Muscle-specific increased expression of <i>JAG1</i> improves the skeletal muscle phenotype in dystrophin-deficient mice

Therapeutic strategies for Duchenne muscular dystrophy (DMD) will likely require complementary approaches. One possibility is to explore genetic modifiers that improve muscle regeneration and function. The beneficial effects of the overexpression of Jagged-1 were described in escaper golden retriever muscular dystrophy (GRMD) dogs that had a near-normal life and validated in dystrophin-deficient zebrafish. To clarify the underlying biology of <i>JAG1</i> overexpression in dystrophic muscles, we generated a transgenic mouse (mdx^5cv-<i>JAG1</i>) model that lacks dystrophin and overexpresses human <i>JAG1</i> in striated muscles. Skeletal muscles from mdx^5cv-<i>JAG1</i> and mdx^5cv mice were studied at 1-, 4-, and 12-mo time points. <i>JAG1</i> expression in mdx^5cv-<i>JAG1</i> increased by 3 to 5 times compared to mdx^5cv. Consequently, mdx^5cv-<i>JAG1</i> muscles were significantly bigger and stronger than dystrophic controls, along with an increased number of myofibers. Proteomics data show increased dysferlin in mdx^5cv-<i>JAG1</i> muscles and an association of the histone methyltransferase Nsd1 with the phenotype. Our data support the positive effect of <i>JAG1</i> overexpression in dystrophic muscles.