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01.12.2023 | Mitochondria at the heart of cardioprotection

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

verfasst von: Sandhya Singh, Aakash Gaur, Rakesh Kumar Sharma, Renu Kumari, Shakti Prakash, Sunaina Kumari, Ayushi Devendrasingh Chaudhary, Pankaj Prasun, Priyanka Pant, Hannah Hunkler, Thomas Thum, Kumaravelu Jagavelu, Pragya Bharati, Kashif Hanif, Pragya Chitkara, Shailesh Kumar, Kalyan Mitra, Shashi Kumar Gupta

Erschienen in: Basic Research in Cardiology | Ausgabe 1/2023

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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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Titel: Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA
verfasst von: Sandhya Singh
Aakash Gaur
Rakesh Kumar Sharma
Renu Kumari
Shakti Prakash
Sunaina Kumari
Ayushi Devendrasingh Chaudhary
Pankaj Prasun
Priyanka Pant
Hannah Hunkler
Thomas Thum
Kumaravelu Jagavelu
Pragya Bharati
Kashif Hanif
Pragya Chitkara
Shailesh Kumar
Kalyan Mitra
Shashi Kumar Gupta
Publikationsdatum: 01.12.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Basic Research in Cardiology / Ausgabe 1/2023
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-023-01016-y

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