Abstract
Diminished peak sodium current (I(Na)) is a causative factor for slowed ventricular conduction and cardiac arrhythmias in patients with Duchenne muscular dystrophy (DMD), a devastating muscle disease triggered by dystrophin deficiency. Recently, we showed that chronic administration of the sodium/glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) restores diminished peak I(Na) in ventricular cardiomyocytes from the dystrophin-deficient mdx mouse model of DMD. Here, we aimed to elucidate the underlying mechanism. Whole cell patch clamp studies revealed that 24-h incubation of dystrophic (mdx) ventricular cardiomyocytes with EMPA significantly increases peak I(Na) in a concentration-dependent manner (EC(50) = 94 nM). The enhancing effect on peak I(Na) also occurred in dystrophic cardiac Purkinje fibers, as well as in dystrophic (DMD(mdx)) rat cardiomyocytes, and was also exerted by other SGLT2 inhibitors. Immunofluorescence studies suggested that chronic EMPA treatment fully restores wild-type Na(v)1.5 plasma membrane expression in mdx cardiomyocytes. Peak I(Na) enhancement by EMPA depended on functional anterograde trafficking of Na(v)1.5. The local anesthetic mexiletine, a well-known pharmacological chaperone of Na(v)1.5, enhanced peak I(Na) in a similar manner to EMPA. Furthermore, mutation of human Na(v)1.5 at a site important for local anesthetic binding (Y1767A) completely abolished the ability of both EMPA and mexiletine to enhance peak I(Na). Finally, the importance of Y1767 for drug-induced modulation of peak I(Na) was confirmed by molecular docking simulations. Our findings suggest that EMPA acts as a pharmacological chaperone of Na(v)1.5 channels. Its chronic administration may reduce arrhythmia vulnerability in patients with DMD and other arrhythmogenic pathologies associated with diminished peak I(Na).NEW & NOTEWORTHY Dystrophin deficiency in cardiomyocytes leads to diminished peak Na currents. These can be fully rescued by long-term treatment with empagliflozin via pharmacochaperoning of Na(v)1.5 channels.