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Ion homeostasis in skeletal muscle fibers underperforms as DMD progresses. But though DMD renders these excitable cells intolerant of exertion, sodium overloaded, depolarized, and spontaneously contractile, they can survive for several decades. We show computationally that underpinning this longevity is a strikingly frugal, robust Pump-Leak\/Donnan (P-L\/D) ion homeostatic process. Unlike neurons, which operate with a costly \u201cPump-Leak\u2013dominated\u201d ion homeostatic steady state, skeletal muscle fibers operate with a low-cost \u201cDonnan-dominated\u201d ion homeostatic steady state that combines a large chloride permeability with an exceptionally small sodium permeability. Simultaneously, this combination keeps fiber excitability low and minimizes pump expenditures. As mechanically active, long-lived multinucleate cells, skeletal muscle fibers have evolved to handle overexertion, sarcolemmal tears, ischemic bouts, etc.; the frugality of their Donnan dominated steady state lets them maintain the outsized pump reserves that make them resilient during these inevitable transient emergencies. Here, P-L\/D model variants challenged with DMD-type insult\/injury (low pump-strength, overstimulation, leaky Nav and cation channels) show how chronic \u201cnonosmotic\u201d sodium overload (observed in DMD patients) develops. Profoundly severe DMD ion homeostatic insult\/injury causes spontaneous firing (and, consequently, unwanted excitation\u2013contraction coupling) that elicits cytotoxic swelling. Therefore, boosting operational pump-strength and\/or diminishing sodium and cation channel leaks should help extend DMD fiber longevity.<\/jats:p>","DOI":"10.1085\/jgp.202112914","type":"journal-article","created":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T02:20:57Z","timestamp":1633054857000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["The Donnan-dominated resting state of skeletal muscle fibers contributes to resilience and longevity in dystrophic fibers"],"prefix":"10.1085","volume":"154","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7401-6545","authenticated-orcid":true,"given":"Catherine E.","family":"Morris","sequence":"first","affiliation":[{"name":"Neuroscience, Ottawa Hospital Research Institute, Ottawa, Canada 1"},{"name":"Center for Neural Dynamics, University of Ottawa, Ottawa, Canada 2"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua J.","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Department of Physics, University of Ottawa, Ottawa, Canada 3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8576-5579","authenticated-orcid":true,"given":"B\u00e9la","family":"Joos","sequence":"additional","affiliation":[{"name":"Center for Neural Dynamics, University of Ottawa, Ottawa, Canada 2"},{"name":"Department of Physics, University of Ottawa, Ottawa, Canada 3"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2021,11,3]]},"reference":[{"key":"2023072706204265400_bib1","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1152\/physrev.00007.2015","article-title":"Absence of dystrophin disrupts skeletal muscle signaling: Roles of Ca2+, reactive oxygen species, and nitric oxide in the development of muscular dystrophy","volume":"96","author":"Allen","year":"2016","journal-title":"Physiol. 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