The role of macrophages in Duchenne Muscular Dystrophy cardiomyopathy

University Of Nevada Reno, Reno NV

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Abstract

Duchenne Muscular Dystrophy (DMD) is a fatal X-linked genetic disorder affecting approximately 1 in 5,000 male births worldwide. DMD is caused by mutations in the DMD gene that encodes for the dystrophin protein. The absence of dystrophin results in cumulative muscle fiber damage and death which ultimately leads to chronic inflammation exacerbating muscle fiber damage and contributing to fibrosis. Corticosteroid treatment and respiratory mechanical support prolong the life expectancy of patients, but these strategies are insufficient to prevent the premature death of DMD patients from heart failure. Cardiomyopathy in DMD patients is characterized by chronic inflammation, myocardial fibrosis, and left ventricular dysfunction. However, the inflammation-related mechanisms underlying cardiac fibrosis and function in DMD-related cardiomyopathy are still unknown. Studies on different cardiac pathologies demonstrate that monocytederived macrophages induce cardiac fibrosis and dysfunction, whereas embryonic-derived resident macrophages have a pro-repair role. Macrophages are the predominant immune cell subtype in the heart of BL10-mdx (C57BL/10ScSn-Dmdmdx/J) mice, a mouse model of DMD, and their accumulation in the myocardium correlates with the increase of fibrosis. Still, the role of macrophages in DMD-related cardiac fibrosis and function is unknown. Here, we will use the BL10-mdx mouse model of DMD to study the role of macrophages in DMD-related cardiomyopathy. We will combine in vivo and in vitro analyses to characterize cardiac macrophage sub-populations. We will determine if monocyte-derived macrophages promote cardiac fibrosis in DMD and if the interplay between monocyte-derived macrophages and embryonic-derived resident macrophages contributes to DMD cardiac fibrosis. The long-term goal of this project is to understand the disease mechanisms driving DMD cardiomyopathy and identify new therapeutic targets. The successful completion of this project will advance our understanding of the role of macrophages in DMD-related cardiomyopathy, particularly cardiac fibrosis and function. This knowledge will be critical to determine if macrophages are potential therapeutic targets for the treatment of DMDrelated cardiomyopathy.