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

摘要: 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 nevertheless survive up 3 decades before succumbing Ca2+-necrosis. Ca2+-necrosis is explicable, the longevity not. Modeling here shows that SMFs' ion homeostasis strategy, a low-cost resilient Pump-Leak/Donnan feedback process we term "Donnan dominated", underpins longevity. Together, huge chloride-permeability tiny sodium-permeability minimize excitability pump costs, facilitating outsized SMF pump-reserve lets withstand deep ischemia 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 too little Na+-pumping) accumulated bleb-damage much Na+-leaking) eventually trigger Ca2+-overloading conditions. Our analysis implies an urgent need identify pivotal small PNa, thereby opening new therapeutic remediation routes.