Molecular remodeling of myocardium in mice with melanocortin-4 receptor deletion before cardiac function impairment

The melanocortin-4 receptor (MC4R) is highly expressed in the hypothalamus and mutations in this gene are closely associated with the development of hereditary obesity and early onset severe obesity in humans. It has been demonstrated that Mc4r is involved in the development of dilated cardiomyopathy. However, the current system of early diagnosis and treatment of heart disease is not well established. In this study, we analyzed the effects of Mc4r knockout on cardiac function and cardiomyocyte morphology, fibrosis, and apoptosis in mice. Meanwhile, we explored the possible early molecular mechanisms of Mc4r affecting cardiac dysfunction by transcriptome sequencing of cardiac cells combined with bioinformatics analysis. The results showed that although the overall heart does not show organic changes, our study suggests that cardiomyocytes already show abnormal changes at the early molecular level. The sequencing results showed that the differentially expressed genes between the two groups of mice were mainly enriched in the p53 signaling pathway and HIF-1 signaling pathway. We screened 10 key target genes using PPI network and Module analysis. Subsequently, drugs targeting key genes were screened and seven genes were identified as potential drug targets. This study will provide important reference and guidance for early prevention, treatment and drug targeting of heart-related diseases caused by Mc4r gene deletion. Overall design: To investigate the role of Mc4r in the development of early cardiac disease, We constructed Mc4r knockout mice. Comparative gene expression profiling analysis of RNA seq data for heart tissues of 12 week old Mc4r knockout mice (MC4R_KO, n=3) and wild-type mice (WT, n=3)