Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizingCluhandSmyd1mRNA

Abstract

AbstractRegulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprisingMsi1andMsi2are known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains entirely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore,Msi2was significantly enriched in the heart’s cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified,Msi2isoforms 1, 4, and 5 and two novel putative isoforms labeled asMsi2isoforms 6 and 7 to be expressed in the heart. Overexpression ofMsi2isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally,Msi2was also found to be significantly increased in a pressure-overload model of cardiac hypertrophy. To validate the hypertrophic effects, we selected isoforms 4 and 7 due to their unique alternative splicing patterns. AAV9-mediated overexpression ofMsi2isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function forMsi2. Using global proteomics, gene ontology, transmission electron microscopy, and transmembrane potential measurement assays increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identifiedCluhandSmyd1as direct downstream targets ofMsi2. Overexpression ofCluhorSmyd1inhibitedMsi2-induced hypertrophy and mitochondrial dysfunction in cardiomyocytes. Collectively, we show thatMsi2induces hypertrophy, mitochondrial dysfunction, and heart failure.