Adiponectin-receptor agonism prevents right ventricular tissue pathology in a mouse model of Duchenne muscular dystrophy

Adiponectin-receptor agonism prevents right ventricular tissue pathology in a mouse model of Duchenne muscular dystrophy

Objective: Cardiac fibrosis during Duchenne muscular dystrophy (DMD) arises from cellular damage and inflammation and is associated with metabolic dysfunction. The extent to which these relationships develop across all 4 cardiac chambers, particularly during early-stage disease, remains unknown. Met...

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Main Authors: Shivam Gandhi, Luca J. Delfinis, Parashar D. Bhatt, Madison C. Garibotti, Catherine A. Bellissimo, Amireza N. Goli, Brooke A. Morris, Aditya N. Brahmbhatt, Simona Yakobov-Shimonov, Fasih A. Rahman, Joe Quadrilatero, Jeremy A. Simpson, Gary Sweeney, Ali A. Abdul-Sater, Peter H. Backx, Henry H. Hsu, Christopher G.R. Perry
Format: Article
Language:English
Published: Elsevier 2025-09-01
Series:Molecular Metabolism
Subjects:
Cardiomyopathy
Inflammation
Mitochondria
Duchenne muscular dystrophy
Fibrosis
Online Access:http://www.sciencedirect.com/science/article/pii/S2212877825000869
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Summary:Objective: Cardiac fibrosis during Duchenne muscular dystrophy (DMD) arises from cellular damage and inflammation and is associated with metabolic dysfunction. The extent to which these relationships develop across all 4 cardiac chambers, particularly during early-stage disease, remains unknown. Methods and Results: We discovered that very young D2.mdx mice exhibit fibrosis exclusively in the right ventricle (RV) and left atrium. Concurrent myocardial disorganization in the RV was related to a highly specific inflammatory signature of increased infiltrating pro-inflammatory macrophages (CD11b+CD45+CD64+F4/80+CCR2+), myofibre mitochondrial-linked apoptosis, and reduced carbohydrate and fat oxidation. This relationship did not occur in the left ventricle. Short-term daily administration of a peptidomimetic adiponectin receptor agonist, ALY688, prevented RV fibrosis, infiltrating macrophages, and mitochondrial stress as well as left atrial fibrosis. Conclusions: Our discoveries demonstrate early-stage cardiac tissue pathology occurs in a chamber-specific manner and is prevented by adiponectin receptor agonism, thereby opening a new direction for developing therapies that prevent tissue remodeling during DMD.
ISSN:2212-8778

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