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

ABSTRACTThe 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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The Donnan-dominated resting state of skeletal muscle fibers contributes to resilience and longevity in dystrophic fibers

The Journal of General Physiology ◽

10.1085/jgp.202112914 ◽

2021 ◽

Vol 154 (1) ◽

Author(s):

Catherine E. Morris ◽

Joshua J. Wheeler ◽

Béla Joos

Keyword(s):

Skeletal Muscle ◽

Steady State ◽

Low Cost ◽

Muscle Fibers ◽

Ion Homeostasis ◽

Chloride Permeability ◽

Sodium Permeability ◽

Homeostatic Process ◽

Skeletal Muscle Fibers ◽

Muscle Wasting Disease

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.

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Special Issue: Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System

Biomedicines ◽

10.3390/biomedicines9121911 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1911

Author(s):

Andrea Farini

Keyword(s):

Immune System ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Wasting ◽

Special Issue ◽

Wasting Disease ◽

Muscle Wasting Disease

Duchenne muscular dystrophy (DMD) is the most common, lethal, muscle-wasting disease of childhood [...]

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From diagnosis to therapy in Duchenne muscular dystrophy

Biochemical Society Transactions ◽

10.1042/bst20190282 ◽

2020 ◽

Vol 48 (3) ◽

pp. 813-821 ◽

Cited By ~ 3

Author(s):

Arran Babbs ◽

Maria Chatzopoulou ◽

Ben Edwards ◽

Sarah E. Squire ◽

Isabel V.L. Wilkinson ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Wasting ◽

Exon Skipping ◽

Short Review ◽

Current Status ◽

Muscle Membrane ◽

Therapeutic Approaches ◽

Wasting Disease ◽

Muscle Wasting Disease

Genetic approaches for the diagnosis and treatment of inherited muscle diseases have advanced rapidly in recent years. Many of the advances have occurred in the treatment of Duchenne muscular dystrophy (DMD), a muscle wasting disease where affected boys are typically wheelchair bound by age 12 years and generally die in their twenties from respiratory failure or cardiomyopathy. Dystrophin is a 421 kD protein which links F-actin to the extracellular matrix via the dystrophin-associated protein complex (DAPC) at the muscle membrane. In the absence of dystrophin, the DAPC is lost, making the muscle membrane more susceptible to contraction-induced injury. The identification of the gene causing DMD in 1986 resulted in improved diagnosis of the disease and the identification of hotspots for mutation. There is currently no effective treatment. However, there are several promising genetic therapeutic approaches at the preclinical stage or in clinical trials including read-through of stop codons, exon skipping, delivery of dystrophin minigenes and the modulation of expression of the dystrophin related protein, utrophin. In spite of significant progress, the problem of targeting all muscles, including diaphragm and heart at sufficiently high levels, remains a challenge. Any therapy also needs to consider the immune response and some treatments are mutation specific and therefore limited to a subgroup of patients. This short review provides a summary of the current status of DMD therapy with a particular focus on those genetic strategies that have been taken to the clinic.

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Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

Frontiers in Physiology ◽

10.3389/fphys.2021.647010 ◽

2021 ◽

Vol 12 ◽

Author(s):

Satvik Mareedu ◽

Emily D. Million ◽

Dongsheng Duan ◽

Gopal J. Babu

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Therapeutic Strategy ◽

Muscle Wasting ◽

Premature Death ◽

Calcium Handling ◽

Muscle Degeneration ◽

Wasting Disease ◽

Fatty Replacement ◽

Muscle Wasting Disease

Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by the loss of dystrophin. DMD is associated with muscle degeneration, necrosis, inflammation, fatty replacement, and fibrosis, resulting in muscle weakness, respiratory and cardiac failure, and premature death. There is no curative treatment. Investigations on disease-causing mechanisms offer an opportunity to identify new therapeutic targets to treat DMD. An abnormal elevation of the intracellular calcium (Cai2+) concentration in the dystrophin-deficient muscle is a major secondary event, which contributes to disease progression in DMD. Emerging studies have suggested that targeting Ca2+-handling proteins and/or mechanisms could be a promising therapeutic strategy for DMD. Here, we provide an updated overview of the mechanistic roles the sarcolemma, sarcoplasmic/endoplasmic reticulum, and mitochondria play in the abnormal and sustained elevation of Cai2+ levels and their involvement in DMD pathogenesis. We also discuss current approaches aimed at restoring Ca2+ homeostasis as potential therapies for DMD.

