Failure to resolve inflammation contributes to juvenile onset cardiac damage in a mouse model of Duchenne muscular dystrophy

TL;DR

A new mouse model shows early heart damage in Duchenne muscular dystrophy, linked to unresolved inflammation, and suggests a new treatment approach to prevent cardiac degeneration.

Contribution

The D2-mdx mouse model reveals juvenile-onset cardiac damage in DMD and introduces pro-resolution therapy as a novel treatment strategy.

Findings

The D2-mdx mouse model exhibits juvenile-onset cardiac degeneration due to unresolved inflammation.

Pro-resolution therapy using an FPR agonist mitigates fibrotic degeneration in the heart.

Chronic inflammation and ECM fibrosis are key drivers of cardiac damage in the D2-mdx model.

Abstract

Absence of dystrophin protein causes cardiac dysfunction in patients with Duchenne muscular dystrophy (DMD). Unlike boys with DMD, the common mouse model of DMD (B10-mdx) does not manifest cardiac deficits until late adulthood. This has limited our understanding of the mechanism and therapeutic approaches to target the pediatric onset of cardiac pathology in DMD. Here we show that the mdx mouse model on the DBA/2 J genetic background (D2-mdx) displays juvenile-onset cardiac degeneration. Molecular and histological analysis revealed that cardiac damage in this model is linked to increased leukocyte chemotactic signaling and an inability to resolve inflammation. These deficiencies result in chronic inflammation and fibrotic conversion of the extracellular matrix (ECM) in the juvenile D2-mdx heart. To address these pathologies, we tested the utility of pro-resolution therapy to clear chronic cardiac inflammation. Use of an N-formyl peptide receptor (FPR) agonist helped physiologically resolve inflammation and mitigate the downstream events that lead to fibrotic degeneration of cardiomyocytes, preventing juvenile onset cardiac muscle loss. These results establish the utility of D2-mdx model to study events associated with pediatric-onset cardiac damage and demonstrates pro-resolution therapy as an alternate to anti-inflammatory therapy for treating degenerative cardiac pathology that leads to cardiomyopathy in DMD.

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