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

Abstract

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.

Keywords: Cardiomyopathy; Duchenne muscular dystrophy; Fibrosis; Inflammation; Mitochondria.