Muscle sodium content in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 2022, Petter, Scheibenbogen, Wirth et al

Abstract
Background

Muscle fatigue and pain are key symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Although the pathophysiology is not yet fully understood, there is ample evidence for hypoperfusion which may result in electrolyte imbalance and sodium overload in muscles. Therefore, the aim of this study was to assess levels of sodium content in muscles of patients with ME/CFS and to compare these to healthy controls.

Methods
Six female patients with ME/CFS and six age, BMI and sex matched controls underwent 23Na-MRI of the left lower leg using a clinical 3T MR scanner before and after 3 min of plantar flexion exercise. Sodium reference phantoms with solutions of 10, 20, 30 and 40 mmol/L NaCl were used for quantification. Muscle sodium content over 40 min was measured using a dedicated plugin in the open-source DICOM viewer Horos. Handgrip strength was measured and correlated with sodium content.

Results
Baseline tissue sodium content was higher in all 5 lower leg muscle compartments in ME/CFS compared to controls. Within the anterior extensor muscle compartment, the highest difference in baseline muscle sodium content between ME/CFS and controls was found (mean ± SD; 12.20 ± 1.66 mM in ME/CFS versus 9.38 ± 0.71 mM in controls, p = 0.0034). Directly after exercise, tissue sodium content increased in gastrocnemius and triceps surae muscles with + 30% in ME/CFS (p = 0.0005) and + 24% in controls (p = 0.0007) in the medial gastrocnemius muscle but not in the extensor muscles which were not exercised. Compared to baseline, the increase of sodium content in medial gastrocnemius muscle was stronger in ME/CFS than in controls with + 30% versus + 17% to baseline at 12 min (p = 0.0326) and + 29% versus + 16% to baseline at 15 min (p = 0.0265). Patients had reduced average handgrip strength which was associated with increased average muscle tissue sodium content (p = 0.0319, R2 = 0.3832).

Conclusion
Muscle sodium content before and after exercise was higher in ME/CFS than in healthy controls. Furthermore, our findings indicate an inverse correlation between muscle sodium content and handgrip strength. These findings provide evidence that sodium overload may play a role in the pathophysiology of ME/CFS and may allow for potential therapeutic targeting.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03616-z

 

Looks interesting but only data on 6 patients and 6 controls.

 

Would also have been better if they had included sedentary controls.

 

I think they did. They write:

"Healthy controls... were required to have sedentary jobs and perform less than three hours of physical activity per week."
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But I agree that this likely does not fully control for the inactivity and deconditioning of ME/CFS patients.

EDIT: the authors write in the discussion section: "it is unclear to what extent the immobility of patients with ME/CFS has infuenced the results."

 

the claim: "there is ample evidence for an autoantibody mediated dysregulation of the autonomic nervous system and disturbed vascular regulation" is supported by 1 x hypothesis rich review paper, 1 x small gene study, 1 x small exercise study and 1 x Rituximab study, while one of the authors of the current study was a contributor to two of the referenced papers. Seems a bit slim and self referential.

the claim: "endothelial dysfunction, hypoperfusion of muscles and impaired cerebral blood flow are assumed to be key mechanisms for symptoms like fatigue, myalgia, post-exertional malaise and impaired cognition" is based on a single (though large) cerebral flow study and an hypothesis paper that is again self referential. All looks a bit 'house of cards' to me.

 

Is this why periodic paralysis and similar presentations appear to be overrepresented among ME/CFS patients (although reliable data is still lacking)?

 

I assume that, if there is a common underlying cause, in ME/CFS, then the gene wide association study (GWAS - Chris Ponting) currently underway, would pick up genetic clues?

Simon McGrath posted recently re a GWAS migraine study - as Simon highlighted, if you knew nothing about the disease that (GWAS) study would clearly identify the drug targets.

 

Table 1 in this study: Sex Differences in Sodium Deposition in Human Muscle and Skin gives some comparator figures for sodium concentration in muscle, albeit the female cohort is older age.

The difference between sodium levels in patients and controls is interesting, but are the levels physiologically significant ?

 

After longer walks, fatigue and weakness set in within seconds as soon as I slow down or stop. This seems like something that could be related to abnormal ion channel function.

The effect for an outside observer would be striking. A person that just walked at decent speed without apaprent difficulty, then quickly loses energy and strength and walks slowly with an abnormal gait due to weak muscles. At least this is what it looks like when it's pronounced. It's quite variable.

And just like in some kinds of periodic paralysis, eating right afterwards help mitigate the issue. As result as I've changed my lifestyle around planning walks and exertion so that I can have a meal right afterwards, or at least a snack.

It is not severe enough to be consistent with actual paralysis, or even a marked weakness, but clearly felt and often visible to outside observers. Sometimes I also get very tired and have to take a nap.

 

Remember that sodium is highly regulated in the body, evidenced by a really tight normal value range in the blood. It means that an excess of sodium intake would be excreted via the kidneys.

 

I don't think I can interpret this finding.

Muscle contains four main ion-containing compartments: muscle cells, interstitial fluid, blood and lymph in vessels. The last four should have sodium levels as in plasma - which are not known to be abnormal in ME. The muscle cell compartment will be much lower in sodium and higher in potassium.

It seems to me most likely that what they are measuring is a difference in proportion of muscle cell volume and the volume of the Na rich compartments. An increase in Na after exercise seems likely to be due either to reactive blood flow, which would be expected immediately, or mild reactive oedema, which very likely occurs after vigorous exercise normally, from mast cell stimulation. During exercise one might expect the interstitial fluid and lymph compartments to be squeezed dry but this does not seem to show up.

Changes in volumes of fluid compartments are likely to relate to exercise and I am not sure one can make much of them. Muscle sodium may be higher in ME if there is a degree of muscle cell atrophy - you would pretty much expect that to a degree - just because a higher proportion of the tissue is the other Na rich compartments.

What I think the study needs to be interpretable is some other marker of the compartments - or maybe several. Perhaps magnesium would be useful, since, like sodium, it is higher outside cells if I remember rightly. The measure of water content does not help us other than to distinguish the water-based compartments from fat.

So I do not think this is likely to be telling us anything about sodium handling. At the moment PWME are told to eat more sodium for OI. The suggestion here is that the sodium may be high and that may start people suggesting lowering it. But until one knows what is causing what there is no rational basis for any sort of treatment. Even if the sodium is high it may be better to be high because it is offsetting some real problem.

 

Yes, the difference quoted in the abstract is way too high to be due to difference in sodium concentration in interstitial fluid or plasma. It pretty much must be a reflection of the relative volumes of tissue sub compartments I think.

 

Perhaps would be more interesting if magnesium calcium and potassium had also been measured ?

 

ME/CFS Muscle Study Results in Drug Company Startup
Written by Cort Johnson

At the very end of the article:
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.”

https://www.healthrising.org/blog/2023/02/22/chronic-fatigue-syndrome-calcium-muscles-startup/

 

I wonder if this fits with my experience that eating something can greatly improve symptoms of orthostatic intolerance. How would eating improve blood flow? Maybe by insulin or some other eating-related hormone stimulating the Na+/K+-ATPase.

It might be worth trying a medication that has a similar effect so that I don't have to eat so often.

 

correction
https://www.researchgate.net/public...gic_EncephalomyelitisChronic_Fatigue_Syndrome