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Unregulated Ca2+ entry is thought to underlie muscular dystrophy. Here, we generated skeletal-muscle-specific transgenic (TG) mice expressing the Na+ -Ca2+ exchanger 1 (NCX1) to model its identified augmentation during muscular dystrophy. The NCX1 transgene induced dystrophy-like disease in all hind-limb musculature, as well as exacerbated the muscle disease phenotypes in δ-sarcoglycan (Sgcd −/− ),Dysf −/− , andmdx mouse models of muscular dystrophy. Antithetically, muscle-specific deletion of theSlc8a1 (NCX1) gene diminished hind-limb pathology inSgcd −/− mice. Measured increases in baseline Na+ and Ca2+ in dystrophic muscle fibers of the hind-limb musculature predicts a net Ca2+ influx state due to reverse-mode operation of NCX1, which mediates disease. However, the opposite effect is observed in the diaphragm, where NCX1 overexpression mildly protects from dystrophic disease through a predicted enhancement in forward-mode NCX1 operation that reduces Ca2+ levels. Indeed,Atp1a2 +/− (encoding Na+ -K+ ATPase α2) mice, which have reduced Na+ clearance rates that would favor NCX1 reverse-mode operation, showed exacerbated disease in the hind limbs of NCX1 TG mice, similar to treatment with the Na+ -K+ ATPase inhibitor digoxin. Treatment ofSgcd −/− mice with ranolazine, a broadly acting Na+ channel inhibitor that should increase NCX1 forward-mode operation, reduced muscular pathology.

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

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