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

Year: 2025

Type: article

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. Generation and characterization of a conditional dystrophin (Dmd) knockout mouse reveals myofiber-specific requirements for muscle homeostasis, and an essential role for Purkinje neuron Dmd in neurobehavior and learning function.

Source: Communications Biology

DOI: 10.1038/s42003-025-09128-y

Authors: Muthukumar Karuppasamy, Katherine G. English, James R. Conner, Shelby N. Rorrer, Michael A. Lopez, David K. Crossman, Jodi R. Paul, Miguel A. Gutierrez-Monreal, Karen L. Gamble, Karyn A. Esser, Jeffrey J. Widrick, Louis M. Kunkel, Matthew S. Alexander

Institutions: Children's of Alabama, University of Alabama at Birmingham, Boston Children's Hospital, University of Florida, Harvard University, Harvard Stem Cell Institute, Manton Center for Orphan Disease Research, Civitan International, UAB Medicine

Language: English

Topic: Muscle Physiology and Disorders

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,190

Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, National Institutes of Health, Center for Exercise Medicine, University of Alabama at Birmingham, National Institute on Aging, National Institute on Drug Abuse, NIH Office of the Director, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Congressionally Directed Medical Research Programs, Bernard F. and Alva B. Gimbel Foundation

OpenAlex ID: W4416910033