The sodium/glucose cotransporter 2 inhibitor empagliflozin is a pharmacological chaperone of cardiac Na _v 1.5 channels

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, Na _v 1.5-expressing tsA201 cells, as well as in dystrophic (DMD ^mdx ) rat cardiomyocytes, and was also exerted by two other SGLT2 inhibitors. Immunofluorescence studies suggested that chronic EMPA treatment increases Na _v 1.5 plasma membrane expression. 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 as EMPA. Further, 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 .