Conditional Dmd ablation in muscle and brain causes profound effects on muscle function and neurobehavior

Abstract

Duchenne muscular dystrophy (DMD) patients suffer from skeletal and cardiopulmonary weakness, and up to one third are diagnosed on the autism spectrum. Dystrophin is an essential protein for regulating intracellular force transmission to the extracellular matrix (ECM) within the skeletal muscle, but also plays key roles in neurobehavior and cognitive function. The mouse Dmd gene is X-linked and has several isoforms with enriched tissue expression in the skeletal muscle, heart, and the brain. Constitutive and inducible deletion of muscle dystrophin resulted in a skeletal muscle myopathy, dystrophic histopathology, and functional deficits compared to the mdx mouse. Transcriptomic analysis of Dmd mKO muscles revealed dysregulation of ECM and cytokine pathways. Purkinje dystrophin knockout (Dmd:Pcp2 KO) mice displayed neurobehavioral deficits in social approach, social memory, and spatial memory. These studies reveal the essential requirement for dystrophin expression in both the skeletal muscle and brain for normal physiological and neurobehavioral function.