Muscle-specific increased expression of JAG1 improves skeletal muscle phenotype in dystrophin-deficient mice.

de Souza Leite, F.; Lambert, M. R.; Zhang, T. Y.; Conner, J. R.; Paulo, J. A.; Oliveira, S. F.; Thakurta, S.; Bowles, J.; Gussoni, E.; Gygi, S. P.; Widrick, J. J.; Kunkel, L. M.

doi:10.1101/2025.03.12.642857

bioRxiv · 10.1101/2025.03.12.642857

Muscle-specific increased expression of JAG1 improves skeletal muscle phenotype in dystrophin-deficient mice.

de Souza Leite, F.·Lambert, M. R.·Zhang, T. Y.·Conner, J. R.·Paulo, J. A.·Oliveira, S. F.·Thakurta, S.·Bowles, J.·Gussoni, E.·Gygi, S. P.·Widrick, J. J.·Kunkel, L. M.

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Abstract

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 (1). To clarify the underlying biology of JAG1 overexpression in dystrophic muscles, we generated a transgenic mouse (mdx5cv-JAG1) model that lacks dystrophin and overexpresses human JAG1 in striated muscles. Skeletal muscles from mdx5cv-JAG1 and mdx5cv mice were studied at one, four, and twelve-month time points. JAG1 expression in mdx5cv-JAG1 increased by three to five times compared to mdx5cv. Consequently, mdx5cv-JAG1 muscles were significantly bigger and stronger than dystrophic controls, along with an increased number of myofibers. Proteomics data show increased dysferlin in mdx5cv-JAG1 muscles and an association of Nsd1 with the phenotype. Our data supports the positive effect of JAG1 overexpression in dystrophic muscles. Significance StatementDuchenne Muscular Dystrophy (DMD) patients present a progressive decline in motor function. DMD is caused by mutations in the DMD gene that lead to the absence of dystrophin - an essential component of muscle cells. However, dystrophin-deficient dogs overexpressing JAG1 had a normal lifespan with remarkable motor function. In this study, we increased expression of human JAG1 in mouse skeletal muscles lacking dystrophin to explore mechanisms responsible for these benefits. Our observations show that overexpression of JAG1 counterbalances the lack of dystrophin by generating bigger and stronger muscles as the mouse ages. Moreover, our proteomics dataset suggests a role of dysferlin in the phenotype. Therefore, our study supports the exploration of JAG1 in pre-clinical models.

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de Souza Leite, F., Lambert, M. R., Zhang, T. Y., Conner, J. R., Paulo, J. A., Oliveira, S. F., Thakurta, S., Bowles, J., Gussoni, E., Gygi, S. P., Widrick, J. J., Kunkel, L. M.. 2025-03-14. Muscle-specific increased expression of JAG1 improves skeletal muscle phenotype in dystrophin-deficient mice.. https://doi.org/10.1101/2025.03.12.642857

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