Donnan dominated ion homeostasis and the longevity of ischemic Na⁺-loaded dystrophic skeletal muscle

Abstract

The inherited muscle-wasting disease, Duchenne muscular dystrophy (DMD), renders skeletal muscle fibers (SMFs) Na+-overloaded, ischemic, membrane-damaged, cation-leaky, depolarized, and prone to myogenic firing. DMD fibers nevertheless survive up to 3 decades before succumbing to Ca2+-necrosis. The Ca2+-necrosis is explicable, the longevity is not. Modeling here shows that SMFs’ ion homeostasis strategy, a low-cost resilient Pump-Leak/Donnan feedback process we term “Donnan dominated”, underpins that longevity. Together, SMFs’ huge chloride-permeability and tiny sodium-permeability minimize excitability and pump costs, facilitating the outsized SMF pump-reserve that lets DMD fibers withstand deep ischemia and leaky channels. We illustrate how, as these impairments intensify, patients’ chronic Na+-overload (now non-invasively evident via Na23-MRI) would change. In simulations, prolonged excitation (→physiological Na+-overloading) and/or intense ischemia (→too little Na+-pumping) and accumulated bleb-damage (→too much Na+-leaking) eventually trigger Ca2+-overloading conditions. Our analysis implies an urgent need to identify SMFs’ pivotal small PNa, thereby opening new therapeutic remediation routes.