A new dystrophin-deficient rat model mirroring exon skipping in patients with DMD exon 45 deletions.

Abstract

Pathogenic variants in the dystrophin (DMD) gene cause muscle-wasting disorders ranging from the milder Becker muscular dystrophy (BMD) to the more severe Duchenne muscular dystrophy (DMD). Exon 45 deletion is the most-frequent single-exon deletion in patients diagnosed with DMD. Here, we generated a novel rat model with an exon 45 deletion using CRISPR/Cas9. The DmdΔ45 rat recapitulate key features of DMD, including progressive skeletal muscle degeneration, impaired muscle and cardiac function, and cognitive deficits. Transcriptomics analyses revealed gene expression patterns consistent with dystrophin deficiency. In skeletal muscle, we observed a transition from early stress responses and regeneration to chronic inflammation, fibrosis and metabolic dysfunction. Cardiac profiles similarly progressed from early inflammatory responses to fibrotic remodelling and metabolic impairment. Notably, DmdΔ45 rats displayed a milder phenotype than other DMD rat models. This attenuation is likely due to spontaneous exon skipping, particularly of exon 44, which partially restores the reading frame and increases revertant dystrophin-positive fibres with age. Downregulation of spliceosome-related genes suggests a potential mechanism for this exon skipping. Overall, this model provides valuable insights into phenotypic variability and therapeutic exon-skipping strategies.