JAG1 overexpression partially rescues muscle function in a zebrafish model of duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration and loss of function due to the absence of dystrophin. In this study, we utilized a zebrafish model with a dmd gene knockout to explore the therapeutic potential of JAG1 overexpression in mitigating DMD-associated muscle dysfunction. Dystrophic zebrafish larvae displayed significant impairments in muscle function, evidenced by reduced swimming abilities, decreased birefringence, and disrupted β-dystroglycan localization, indicative of structural degeneration. Overexpression of JAG1, achieved via plasmid injection, partially restored muscle function, as reflected by improvements in stride length and total swimming distance. However, the structural integrity of slow oxidative muscle fibers remained largely unaffected, with a functional decline from 4 to 8 days post-fertilization (dpf) being more indicative of disease progression than structural changes. These findings suggest that the rescue effect of JAG1 overexpression may not be due to the preservation of slow oxidative fibers but rather through a mechanism that reduces susceptibility to contraction-induced injury. Notably, our study faced limitations related to the control of JAG1 expression levels and tissue specificity. Our results highlight the complexity of DMD pathology, where muscle structure and function do not always correlate, emphasizing the need for refined functional assays to better assess therapeutic outcomes. By incorporating functional recovery assessments at 8-10 dpf, zebrafish models can serve as more predictive preclinical tools, potentially enhancing the translational relevance of findings and reducing risks for patients in clinical trials. This study investigates how increasing the levels of a protein called JAG1 can help improve muscle function in a zebrafish model of DMD. By showing partial recovery of muscle activity, the findings suggest new therapeutic strategies that could potentially slow disease progression and improve patient outcomes.