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, Nav1.4, 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 Nav1.4, leading to an increased Na+ concentration under the sarcolemma. Moreover, the distribution of Nav1.4 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 Nav1.4. Additionally, we show that these modifications of Nav1.4 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 Nav1.4 blocker.

Na+ Dysregulation Coupled with Ca2+ Entry through NCX1 Promotes Muscular Dystrophy in Mice

“…Moreover, blocking this known increase in the activity of TRP channels with either a dnTRPC or a dnTRPV construct abrogated MD in mouse models of disease, suggesting that unregulated or greater activation of the TRP class of cation channels is a primary disease determinant. These channels also permeate Na ϩ , which would enhance Ca 2ϩ entry through NCX1 by favoring reverse-mode activity (7,(17)(18)(19)(20). Finally, we also previously showed that overexpression of SERCA1 in skeletal muscle, which produces higher rates of Ca 2ϩ clearance back into the SR, was protective against MD in the mouse (16).…”

“…Importantly, cytosolic Na ϩ levels appear to be elevated in myofibers from the mdx mouse, a model of Duchenne MD (7,(17)(18)(19)(20). Indeed, recent evidence suggests that intracellular Na ϩ levels are also elevated in Duchenne MD patients (21,22).…”

Airway Surface Liquid Volume Regulation Determines Different Airway Phenotypes in Liddle Compared with βENaC-overexpressing Mice

“…Interestingly, a link between Na ϩ channel dysregulation and cell death was also established in an animal model for Duchenne muscular dystrophy. In mdx mice, the absence of dystrophin causes dysregulation of the skeletal muscle isoforms of the voltage-gated Na ϩ channel Na v 1.4, producing intracellular Na ϩ overload and cell death, which were both prevented by a specific Na v 1.4 blocker (62). Taken together, these data indicate that degeneration and cell death were a direct consequence of dysregulated airway Na ϩ absorption in ␤ENaC-Tg mice.…”

Age-dependent changes in diastolic Ca2+ and Na+ concentrations in dystrophic cardiomyopathy: Role of Ca2+ entry and IP3

“…These dysfunctional ion concentrations are considered the hallmark of the muscle pathology and a triggering agent for muscle destruction [2]. Excessive elevation of intracellular Ca 2+ and Na + , a status known as Ca 2+ and Na + overload respectively, have been shown to be deleterious to skeletal and cardiac cells, and associated with either necrotic or apoptotic cell death [14,15]. In addition, in heart this abnormal handling of intracellular Ca 2+ and Na + may induce severe arrhythmias and ventricular fibrillation [16].…”