Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.20.391839v1?rss=1 Authors: Morris, C. E., Wheeler, J. J., Joos, B. 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. Copy rights belong to original authors. Visit the link for more info