Histological, functional, and behavioral comparison of three Duchenne muscular dystrophy mouse models

Mouse models carrying specific subsets of mutations are particularly suitable for personalized medicine research. Nonetheless, mouse models do not completely mimic the human phenotype. This is the case for different Duchenne muscular dystrophy (DMD) mouse models, in which several aspects like muscle force, histopathology, cognition, and behavior can vary considerably, confounding the interpretation of therapy outcomes in preclinical studies. Two main common mutations in the DMD gene are exon 2 duplication and exon 45 deletion (1% and 4% of DMD patients respectively). Two mouse models carrying these mutations have been previously developed, named Dup2 and hDMDdel45, respectively. However, detailed studies on the locomotor, functional, behavioral, and histopathological aspects are lacking and would be beneficial for studies assessing treatment outcomes. This study also compares those features to the first mouse model identified for DMD, the mdx. We assessed histopathological features (fibrosis, inflammation, and centronucleation), isometric and isotonic (eccentric contraction) muscle force generation, locomotion (hang-wire and rotarod tests), and behavioral (open-field test) features in those mice. Our studies show that Dup2 and hDMDdel45 mice present significant deficits in function and behavior. Diaphragm and skeletal muscles have elevated levels of inflammation and fibrosis in comparison to wild-type controls. This study demonstrated that Dup2 and hDMDdel45 mice have the same degree of pathology as the classical DMD mouse model, the mdx.