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Nav1.4 deregulation in dystrophic skeletal muscle leads to Na+ overload and enhanced cell death
Carole Hirn1, George Shapovalov, Olivier Petermann
1Laboratory of Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences, University of Geneva, CH 1211 Geneva 4, Switzerland.
Abstract:
Duchenne muscular dystrophy (DMD) is a hereditary degenerative disease manifested by the absence of dystrophin, a structural, cytoskeletal protein, leading to muscle degeneration and early death through respiratory and cardiac muscle failure. Whereas the rise of cytosolic Ca(2+) concentrations in muscles of mdx mouse, an animal model of DMD, has been extensively documented, little is known about the mechanisms causing alterations in Na(+) concentrations. Here we show that the skeletal muscle isoform of the voltage-gated sodium channel, Na(v)1.4, which represents over 90% of voltage-gated sodium channels in muscle, plays an important role in development of abnormally high Na(+) concentrations found in muscle from mdx mice. The absence of dystrophin modifies the expression level and gating properties of Na(v)1.4, leading to an increased Na(+) concentration under the sarcolemma. Moreover, the distribution of Na(v)1.4 is altered in mdx muscle while maintaining the colocalization with one of the dystrophin-associated proteins, syntrophin alpha-1, thus suggesting that syntrophin is an important linker between dystrophin and Na(v)1.4. Additionally, we show that these modifications of Na(v)1.4 gating properties and increased Na(+) concentrations are strongly correlated with increased cell death in mdx fibers and that both cell death and Na(+) overload can be reversed by 3 nM tetrodotoxin, a specific Na(v)1.4 blocker.
Insights
Duchenne muscular dystrophy (DMD) is linked to altered sodium channel Na(v)1.4 function, causing sodium overload and cell death in muscles. Blocking this channel with tetrodotoxin reversed these effects in mdx mice.
Area of Science:
- Muscle physiology
- Molecular biology
- Genetics
Background:
- Duchenne muscular dystrophy (DMD) is a fatal genetic disorder characterized by progressive muscle degeneration due to dystrophin deficiency.
- While calcium (Ca2+) dysregulation in DMD is known, the mechanisms behind sodium (Na+) alterations remain unclear.
- The mdx mouse is a widely used animal model for studying DMD.
Purpose of the Study:
- To investigate the role of the voltage-gated sodium channel Na(v)1.4 in the abnormal Na+ accumulation observed in Duchenne muscular dystrophy.
- To elucidate the relationship between dystrophin absence, Na(v)1.4 function, and muscle cell death in the mdx mouse model.
Main Methods:
- Utilized the mdx mouse model of Duchenne muscular dystrophy.
- Examined expression levels, gating properties, and distribution of the Na(v)1.4 channel in skeletal muscle.
- Assessed the impact of Na(v)1.4 alterations on Na+ concentration and muscle cell viability.
- Investigated the effect of tetrodotoxin (TTX), a Na(v)1.4 blocker, on mdx muscle fibers.
Main Results:
- Absence of dystrophin in mdx mice alters Na(v)1.4 expression and gating, leading to increased Na+ concentration beneath the sarcolemma.
- Na(v)1.4 distribution is modified in mdx muscle, maintaining colocalization with syntrophin alpha-1, suggesting a link between dystrophin and Na(v)1.4 via syntrophin.
- Increased Na+ overload and Na(v)1.4 modifications strongly correlate with heightened cell death in mdx muscle fibers.
- Treatment with low-dose tetrodotoxin (3 nM) reversed both Na+ overload and cell death in mdx fibers.
Conclusions:
- The skeletal muscle sodium channel Na(v)1.4 plays a critical role in the pathophysiology of Duchenne muscular dystrophy.
- Dystrophin deficiency impacts Na(v)1.4 function and localization, contributing to muscle degeneration.
- Targeting Na(v)1.4 with blockers like tetrodotoxin shows therapeutic potential for Duchenne muscular dystrophy.
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