comes from the efficacy of a drug principle that is derived out of the disease hypothesis.”


“With the demonstration of efficacy of a drug principle, the hypothesis would be proven and a drug treatment would be available, supposed it would be sufficiently tolerated. We are at that point now and have derived pharmacological mechanisms necessary to address the core of the pathophysiological mechanisms, the vicious circles, that keep the disease process running. Key disturbances are the ionic disturbances in skeletal muscle and disturbed skeletal muscle and cerebral blood flow. To realize this drug project, a company has been recently founded and is looking for seed funding to finance the project.”

Keep the Information Coming!’ 

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