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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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Nav1.4 colocalizes with α1-syntrophin. High magnification views of C57BL/6J fibers (left) and mdx5cv fibers (right). Coimmunolabeling of Nav1.4 (A) and α1-syntrophin (B) in C57BL/6J fibers and mdx5cv fibers. (C) Merged fluorescence.
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fig7: Nav1.4 colocalizes with α1-syntrophin. High magnification views of C57BL/6J fibers (left) and mdx5cv fibers (right). Coimmunolabeling of Nav1.4 (A) and α1-syntrophin (B) in C57BL/6J fibers and mdx5cv fibers. (C) Merged fluorescence.

Mentions: To investigate the localization of the Nav1.4, we coimmunolabeled it with α1-syntrophin, the main syntrophin expressed in muscle. We observed a reduced expression of this syntrophin in mdx5cv muscle (Fig. 7 B), similar to what was reported by Williams and Bloch (1999b). As expected, Nav1.4 colocalized quite well with α1-syntrophin at the sarcolemma in both types of muscle (Fig. 7 C), repeating a costameric pattern similar to that of Nav1.4 channels, strongly suggesting that syntrophins are an important link between Nav1.4 and dystrophin, whose absence leads to alterations in distribution patterns of both proteins studied here.


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)

Nav1.4 colocalizes with α1-syntrophin. High magnification views of C57BL/6J fibers (left) and mdx5cv fibers (right). Coimmunolabeling of Nav1.4 (A) and α1-syntrophin (B) in C57BL/6J fibers and mdx5cv fibers. (C) Merged fluorescence.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2483333&req=5

fig7: Nav1.4 colocalizes with α1-syntrophin. High magnification views of C57BL/6J fibers (left) and mdx5cv fibers (right). Coimmunolabeling of Nav1.4 (A) and α1-syntrophin (B) in C57BL/6J fibers and mdx5cv fibers. (C) Merged fluorescence.
Mentions: To investigate the localization of the Nav1.4, we coimmunolabeled it with α1-syntrophin, the main syntrophin expressed in muscle. We observed a reduced expression of this syntrophin in mdx5cv muscle (Fig. 7 B), similar to what was reported by Williams and Bloch (1999b). As expected, Nav1.4 colocalized quite well with α1-syntrophin at the sarcolemma in both types of muscle (Fig. 7 C), repeating a costameric pattern similar to that of Nav1.4 channels, strongly suggesting that syntrophins are an important link between Nav1.4 and dystrophin, whose absence leads to alterations in distribution patterns of both proteins studied here.

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