Muscle-specific JAG1 overexpression increases skeletal muscle mass in a mouse model of Duchenne Muscular Dystrophy


Pre-Clinical Research

Poster Number: S25


Felipe de Souza Leite, PhD, Boston Children's Hospital / Harvard Medical School, Matthias Lambert, PhD, Boston Children's Hospital, Tracy Zhang, PhD, Boston Children's Hospital - Harvard Medical School, Jeffrey Widrick, PhD, Boston Children's Hospital, James Conner, BS, Boston Children's Hospital, Sheldon Oliveira, BS, Boston Children's Hospital - Harvard Medical School, Holland Bowles, Boston Children's Hospital, Emanuela Gussoni, PhD, Division of Genetics and Genomics, Louis Kunkel, PhD, Boston Children's Hospital

Introduction: The progressive decline of motor function and muscle mass in Duchenne Muscular Dystrophy (DMD) will likely require complementary therapy approaches. Among the described DMD genetic modifiers, Jagged-1 was found in escaper golden retriever muscular dystrophy (GRMD). Our previous study showed that dystrophin-deficient dogs overexpressing JAG1 had an expected lifespan with remarkable motor function. Methods: To clarify the consequences of JAG1 overexpression in dystrophic muscles, we created a transgenic mouse model that lacks dystrophin and expresses human JAG1 driven by MCK-Cre (mdx5cv-JAG1) – granting striated muscle-specific overexpression. Skeletal muscles from mdx5cv-JAG1 and mdx5cv were studied at three timepoints: one, four, and twelve months. Results: (1) Western blots and immunofluorescence analyses confirmed increased expression of JAG1 in mdx5cv-JAG1 skeletal muscles. (2) Hematoxylin and eosin staining showed mild histological improvements. (3) Immunofluorescence for different types of myosin-heavy chains showed a higher number of newly formed fibers by the first month and a steep increase in type IIX and IIB fibers from four to twelve months. Consequently, one-year-old mdx5cv-JAG1 muscles were bigger and had a statistically higher number of fibers per section than mdx5cv. (4) Finally, ex-vivo physiology showed that twelve-months mdx5cv-JAG1’s whole muscles generated higher forces than dystrophic controls. Conclusion: Our observations show that overexpression of JAG1 counterbalances the lack of dystrophin by generating bigger and stronger muscles as the mouse ages.