Conditional ablation in the skeletal muscle and brain causes profound effects on muscle function, neurobehavior, and extracellular matrix pathways.

Duchenne muscular dystrophy (DMD) patients suffer from skeletal and cardiopulmonary weakness, and interestingly up to one third are diagnosed on the autism spectrum. Dystrophin is an essential protein for regulating the transmission of intracellular force to the extracellular matrix within the skeletal muscle, but also plays key roles in neurobehavior and cognitive function. The mouse dystrophin gene (also abbreviated ) is X-linked and has several isoforms with tissue-specific expression, including the large muscle transcript found in heart and skeletal muscle, and the transcript that encodes the brain-specific dystrophin cerebellar protein. Understanding the functional requirements and pathways that are affected by dystrophin loss will impact dystrophin replacement gene therapy and exon-skipping correction strategies. We generated conditional knockout mice by targeting exon 52 of the mouse ( ) locus. We generated dystrophin constitutive and inducible myofiber knockout ( mKO) mice to evaluate the tissue-specific function of the large skeletal muscle dystrophin isoform. Constitutive embryonic deletion of the gene exclusively in skeletal myofibers resulted in a severe skeletal muscle myopathy, dystrophic histopathology, and functional deficits compared to the mouse. Transcriptomic analysis of skeletal myofibers of the mKO mice revealed the dysregulation of key extracellular matrix and cytokine signaling pathways. Separately, we generated Purkinje neuron cerebellar dystrophin knockout (:Pcp2 KO) mice that displayed neurobehavioral deficits in social approach, social memory, and spatial navigation and working memory. These studies reveal the essential requirement for dystrophin expression in both the skeletal muscle and brain for normal physiological and neurobehavioral function.