Background: Duchenne muscular dystrophy (DMD) is a devastating X-linked disease that causes progressive muscle degeneration and early cardiopulmonary failure. Despite several existing DMD mouse models, none allow precise and comprehensive regulation over when and where dystrophin is expressed. To address this, we developed a conditional dystrophin knockout (Dmdflox52/Y; HSA mKO) that selectively deletes exon 52 in skeletal muscle, allowing us to dissect dystrophin’s role in muscle maintenance and regeneration. We also generated a Purkinje neuron–specific knockout (Dmd: Pcp2 KO) to explore dystrophin’s contribution to neurobehavior.
Hypothesis: We proposed that dystrophin plays distinct and essential roles in maintaining muscle integrity and promoting regeneration, and that brain dystrophin independently supports normal cognitive and behavioral function.
Methods: Using TREAT-NMD and ASD mouse phenotyping protocols, we performed comprehensive histopathologic, functional, and behavioral testing in both conditional knockout lines.
Results: Muscle-specific Dmd mKO mice showed striking reductions in locomotor activity, grip strength, and eccentric muscle force. Histology revealed increased centralized myonuclei and fibrosis, closely mirroring mdx pathology. These mice also had elevated muscle satellite cell pools but impaired muscle regeneration after injury. Transcriptomic profiling confirmed broad dysregulation in extracellular matrix, cytokine, and regenerative signaling pathways. In parallel, Dmd: Pcp2 KO mice exhibited clear social and learning deficits, underscoring a key role for neuronal dystrophin in normal brain function.
Conclusions: Our conditional Dmd models uncover how dystrophin loss drives both muscle degeneration and neurobehavioral dysfunction in a tissue-specific manner. The Dmd mKO model faithfully recapitulates DMD pathology and provides a powerful platform to study disease mechanisms and test next-generation gene replacement or exon-skipping therapies.