A Comprehensive Disease Concept Based on Exercise Intolerance and a Derived Therapeutic Strategy

Prof Klaus Wirth, Chief Scientific Officer (CSO) at Mitodicure GmbH, addressed muscular and mitochondrial dysfunction in ME/CFS, based on clinical research results and his own hypothesis. It describes a vicious cycle that, based on impaired muscle perfusion and anaerobic metabolism under stress in ME/CFS, leads to and can maintain mitochondrial dysfunction and damage via impaired electrolyte homeostasis. Specifically, due to a proton surplus on the cellular level (based on anaerobic metabolism), increased sodium is transported into the cell. The increased cellular sodium can then not be adequately transported out of the skeletal muscle cells due to very high Adenosine triphosphate (ATP) consumption. G-protein coupled receptor (GPCR) autoantibodies against the β-adrenergic receptor or small fiber neuropathy (SFN) negatively impact the excretion via the Na+/K+-ATPase. The increased intracellular sodium concentration influences the intracellular calcium concentration, resulting in calcium overload, which ultimately leads to mitochondrial dysfunction and mitochondrial damage. An excess of calcium reduces oxidative ATP production, which means that damaged mitochondria consume ATP instead of producing it. This could explain the symptom of post-exertional malaise (PEM). In severely affected individuals with ME/CFS, skeletal muscles may be in a constant state of depolarization, leading to loss of strength and muscle twitching. The sodium concentration threshold in this mechanism, above which effective sodium expulsion from the cell is no longer possible, may physiologically explain the exercise threshold in PEM. The pharmacological molecule MDC002, developed by Mitodicure and administered in tablet form, stimulates the sodium-potassium pump to produce ATP and promotes sodium-calcium exchange in the mitochondria of skeletal muscles. As a therapeutic approach, it could interrupt the mechanisms that lead to mitochondrial damage, allowing them to regenerate. In conclusion, according to Prof Wirth, ME/CFS is an acquired mitochondrial myopathy.