Conditional Dmd ablation in muscle and brain causes profound effects on muscle function and neurobehavior
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.
Authors
- Miguel A. Gutierrez‐Monreal (ORCID: https://orcid.org/0000-0001-8601-4080)
- Jeffrey J. Widrick (ORCID: https://orcid.org/0000-0002-5597-1141)
- Katherine G. English (ORCID: https://orcid.org/0000-0003-2757-5157)
- Karyn A. Esser (ORCID: https://orcid.org/0000-0002-5791-1441)
- Michael A. Lopez (ORCID: https://orcid.org/0000-0002-3029-0761)
- Jodi R. Paul (ORCID: https://orcid.org/0000-0002-5409-5944)
- Louis M. Kunkel (ORCID: https://orcid.org/0000-0001-6126-0242)
- David K. Crossman (ORCID: https://orcid.org/0000-0002-0981-169X)
- Matthew S. Alexander (ORCID: https://orcid.org/0000-0001-7406-5171)
- Karen L. Gamble (ORCID: https://orcid.org/0000-0003-3813-8577)
- Muthukumar Karuppasamy (ORCID: https://orcid.org/0000-0003-0034-9950)
- Shelby N. Rorrer (ORCID: https://orcid.org/0009-0009-5640-9669)
- James R. Conner (ORCID: https://orcid.org/0000-0002-8886-1475)
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- German Center for Neurodegenerative Diseases (DE)
- Civitan International (US)
- Children's of Alabama (US)
- University of Alabama at Birmingham (US)
- University of Florida (US)
- NeuroDevelopment Center (US)
- Harvard Stem Cell Institute (US)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-12-02
- DOI
- https://doi.org/10.1038/s42003-025-09128-y
- Citations
- 2
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- U.S. Department of Defense
- National Institutes of Health
- Center for Exercise Medicine, University of Alabama at Birmingham
- National Institute on Drug Abuse
- National Institute of Neurological Disorders and Stroke
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- Congressionally Directed Medical Research Programs