Disclaimer:
This article further explores the hypothesis that dysfunction of the sodium-potassium pump plays a central role in ME/CFS. The theory was discussed in a recent paper by Prof. Dr Klaus Wirth and Prof. Dr Jurgen Steinacker.
The aim of this article is to provide broader context for this hypothesis and discuss future therapeutic possibilities, based on a 2025 interview between Prof. Dr Wirth and Gez Medinger, a journalist and Long COVID patient advocate.
It is important to note that this model is one of several competing explanations for the underlying biology of ME/CFS. Not all research groups agree with this interpretation, and therapeutics based on the theory are still in early development. Drug development typically takes many years before treatments become available.
This article is purely for informational purposes and not a recommendation by ME Research UK of a particular drug or management strategy.
Part 1: Mitochondrial dysfunction in skeletal muscle
In the first part of the interview, Wirth argues that mitochondrial dysfunction in skeletal muscle plays a major role in ME/CFS (including ME/CFS following COVID). He points to evidence from scientific literature showing damage/impairment of skeletal muscle function following exercise, including electron microscopy revealing mitochondrial damage.
Based on these findings, Wirth describes the condition as a possible “acquired skeletal muscle mitochondriopathy.”
He proposes the following sequence:
- Physical exertion leads to sodium accumulation inside cells
- Elevated sodium levels trigger calcium overload
- Excess calcium damages mitochondria
According to Wirth, this leads to a vicious cycle that is linked to occurrence of post-exertional malaise (PEM). Specifically, he said “assume that with every PEM there is mitochondrial damage”. Even though the intensity of mitochondrial damage is not high each time, this pathological process is repetitive and cumulative, therefore the pool of intact mitochondria becomes smaller and smaller.
Mitochondria can regenerate but it takes a long time.
Tying in other concepts, Wirth suggests that ME/CFS following long COVID starts with severe and complex vascular dysfunction (problems with the blood vessels). He states hypoperfusion (not enough blood reaching tissues) is always associated with sodium accumulation which in turn causes calcium accumulation etc. Additionally, in relation to the immune system, autoantibodies against elements that keep the sodium-potassium pump functioning contribute to the same imbalances of ions that lead to cellular damage.
Part 2: Pathophysiology of ME/CFS and drug targeting sodium-potassium pump
In the second part of the interview, Wirth further discusses pathophysiology of ME/CFS and moreover the drug he is hoping to develop to counteract issues relating to the sodium-potassium pump and hopefully alleviate ME/CFS symptoms.
He states that brain and skeletal muscle require lots of energy to function and implies that there is less energy in ME/CFS, hence these organs are most affected. He also highlights several physiological findings that he believes support the presence of objective abnormalities, including:
- Orthostatic dysfunction (problems occurring when upright)
- Reduced cerebral blood flow
- High sympathetic tone (overactive sympathetic nervous system)
- Early anaerobic metabolism (generating energy in absence of oxygen, with lactic acid as byproduct) during exercise testing
What about viral persistence?
Wirth expresses skepticism about the role of long-term viral persistence, although it may be present initially and there might be a role for occasional reactivation of Epstein-Barr Virus (EBV).
A potential drug targeting sodium-potassium pump
Wirth also discusses the development of a drug called MDC002 (by Mitodicure).
It is important to note that Prof. Dr Wirth is Chief Scientific Officer and co-founder of the company developing this drug, and this relationship has been declared as a conflict of interest.
The drug is designed to interrupt the pathological cycle described in his model.
Its proposed mechanism is to stimulate the sodium-potassium pump and sodium-calcium exchanger in order to break the proposed sodium overload → calcium overload → mitochondrial damage cycle that Wirth believes contributes to the disease process.
Plus, it has additional effects:
- Improving blood flow in the brain and skeletal muscle
- Providing mild analgesic (pain-relieving) effects
- Reducing vascular leakage (oedema)
Drug development is a lengthy and complex process
However, the treatment remains in early development. At the time of interview, Wirth mentioned they were two years from first clinical testing and there is always five to six years needed for a drug to reach the market. He acknowledges that it is disappointing to patients that the process takes so long, however if you never start the journey then you can never develop a drug.
Read more about the sodium-potassium pump hypothesis in ME/CFS
