PT  - JOURNAL ARTICLE
AU  - Fabiana Martino
AU  - Nandan Mysore Varadarajan
AU  - Ana Rubina Perestrelo
AU  - Vaclav Hejret
AU  - Helena Durikova
AU  - Vladimir Horvath
AU  - Francesca Cavalieri
AU  - Frank Caruso
AU  - Waleed S. Albihlal
AU  - André P. Gerber
AU  - Mary A. O’Connell
AU  - Stepanka Vanacova
AU  - Stefania Pagliari
AU  - Giancarlo Forte
TI  - The mechanical regulation of RNA binding protein hnRNPC in the failing heart
AID  - 10.1101/2021.08.27.457906
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2021.08.27.457906
4099  - http://biorxiv.org/content/early/2022/03/07/2021.08.27.457906.short
4100  - http://biorxiv.org/content/early/2022/03/07/2021.08.27.457906.full
AB  - Cardiac pathologies are characterized by intense remodeling of the extracellular matrix (ECM) that eventually leads to heart failure. Cardiomyocytes respond to the ensuing biomechanical stress by re-expressing fetal contractile proteins via transcriptional and post-transcriptional processes, like alternative splicing (AS). Here, we demonstrate that the heterogeneous nuclear ribonucleoprotein C (hnRNPC) is upregulated and relocates to the sarcomeric Z-disk upon ECM pathological remodeling. We show that this is an active site of localized translation, where the ribonucleoprotein associates to the translation machinery. Alterations in hnRNPC expression and localization can be mechanically determined and affect the AS of numerous mRNAs involved in mechanotransduction and cardiovascular diseases, like Hippo pathway effector YAP1. We propose that cardiac ECM remodeling serves as a switch in RNA metabolism by impacting an associated regulatory protein of the spliceosome apparatus. These findings offer new insights on the mechanism of mRNAs homeostasis mechanoregulation in pathological conditions.Competing Interest StatementThe authors have declared no competing interest.