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The Pump-Leak/Donnan ion homeostasis strategies of skeletal muscle fibers and neurons

10.1101/2020.11.20.391813 ◽

2020 ◽

Author(s):

Béla Joos ◽

Catherine E Morris

Keyword(s):

Skeletal Muscle ◽

Neuron Model ◽

Low Cost ◽

Muscle Fibers ◽

Ion Homeostasis ◽

Realistic Model ◽

Excitable Cells ◽

Chloride Permeability ◽

High Duty Cycle ◽

Skeletal Muscle Fibers

ABSTRACTSkeletal muscle fibers (SMFs) and neurons are low and high duty-cycle excitable cells constituting exceptionally large and extraordinarily small fractions of vertebrate bodies. The immense ClC-1-based chloride-permeability (PCl) of SMFs has thwarted understanding of their Pump-Leak/Donnan (P-L/D) ion homeostasis. After formally defining P-L/D set-points and feedbacks, we therefore devise a simple yet demonstrably realistic model for SMFs. Hyper-stimulated, it approximates rodent fibers’ ouabain-sensitive ATP-consumption. Size-matched neuron-model/SMF-model comparisons reveal steady-states occupying two ends of an energetics/resilience P-L/D continuum. Excitable neurons’ costly vulnerable process is Pump-Leak dominated. Electrically-reluctant SMFs’ robust low-cost process is Donnan dominated: collaboratively, Donnan effectors and [big PCl] stabilize Vrest, while SMFs’ exquisitely small PNa minimizes ATP-consumption, thus maximizing resilience. “Classic” excitable cell homeostasis ([small PCl][big INaleak]), de rigueur for electrically-agile neurons, is untenable for vertebrates’ (including humans’) major tissue. Vertebrate bodies evolved thanks to syncytially-efficient SMFs using a Donnan dominated ([big PCl][small INaleak]) ion homeostatic strategy.

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Ayurvedic management of Ducchen’s Muscular Dystrophy - A Case report

Journal of Ayurveda and Integrated Medical Sciences (JAIMS) ◽

10.21760/jaims.v2i4.9376 ◽

2017 ◽

Vol 2 (4) ◽

Author(s):

Jayaraj R. ◽

Veena G. Rao ◽

Jyothi Nagalikar

Keyword(s):

Muscular Dystrophy ◽

Cardiac Dysfunction ◽

Muscle Wasting ◽

Progressive Disease ◽

Genetic Disorder ◽

Dystrophin Gene ◽

Wasting Disease ◽

Number Of Patients ◽

Choice Of Treatment ◽

Muscle Wasting Disease

Ducchen’s muscular dystrophy is most common X-linked recessive disorder affecting 30 in 100,000 live male births. The primary cause of this disease is mutations in Dystrophin gene which is essential for the structural and functional integrity of muscle. It is a progressive muscle wasting disease in which patients frequently develop contractures and lose the ability to walk between 6 and 12 years of age. With progressive disease most patients succumb to death from respiratory failure and cardiac dysfunction in their twenties. As this is a genetic disorder we can consider it as Adibala Pravritta Vyadhi. As Mamsa Kshaya is seen at some muscles and Mamsa Vriddhi at other this is an Avarana Vata Vyadhi. In both Upsthambha and Nirupasthmbha Vatavyadhi, Basthi is considered as prime choice of treatment. A Variety of Ksheerabasti in the form of Kalabasti is studied in this condition by taking subjective and objective parameters. As this has given better improvement with no adverse effects in the patient, it can be tried in large number of patients.

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Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

JRSM Cardiovascular Disease ◽

10.1177/2048004019879581 ◽

2019 ◽

Vol 8 ◽

pp. 204800401987958

Author(s):

HR Spaulding ◽

C Ballmann ◽

JC Quindry ◽

MB Hudson ◽

JT Selsby

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Gene Mutations ◽

Dystrophin Gene ◽

Mdx Mice ◽

Dystrophin Deficiency ◽

Muscle Wasting Disease ◽

Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

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