Growth Hormone Secretagogue Receptor (GHSR) Is Elevated in Myocardial Tissues of DMD <i>mdx:utrn</i>^−/− Mice, and Correlates Strongly with Inflammatory Markers, and Negatively with Cardiac Function

Abstract

Dilated cardiomyopathy affects greater than 1 in 2500 patients worldwide, including those with the neuromuscular disorder Duchenne muscular dystrophy (DMD). While inflammation within skeletal muscle is strongly associated with DMD pathology, the key biomarkers for inflammation and possible targets for therapy within cardiac tissue in DMD-associated dilated cardiomyopathy remain to be identified. One such potential target is the myocardial ghrelin-growth hormone secretagogue receptor (GHSR) system, which is associated with cardiomyocyte survival and inhibition of inflammation. We sought to determine alterations in myocardial GHSR together with markers of cardiac inflammation using mdx:utrn−/− mice as a model for DMD-associated dilated cardiomyopathy. With traditional histopathology, we determined that the pathology of DMD in mdx:utrn−/− mice was characterized by disruption of myofiber organization, lymphocytic infiltration, and extensive cardiomyocyte vacuolization and necrosis surrounding areas of fibrosis in the left ventricular wall and apex. Using a fluorescent ghrelin analog, Cy5-ghrelin (1–19), to visualize GHSR with fluorescence confocal microscopy, we demonstrate that GHSR is elevated in mdx/utrn−/− myocardial tissues and correlates strongly with both F4-80 (activated macrophages) and IL-6 (pro-inflammatory cytokine), and negatively with cardiac function. We also show that GHSR can be visualized in pro-inflammatory macrophages, suggesting a direct role for GHSR in the inflammatory progression of DMD.

Keywords

• dilated cardiomyopathy
• Duchenne muscular dystrophy
• inflammation
• GHSR