Abstract
MicroRNAs (miRNAs), short noncoding RNAs that posttranscriptionally regulate gene expression, have emerged as critical regulators of cardiac genes. Although circulating miRNAs have been implicated in cardiovascular disease, their precise functional roles remain poorly understood. Using Drosophila as a model, we applied miRNA sponge technology to competitively inhibit miR-6 (the mammalian homolog, miR-27), enabling us to systematically assess its impact on heart function, morphology, and lifespan. Functional and structural cardiac changes were analyzed with semiautomatic optical heartbeat analysis (SOHA) software and immunohistochemistry. In silico target analysis revealed 149 conserved predicted gene targets shared by this miRNA family, highlighting its potential regulatory scope. Our findings uncover a novel cardioprotective role for miR-6 inhibition, demonstrating that heart-specific miR-6 suppression mitigates age-related changes to heart size and function, significantly extends lifespan, and leads to increased lipid accumulation in cardiomyocytes. Importantly, we observed elevated expression of the conserved target gene low-density lipoprotein receptor-related protein 1 (LRP1) in miR-6-inhibited hearts, and genetic disruption of LRP1 expression in miR-6 inhibition decreased lipid accumulation in the heart. Conservation of miR-27b and LRP1B expression in mammalian cardiac tissue further validates the translational relevance of these findings.NEW & NOTEWORTHY This work establishes miR-6 as a novel regulator of cardiac health, specifically in aging, through its modulation of lipid metabolism, heart function, and longevity. These insights expand our understanding of miRNA-mediated cardiac regulation and provide a foundation for developing miRNA-targeted therapies to combat heart disease and age-related cardiac decline.
