Generation and characterization of a mouse model of Becker muscular dystrophy with a deletion of Dmd exons 52 to 55.

Abstract

Becker muscular dystrophy (BMD) is a rare X-linked recessive neuromuscular disorder, frequently caused by in-frame deletions in the DMD gene that result in the production of a truncated, yet functional, dystrophin protein. The consequences of BMD-causing in-frame deletions on the organism are difficult to predict, especially in regard to long-term prognosis. Here, we used CRISPR-Cas9 to generate a new Dmd Δ52-55 mouse model by deleting exons 52-55 in the Dmd gene, resulting in a BMD-like in-frame deletion. To delineate the long-term effects of this deletion, we studied these mice over 52 weeks by performing histology and echocardiography analyses and assessing motor functions. Our results suggest that truncated dystrophin is sufficient to maintain wildtype-like muscle and heart histology and functions in young mice. However, the truncated protein appeared to be insufficient to maintain normal muscle homeostasis and protect against exercise-induced damage at 52 weeks. To further delineate the effects of this exon 52-55 in-frame deletion, we performed RNA sequencing pre- and post-exercise and identified several differentially expressed pathways that reflect the abnormal muscle phenotype observed at 52 weeks in the BMD model.