Nav1.4 Deregulation in Dystrophic Skeletal Muscle Leads to Na+ Overload and Enhanced Cell Death
| Autor: | Emmanuelle Roulet, Olivier Petermann, Urs T. Ruegg, Carole Hirn, George Shapovalov |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Male
musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty mdx mouse Cell Survival Physiology Duchenne muscular dystrophy Muscle Fibers Skeletal Muscle Proteins Tetrodotoxin Article Sodium Channels Dystrophin Mice 03 medical and health sciences Sarcolemma 0302 clinical medicine Internal medicine medicine Animals NAV1.4 Voltage-Gated Sodium Channel Muscle Skeletal 030304 developmental biology Syntrophin 0303 health sciences Cell Death biology Sodium Cardiac muscle Skeletal muscle Articles musculoskeletal system medicine.disease Mice Inbred C57BL medicine.anatomical_structure Endocrinology Gene Expression Regulation Mice Inbred mdx biology.protein ITGA7 Ion Channel Gating 030217 neurology & neurosurgery |
| Zdroj: | The Journal of General Physiology |
| ISSN: | 1540-7748 0022-1295 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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