Can Amiloride Fix the Sodium Overload Problem in Muscle Cells?

[jasperfw]

In 2022 Wirth and Scheibenbogen showed a ~20% increased sodium muscle content in ME/CFS patients:
https://refubium.fu-berlin.de/handle/fub188/43366

Why is the sodium overload important?
Because according to their hypothesis it is the sodium overload which causes a calcium overload which causes the mitochondrial dysfunction in muscle cells!
(With some feedback loops and more details ofc. I will skip over this. There is another major factor at play)

They further hypothesize in another paper that this sodium overload is mainly due to an upregulated NHE1 (Sodium Hydrogen Exchanger 1):
https://refubium.fu-berlin.de/handle/fub188/38280

Could Amiloride be a cheap way to test this hypothesis?

Amiloride has been shown to inhibit NHE1 with a Ki value of around 2-3*10^-5M, for example this paper:
https://journals.physiology.org/doi/pdf/10.1152/ajprenal.1981.241.4.F374

Can we achieve this concentration in humans?

According to this paper, the achievable blood concentration after a single 20mg dose of Amiloride was 48ng/ml:
https://journals.sagepub.com/doi/pdf/10.1177/1470320320975893?download=true

This is not enough, as a Ki of 0.03 mmol/L would translate to approx. 7mg/L (molar mass of Amiloride is 230g/mol). A factor of about 100 too low!

But here's the thing:
Amiloride distributes outside of the vasculature. For example, the same paper has shown concentrations of 3*10^-6M to 20*10^-6M for a single dose of 20mg Amiloride in the renal tubulus.

Now 20mg is quite high. If we assume a dose of 10mg instead and (perhaps!) a concentration of 10*10^-6M at the NHE1 ports of the muscle cells, we could still get ~30% inhibition of NHE1!

The last assumption is crucial, I believe. I haven't found any data if/how amiloride accumulates at this port. A concentration of, say, 3*10^-6M would be much less desirable (10% inhibition).

Note that this all just builds on a hypothesis, there is just the small study on the sodium overload, not much more. Most of it is speculation.

 

[SlamDancin]

Thanks for doing these calculations. I asked my last doctor but she said there wasn’t enough evidence to prescribe. Following this thread in case anyone tries

 

[Hip]

I take amiloride 5 mg quite often, as I discovered by accident it helps one of my psychiatric symptoms. I have not notice any benefits for my ME/CFS symptoms though.

 

[jasperfw]

I take amiloride 5 mg quite often, as I discovered by accident it helps one of my psychiatric symptoms. I have not notice any benefits for my ME/CFS symptoms though.

Thanks for reporting, @Hip
But as far as I can remember, you don't have muscle issues? Or at least don't get PEM from physical exertion?
If I understand their hypothesis correctly, this sodium overload occurs primarily in skeletal muscle cells.

 

[Hip]

But as far as I can remember, you don't have muscle issues? Or at least don't get PEM from physical exertion?
If I understand their hypothesis correctly, this sodium overload occurs primarily in skeletal muscle cells.

Yes, for PEM from physical exertion is minimal for me.

Although I do have poor muscular stamina (muscles rapidly weaken when starting physical exertion). Both PEM and poor stamina (rapid fatigability) are mandator symptoms in the CCC and ICC criteria.

Having said that, I don't think I have ever checked whether amiloride can reduce the poor muscular stamina.

 

[Florida Guy]

according to their hypothesis it is the sodium overload which causes a calcium overload which causes the mitochondrial dysfunction in muscle cells!

Is that really true? I've read posts here where people ate salt because they were low on sodium and felt better afterward. If too much sodium was the problem, avoiding it should quickly solve the problem but this does not seem to be the case. Doctors like to come up with theories because that may lead to grant money being dispensed for a study

They found around 20% higher sodium in cfs patients. They theorize that this is the cause or one big factor in the symptoms that we see. However interesting that anomaly might be, it has not been shown yet to cause a problem. What they would need to do is inject sodium into volunteers to bring the level in muscles up to the levels seen in cfs patients. If that caused pem, or low energy, or any of the 100+ symptoms of cfs then its important. If not then either thats not so important or it may take long term high levels to do it

Unfortunately we do not have mouse models of cfs to experiment with so it has to be volunteers. If high Na levels cause those symptoms after a month or two that would be a big find.

Other scientists are equally sure it must be oxygen that is the problem.

 

[jasperfw]

According to their hypothesis it "The proximity of the intracellular sodium concentration to this reverse mode threshold of the NCX is the presumed main cause for exercise intolerance in ME/CFS and the potential explanation for the characteristics of a threshold of effort for the induction of PEM".
So I presume that Amiloride could act as a (physical) PEM inhibitor if it turns out to inhibit NHE1 at normal doses.

