A scalable, clinically severe pig model for Duchenne muscular dystrophy

Large animal models for Duchenne muscular dystrophy (DMD) are crucial for preclinical evaluation of novel diagnostic procedures and treatment strategies. Pigs cloned from male cells lacking DMD exon 52 ( DMD Δ52) resemble molecular, clinical and pathological hallmarks of DMD, but cannot be propagated by breeding due to death before sexual maturity. Therefore, female DMD +/- carriers were generated. A single founder animal had 11 litters with 29 DMD Y/-, 34 DMD +/- as well as 36 male and 29 female wild-type (WT) offspring. Breeding with F1 and F2 DMD +/- carriers resulted in additional 114 DMD Y/- piglets. The majority of them survived for 3-4 months, providing large cohorts for experimental studies. Pathological investigations and proteome studies of skeletal muscles and myocardium confirmed the resemblance of human disease mechanisms. Importantly, DMD Y/- pigs reveal progressive fibrosis of myocardium and increased expression of connexin-43, associated with significantly reduced left ventricular fractional shortening and ejection fraction already at age 3 months. Furthermore, behavioral tests provided evidence for impaired cognitive ability of DMD Y/- pigs. Our breeding cohort of DMD Δ52 pigs and standardized tissue repositories from DMD Y/- pigs, DMD +/- carriers, and WT littermate controls provide important resources for studying DMD disease mechanisms and for testing novel diagnostic procedures and treatment strategies. ### Competing Interest Statement The authors have declared no competing interest.