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Nav1.4 deregulation in dystrophic skeletal muscle leads to Na+ overload and enhanced cell death.

Hirn C, Shapovalov G, Petermann O, Roulet E, Ruegg UT - J. Gen. Physiol. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory 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.

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Distribution pattern of Nav1.4 is altered in mdx fibers. Nav1.4 channel distribution in isolated FDB fibers; comparison between C57BL/6J and mdx5cv (four mice each condition). Nav1.4 immunofluorescence (green) in single C57BL/6J fibers (left) and mdx5cv fibers (right) captured at the surface (A) or in deeper part of the cells (B). (C) 4× zoom of A.
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fig6: Distribution pattern of Nav1.4 is altered in mdx fibers. Nav1.4 channel distribution in isolated FDB fibers; comparison between C57BL/6J and mdx5cv (four mice each condition). Nav1.4 immunofluorescence (green) in single C57BL/6J fibers (left) and mdx5cv fibers (right) captured at the surface (A) or in deeper part of the cells (B). (C) 4× zoom of A.

Mentions: Confocal images captured at the surface of the cells revealed an intense signal at the muscle endplate, as assessed by fluorescently labeled α-bungarotoxin (not depicted), and on the surface of the fiber, dispersed over the area of the fiber (Fig. 6 A). By contrast, in the confocal planes crossing the cells, labeling was localized to the sarcolemma, with only a background level of fluorescence in the cytoplasm (Fig. 6 B). No fluorescence was detected when primary antibodies were omitted (not depicted).


Nav1.4 deregulation in dystrophic skeletal muscle leads to Na+ overload and enhanced cell death.

Hirn C, Shapovalov G, Petermann O, Roulet E, Ruegg UT - J. Gen. Physiol. (2008)

Distribution pattern of Nav1.4 is altered in mdx fibers. Nav1.4 channel distribution in isolated FDB fibers; comparison between C57BL/6J and mdx5cv (four mice each condition). Nav1.4 immunofluorescence (green) in single C57BL/6J fibers (left) and mdx5cv fibers (right) captured at the surface (A) or in deeper part of the cells (B). (C) 4× zoom of A.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2483333&req=5

fig6: Distribution pattern of Nav1.4 is altered in mdx fibers. Nav1.4 channel distribution in isolated FDB fibers; comparison between C57BL/6J and mdx5cv (four mice each condition). Nav1.4 immunofluorescence (green) in single C57BL/6J fibers (left) and mdx5cv fibers (right) captured at the surface (A) or in deeper part of the cells (B). (C) 4× zoom of A.
Mentions: Confocal images captured at the surface of the cells revealed an intense signal at the muscle endplate, as assessed by fluorescently labeled α-bungarotoxin (not depicted), and on the surface of the fiber, dispersed over the area of the fiber (Fig. 6 A). By contrast, in the confocal planes crossing the cells, labeling was localized to the sarcolemma, with only a background level of fluorescence in the cytoplasm (Fig. 6 B). No fluorescence was detected when primary antibodies were omitted (not depicted).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory 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.

Show MeSH
Related in: MedlinePlus