Failure to Resolve Inflammation Contributes to Juvenile-Onset Cardiomyopathy in a Mouse Model of Duchenne Muscular Dystrophy
Authors
James S. Novak, 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.
Amy Lischin, 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.
Prech Uapinyoying, 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.
Ravi Hindupur, 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.
Young Jae Moon, 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.
Surajit Bhattacharya, 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.
Sarah Tiufekchiev, 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.
Victoria Barone, 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.
Davi A. Mázala, 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.
Iteoluwakishi H. Gamu, 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.
Gabriela Walters, 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.
Karuna Panchapakesan, 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.
Jyoti K. Jaiswal, 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.
Document Type
Journal Article
Publication Date
8-15-2024
Journal
bioRxiv : the preprint server for biology
DOI
10.1101/2024.08.15.607998
Keywords
B10-mdx; D2-mdx; Duchenne muscular dystrophy; calcification; cardiomyopathy; cytokine signaling; extracellular matrix remodeling; fibrosis; inflammation; inflammatory response; macrophage; macrophage migration; pathology
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.
APA Citation
Novak, James S.; Lischin, Amy; Uapinyoying, Prech; Hindupur, Ravi; Jae Moon, Young; Bhattacharya, Surajit; Tiufekchiev, Sarah; Barone, Victoria; Mázala, Davi A.; Gamu, Iteoluwakishi H.; Walters, Gabriela; Panchapakesan, Karuna; and Jaiswal, Jyoti K., "Failure to Resolve Inflammation Contributes to Juvenile-Onset Cardiomyopathy in a Mouse Model of Duchenne Muscular Dystrophy" (2024). GW Authored Works. Paper 5476.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/5476
Department
Genomics and Precision Medicine
