Cardiac and Skeletal Muscle Pathology in the D2/mdx Mouse Model and Caveats Associated with the Quantification of Utrophin.

Abstract

Duchenne muscular dystrophy (DMD) (the most common form of muscular dystrophy) is caused by a lack of dystrophin protein. Currently, although many therapeutic strategies are under investigation, there is no cure for DMD and unfortunately, patients succumb to respiratory and/or cardiac failure in their second or third decade of life. Preclinical work has focused on the mouse model C57BL/10ScSn-Dmdmdx/J (BL10/mdx), which does not exhibit a robust pathophenotype. More recently, the D2.B10-Dmdmdx/J (D2/mdx) mouse has been utilized, which presents a more severe pathology and therefore more closely mimics the human pathophenotype, particularly in the heart. Here, we outline important considerations when utilizing the D2/mdx model by highlighting the differences between these models in addition to describing histological and immunohistochemical methods utilized in Kennedy et al. (Mol Ther Methods Clin Dev 11:92-105, 2018) for both cardiac and skeletal muscle, which can quantify these differences. These considerations are particularly important when investigating treatment strategies that may be affected by regeneration; such is the case for upregulation of the dystrophin paralogue, utrophin.