2. Academic Validation
  3. Failure to Resolve Inflammation Contributes to Juvenile-Onset Cardiomyopathy in a Mouse Model of Duchenne Muscular Dystrophy

Failure to Resolve Inflammation Contributes to Juvenile-Onset Cardiomyopathy in a Mouse Model of Duchenne Muscular Dystrophy

  • bioRxiv. 2024 Aug 15:2024.08.15.607998. doi: 10.1101/2024.08.15.607998.
James S Novak 1 2,  Amy Lischin 1 3,  Prech Uapinyoying 1 4,  Ravi Hindupur 1,  Young Jae Moon 1 5,  Surajit Bhattacharya 1,  Sarah Tiufekchiev 1 6,  Victoria Barone 1 3,  Davi A G Mázala 1 7,  Iteoluwakishi H Gamu 1,  Gabriela Walters 1,  Karuna Panchapakesan 1,  Jyoti K Jaiswal 1 2
Affiliations

Affiliations

  • 1 Center for Genetic Medicine Research, Children's National Research Institute, Children's National Research and Innovation Campus, Children's National Hospital, Washington, D.C., 20012, USA.
  • 2 Departments of Pediatrics and Genomics and Precision Medicine, The George Washington University School of Medicine and Health Sciences, Washington, D.C., 20037, USA.
  • 3 Columbian College of Arts and Sciences, The George Washington University, Washington, D.C. 20052, USA.
  • 4 Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • 5 Department of Biochemistry and Orthopaedic Surgery, Jeonbuk National University Medical School and Hospital, Jeonju, 54907, Republic of Korea.
  • 6 Integrated Biomedical Sciences, The George Washington University School of Medicine and Health Sciences, Washington, D.C., 20037, USA.
  • 7 Department of Kinesiology, College of Health Professions, Towson University, Towson, MD, 21252, USA.
PMID: 39185176 DOI: 10.1101/2024.08.15.607998
Abstract

The absence of dystrophin protein causes cardiac dysfunction in boys with Duchenne Muscular Dystrophy (DMD). However, the common mouse model of DMD (B10-mdx) does not manifest cardiac deficits until late adulthood limiting our understanding of the mechanism and therapeutic approaches to target the pediatric-onset cardiac pathology in DMD. We show the mdx mouse model on the DBA/2J genetic background (D2-mdx) displays juvenile-onset cardiomyopathy. Molecular and histological analysis revealed heightened leukocyte chemotactic signaling and failure to resolve inflammation, leading to chronic inflammation and extracellular matrix (ECM) fibrosis, causing cardiac pathology in juvenile D2-mdx mice. We show that pharmacologically activating the N-formyl peptide receptor 2 (FPR2) - a receptor that physiologically resolves acute inflammation, mitigated chronic cardiac inflammation and fibrosis, and prevented juvenile onset cardiomyopathy in the D2-mdx mice. These studies offer insights into pediatric onset of cardiac damage in DMD, a new therapeutic target, and identify a drug-based potential therapy.

Keywords

B10-mdx; D2-mdx; Duchenne muscular dystrophy; calcification; cardiomyopathy; cytokine signaling; extracellular matrix remodeling; fibrosis; inflammation; inflammatory response; macrophage; macrophage migration; pathology.

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