Chloroquine decreases cardiac fibrosis and improves cardiac function in a mouse model of Duchenne muscular dystrophy

TL;DR

Chloroquine reduces heart scarring and improves heart function in a mouse model of Duchenne muscular dystrophy.

Contribution

This study shows chloroquine can alleviate cardiac fibrosis and improve heart function in DMD.

Findings

Chloroquine decreased cardiomyocyte fibrosis in mdx mice after isoproterenol treatment.

Chloroquine improved left ventricular contraction in mdx mice under cardiac stress.

Autophagosome numbers increased in mdx mice under stress but not in wild-type mice.

Abstract

Duchenne muscular dystrophy (DMD), a severe degenerative skeletal and cardiac muscle disease, has a poor prognosis, and no curative treatments are available. Because decreased autophagy has been reported to contribute to skeletal muscle degeneration, therapies targeting autophagy are expected to improve skeletal muscle hypofunction. However, the role of this regulatory mechanism has not been evaluated clearly in DMD cardiomyocytes.

In this present study, we evaluated myocardial fibrosis and its mechanism in mdx mice, a model of DMD, and also evaluated changes in cardiac function.

As assessed by LC3 immunohistochemistry, a small number of autophagosomes were detected in cardiomyocytes of both mdx mice and control wild-type (WT) mice. The number of autophagosomes was significantly enhanced by 4 weeks of isoproterenol-induced cardiac stress in cardiomyocytes of mdx but not WT mice. Simultaneously, isoproterenol increased cardiomyocyte fibrosis in mdx but not WT mice. Administration of chloroquine significantly decreased cardiomyocyte fibrosis in mdx mice, even after isoproterenol treatment. Left ventricle size and function were evaluated by echocardiography. Left ventricular contraction was decreased in mdx mice after isoproterenol treatment compared with control mice, which was alleviated by chloroquine administration.

Heart failure in DMD patients is possibly treated with chloroquine, and the mechanism probably involves chloroquine’s anti-inflammatory effects.

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