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bioRxiv · 10.1101/2020.11.20.391839

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

Morris, C. E.·Wheeler, J. J.·Joos, B.
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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.

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Morris, C. E., Wheeler, J. J., Joos, B.. 2020-11-20. Donnan dominated ion homeostasis and the longevity of ischemic Na+-loaded dystrophic skeletal muscle. https://doi.org/10.1101/2020.11.20.391839

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