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

Sly Saint

Sly Saint

Senior Member (Voting Rights)
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
 
John Mac said:
Would also have been better if they had included sedentary controls.
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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.
 
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.
 
It is interesting - to get statistically significant results with such a small sample suggests that there might be something here.

The researchers paid attention to pre-testing factors that might confound things e.g. the matching of participants and
Study participants were instructed not to exercise or perform intense leg movements for 1 week before the MR examination. On examination day, patients were picked up from home by taxi and healthy controls used public transportation or car to not overstress their muscles.
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Age, BMI, and sex did not differ between the groups, neither did behaviors regarding salt appetite, salty food craving and consumption of beverages.
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I thought salt intake might differ, as people with ME/CFS are often told to consume more salt to keep blood volume up. I'm not completely sure that what is reported here rules that possibility out?


The findings of our study are in line with our recent hypothesis paper on the mechanisms of the energetic situation in muscles in ME/CFS and the underlying disturbance in ion homeostasis [14]. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. The sodium-proton exchanger subtype1 (NHE1) exports protons via the import of sodium ions. In poor energetic situations increased proton production raises intracellular sodium via NHE1, the most important proton-extruder in skeletal muscle. Endothelial dysfunction leads to muscle hypoperfusion and diminished ATP generation in ME/CFS [9]. Sodium is removed from the muscle by the Na+/K+-ATPase at the expense of ATP consumption. We assume that the removal of sodium is further impaired due to dysfunction of the ß2 adrenergic receptor which leads to an insufficient stimulation of the Na+/K+-ATPase [14]. High intracellular sodium can reverse the transport direction of the sodium–calcium exchanger (NCX) to import calcium instead of exporting which is also known from the ischemia–reperfusion paradigm [38].

Channels and transporters that play a role in ion transport in myocytes are depicted in Fig. 5. The ensuing calcium overload affects the mitochondrial metabolism and the endothelium, which further worsens the energetic situation in a vicious circle which can explain post-exertional malaise, exercise intolerance and chronification. 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 as outlined in a recent hypothesis paper [9, 14] but cannot be directly demonstrated with current methods in vivo. The demonstration of elevated intramuscular sodium in this study provides, however, evidence that the conditions for a disturbed calcium handling via the NCX are indeed present in skeletal muscles in ME/CFS.
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I can only skim this paper now, but I think these ideas are worth poking into. I'm not sure how what seems to be a phenomenon isolated to the muscles that are used causes the systemic phenomenon of PEM.

Reference 14 is
Wirth KJ, Scheibenbogen C. Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). J Transl Med. 2021;19(1):162.
Forum thread here:Pathophysiology of skeletal muscle disturbances in (ME/CFS): 2021, Wirth, Scheibenbogen
 
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.
 
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Hutan said:
It is interesting - to get statistically significant results with such a small sample suggests that there might be something here.

The researchers paid attention to pre-testing factors that might confound things e.g. the matching of participants and

I thought salt intake might differ, as people with ME/CFS are often told to consume more salt to keep blood volume up. I'm not completely sure that what is reported here rules that possibility out?
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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.
 
Milo said:
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.
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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.
 
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