Duchenne muscular dystrophy (DMD) is an X-linked dystrophin-minus muscle-wasting disease. 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 “Pump-Leak–dominated” ion homeostatic steady state, skeletal muscle fibers operate with a low-cost “Donnan-dominated” 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 “nonosmotic” sodium overload (observed in DMD patients) develops. Profoundly severe DMD ion homeostatic insult/injury causes spontaneous firing (and, consequently, unwanted excitation–contraction coupling) that elicits cytotoxic swelling. Therefore, boosting operational pump-strength and/or diminishing sodium and cation channel leaks should help extend DMD fiber longevity.
Skip Nav Destination
Article navigation
3 January 2022
Article|
November 03 2021
The Donnan-dominated resting state of skeletal muscle fibers contributes to resilience and longevity in dystrophic fibers
Catherine E. Morris
,
Catherine E. Morris
1
Neuroscience, Ottawa Hospital Research Institute, Ottawa,
Canada
2
Center for Neural Dynamics, University of Ottawa, Ottawa,
Canada
Search for other works by this author on:
Joshua J. Wheeler,
Joshua J. Wheeler
3
Department of Physics, University of Ottawa, Ottawa,
Canada
Search for other works by this author on:
Béla Joos
2
Center for Neural Dynamics, University of Ottawa, Ottawa,
Canada
3
Department of Physics, University of Ottawa, Ottawa,
Canada
Correspondence to Béla Joos: bjoos@uottawa.ca
Search for other works by this author on:
Catherine E. Morris
1
Neuroscience, Ottawa Hospital Research Institute, Ottawa,
Canada
2
Center for Neural Dynamics, University of Ottawa, Ottawa,
Canada
Joshua J. Wheeler
3
Department of Physics, University of Ottawa, Ottawa,
Canada
Correspondence to Béla Joos: bjoos@uottawa.ca
Received:
March 17 2021
Accepted:
September 30 2021
Online Issn: 1540-7748
Print Issn: 0022-1295
Funding
Funder(s):
Natural Sciences and Engineering Council
- Award Id(s): RGPIN-06835-2018
Funder(s):
Ottawa Hospital Research Institute
© 2021 Morris et al.
2021
This article is distributed under the terms of an
Attribution–Noncommercial–Share Alike–No Mirror Sites
license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is
available under a Creative Commons License
(Attribution–Noncommercial–Share Alike 4.0 International
license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2022) 154 (1): e202112914.
Article history
Received:
March 17 2021
Accepted:
September 30 2021
Citation
Catherine E. Morris, Joshua J. Wheeler, Béla Joos; The Donnan-dominated resting state of skeletal muscle fibers contributes to resilience and longevity in dystrophic fibers. J Gen Physiol 3 January 2022; 154 (1): e202112914. doi: https://doi.org/10.1085/jgp.202112914
Download citation file:
Sign in
Don't already have an account? Register
Client Account
You could not be signed in. Please check your email address / username and password and try again.
Sign in via your Institution
Sign in via your Institution
249
Views
0
Citations
Suggested Content
Effects of HOCl oxidation on excitation–contraction coupling: Implications for the pathophysiology of Duchenne muscular dystrophy: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle
J Gen Physiol (November,2021)
Nav1.4 Deregulation in Dystrophic Skeletal Muscle Leads to Na+ Overload and Enhanced Cell Death
J Gen Physiol (July,2008)
DONNAN EQUILIBRIUM AND THE PHYSICAL PROPERTIES OF PROTEINS : I. MEMBRANE POTENTIALS.
J Gen Physiol (May,1921)
Advertisement