Nav1.4 Deregulation in Dystrophic Skeletal Muscle Leads to Na+ Overload and Enhanced Cell Death

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 Ca²⁺ 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_v1.4, 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_v1.4, leading to an increased Na⁺ concentration under the sarcolemma. Moreover, the distribution of Na_v1.4 is altered in mdx muscle while maintaining the colocalization with one of the dystrophin-associated proteins, syntrophin α-1, thus suggesting that syntrophin is an important linker between dystrophin and Na_v1.4. Additionally, we show that these modifications of Na_v1.4 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_v1.4 blocker.