As for muscle fatigability - I'm not so sure. Maybe just try it out? My personal guess is that it won't show an immediate effect, since it won't magically repair the mitochondria, just prevent more damage from calcium overload and allow for slow regeneration.

 

[kushami]

@Florida Guy, I’m no expert, but I believe this hypothesis relates to how sodium is used in or cleared from muscle cells and the knock-on effects of this not happening normally, rather than how much sodium is present in the body.

People with ME/CFS who felt better after increasing their sodium intake may have felt better because they boosted their blood volume, which helps with orthostatic intolerance, or for other reasons.

The researchers did question all participants beforehand about their salt and fluid intake and whether they had salt cravings. Maybe a blood test to make sure their blood sodium was normal (or some other testing) would have been a sensible precaution.

A mouse model would definitely help. If researchers could find the same abnormal levels of sodium in the muscles of mice with an ME/CFS analogue, that would be progress for this hypothesis, and then they could see whether they could fix the problem, and whether that had any effect on the mouse’s exercise ability, PEM, etc.

Or perhaps they could induce the same sodium problem in healthy mice and see whether the mice suffered from exercise intolerance or PEM as a result. This option would be easier, although I wonder whether it would be as straightforward as injecting a sodium solution into the muscle. Healthy bodies/muscle cells might quickly dissipate the extra sodium before the subjects could do the exercise test or the MRI scan.

Also, and this is just me being silly, do they have to build teeny tiny MRI scanners for mice?

 

[kushami]

I didn’t know there was an MRI scan for sodium levels in tissue. I wonder why this type of scan was invented.

A quick Google reveals that it seems to be used mostly for research at this stage, e.g. understanding how the kidney works, but it could soon be used to detect tumours and heart disease as well as muscle and kidney problems.

The authors of the study say that they believe they are the first to use it to study ME/CFS.

 

[kushami]

Yes, there are MRI scanners built especially for small animals:
https://www.monash.edu/researchinfrastructure/mbi/facilities/pre-clinical/9.4t-mri

(Has photo of scanner but no animal is visible.)

 

[Florida Guy]

If the sodium causes a calcium overload, somehow, then why not cut back on calcium if that is the real problem? I have little doubt that many of us have imbalances in minerals, hormones and other things. Whether this is the cause or merely a downstream effect is hard to say. If cutting back on sodium or calcium fixes mecfs then we should all do it. But has anyone improved by following this theory?

Oxygen, the lack or or using improperly has been accused of being the cause but has anyone gotten better or recovered using it? Oxygen helps with various things but ME is not one of them, it seems. And then there is the factor of oxygen toxicity. I have not been able to find out what levels, pressure or length of time that causes it to become toxic. All source are vague and say "too high partial pressure" or for too long but give no guidelines. There probably are guidelines somewhere for divers perhaps.

 

[jasperfw]

If the sodium causes a calcium overload, somehow, then why not cut back on calcium if that is the real problem? I have little doubt that many of us have imbalances in minerals, hormones and other things. Whether this is the cause or merely a downstream effect is hard to say. If cutting back on sodium or calcium fixes mecfs then we should all do it. But has anyone improved by following this theory?

The reversal of the NCX depends on more than just the calcium gradient, most importantly it also depends on intracellular sodium. My guess (?) is that the NCX would reverse during/post exercise as this is when sodium sharply rises, regardless of calcium contrentration

They write the following:
"What is needed to cause calcium overload is a certain extent of sodium overload only to reverse the transport direction of the NCX. The reversal potential of the NCX does not only depend on sodium concentrations and gradient, but also on calcium concentrations and the membrane potential so that it is not possible to give the sodium concentration at which this occurs."

 

[Florida Guy]

The reversal of the NCX depends on more than just the calcium gradient, most importantly it also depends on intracellular sodium. My guess (?) is that the NCX would reverse during/post exercise as this is when sodium sharply rises, regardless of calcium contrentration

They write the following:
"What is needed to cause calcium overload is a certain extent of sodium overload only to reverse the transport direction of the NCX. The reversal potential of the NCX does not only depend on sodium concentrations and gradient, but also on calcium concentrations and the membrane potential so that it is not possible to give the sodium concentration at which this occurs."

Ok but has anyone gotten better by avoiding Ca or Na? They give an answer that sounds like a politician wrote it. Apparently reducing dietary intake of these minerals does not help or they would be talking about that. We need both and if there is a higher concentration in pwcfs, we need to find out if that is a problem or is it a result of another problem. Is the calcium level causing pem? One day we may find out