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Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA. | LitMetric

AI Article Synopsis

  • Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is important for gene expression, with the Musashi family (including Msi1 and Msi2) playing a key role, particularly in the heart where Msi2's function was previously unclear.
  • This study confirmed the presence of Msi2 in adult mouse and rat hearts, identifying multiple isoforms of Msi2 expressed, and demonstrated that overexpression of these isoforms led to cardiac hypertrophy and heart failure in models.
  • Additionally, increased Msi2 levels were linked to mitochondrial dysfunction, and it was found that the proteins Cluh and Smyd1 could counteract some of the damaging effects of Msi2, underlining Msi2

Article Abstract

Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely 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, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.

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Source
http://dx.doi.org/10.1007/s00395-023-01016-yDOI Listing

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