Loss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction

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dc.contributor.authorOrtiz-Sánchez, Paula
dc.contributor.authorVillalba Orero, María
dc.contributor.authorLópez-Olañeta, Marina M.
dc.contributor.authorLarrasa-Alonso, Javier
dc.contributor.authorSánchez-Cabo, Fátima
dc.contributor.authorMartí-Gómez, Carlos
dc.contributor.authorCamafeita, Emilio
dc.contributor.authorGómez-Salinero, Jesús M.
dc.contributor.authorRamos-Hernández, Laura
dc.contributor.authorNielsen, Peter J.
dc.contributor.authorVázquez, Jesús
dc.contributor.authorMüller-McNicoll, Michaela
dc.contributor.authorGarcía-Pavía, Pablo
dc.contributor.authorLara-Pezzi, Enrique
dc.date.accessioned2024-01-29T09:14:30Z
dc.date.available2024-01-29T09:14:30Z
dc.date.issued2019-05-30
dc.descriptionThis study was supported by grants from the European Union (CardioNeT-ITN-289600 and CardioNext-ITN-608027 to E. Lara-Pezzi), from the Spanish Ministerio de Economía y Competitividad (RTI2018-096961-B-I00, SAF2015-65722-R, and SAF2012-31451 to E. Lara-Pezzi; BIO2015-67580-P and PGC2018-097019-B-I00 to J. Vázquez), the Spanish Carlos III Institute of Health (CPII14/00027 to E. Lara-Pezzi, RD12/0042/066 to P. García-Pavía and E. Lara-Pezzi, and RD12/0042/0056, PRB2-IPT13/0001-ISCIII-SGEFI/FEDER, ProteoRed to J. Vázquez), the Madrid Regional Government (2010-BMD-2321 Fibroteam to E. Lara-Pezzi). This study was also supported by the Plan Estatal de I+D+I 2013–2016—European Regional Development Fund (ERDF) A way of making Europe, Spain. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).
dc.description.abstractRationale: RBPs (RNA binding proteins) play critical roles in the cell by regulating mRNA transport, splicing, editing, and stability. The RBP SRSF3 (serine/arginine-rich splicing factor 3) is essential for blastocyst formation and for proper liver development and function. However, its role in the heart has not been explored. Objective: To investigate the role of SRSF3 in cardiac function. Methods and Results: Cardiac SRSF3 expression was high at mid gestation and decreased during late embryonic development. Mice lacking SRSF3 in the embryonic heart showed impaired cardiomyocyte proliferation and died in utero. In the adult heart, SRSF3 expression was reduced after myocardial infarction, suggesting a possible role in cardiac homeostasis. To determine the role of this RBP in the adult heart, we used an inducible, cardiomyocyte-specific SRSF3 knockout mouse model. After SRSF3 depletion in cardiomyocytes, mice developed severe systolic dysfunction that resulted in death within 8 days. RNA-Seq analysis revealed downregulation of mRNAs encoding sarcomeric and calcium handling proteins. Cardiomyocyte-specific SRSF3 knockout mice also showed evidence of alternative splicing of mTOR (mammalian target of rapamycin) mRNA, generating a shorter protein isoform lacking catalytic activity. This was associated with decreased phosphorylation of 4E-BP1 (eIF4E-binding protein 1), a protein that binds to eIF4E (eukaryotic translation initiation factor 4E) and prevents mRNA decapping. Consequently, we found increased decapping of mRNAs encoding proteins involved in cardiac contraction. Decapping was partially reversed by mTOR activation. Conclusions: We show that cardiomyocyte-specific loss of SRSF3 expression results in decapping of critical mRNAs involved in cardiac contraction. The molecular mechanism underlying this effect likely involves the generation of a short mTOR isoform by alternative splicing, resulting in reduced 4E-BP1 phosphorylation. The identification of mRNA decapping as a mechanism of systolic heart failure may open the way to the development of urgently needed therapeutic tools. (Circ Res. 2019;125:170-183. DOI: 10.1161/CIRCRESAHA.118.314515.)
dc.description.departmentDepto. de Medicina y Cirugía Animal
dc.description.facultyFac. de Veterinaria
dc.description.refereedTRUE
dc.description.sponsorshipUnión Europea
dc.description.sponsorshipMinisterio de Economía y Competitividad, de la Comunidad de Madrid
dc.description.sponsorshipPlan Estatal de I+D+I 2013–2016 European Regional Development Fund (ERDF)
dc.description.sponsorship“A way to build Europe” de la European Regional Development Fund (ERDF).
dc.description.sponsorshipThe Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence
dc.description.sponsorshipMinisterio de Ciencia, Innovación y Universidades (MCNU)
dc.description.statuspub
dc.identifier.citationOrtiz-Sánchez, P., Villalba-Orero, M., López-Olañeta, M. M., Larrasa-Alonso, J., Sánchez-Cabo, F., Martí-Gómez, C., Camafeita, E., Gómez-Salinero, J. M., Ramos-Hernández, L., Nielsen, P. J., Vázquez, J., Müller-McNicoll, M., García-Pavía, P., & Lara-Pezzi, E. (2019). Loss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction. Circulation research, 125(2), 170–183. https://doi.org/10.1161/CIRCRESAHA.118.314515
dc.identifier.doi10.1161/circresaha.118.314515
dc.identifier.issn0009-7330
dc.identifier.officialurlhttps://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.314515#d1e1417
dc.identifier.pmid31145021
dc.identifier.urihttps://hdl.handle.net/20.500.14352/95770
dc.journal.titleCirculation Research
dc.language.isoeng
dc.page.final183
dc.page.initial170
dc.publisherAHA Journals
dc.relation.projectID(CardioNeT-ITN-289600)
dc.relation.projectID(CardioNext-ITN-608027
dc.relation.projectID(2010-BMD-2321 “Fibroteam”)
dc.relation.projectID(RTI2018-096961-B-I00)
dc.relation.projectID(SAF2015-65722-R)
dc.relation.projectID(SAF2012-31451)
dc.relation.projectID(BIO2015-67580-P)
dc.relation.projectID(PGC2018-097019-B-I00)
dc.relation.projectID(CPII14/00027)
dc.relation.projectID(RD12/0042/066)
dc.relation.projectID(RD12/0042/0056)
dc.relation.projectID(PRB2-IPT13/0001-ISCIII-SGEFI/FEDER)
dc.relation.projectID(2010-BMD-2321 Fibroteam)
dc.relation.projectID(SEV-2015-0505)
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.cdu61
dc.subject.keywordAlternative splicing
dc.subject.keywordmRNA decapping
dc.subject.keywordMyocardial contraction
dc.subject.keywordMyocardial infarction
dc.subject.keywordPhosphorylation
dc.subject.ucmCiencias Biomédicas
dc.subject.unesco32 Ciencias Médicas
dc.titleLoss of SRSF3 in Cardiomyocytes Leads to Decapping of Contraction-Related mRNAs and Severe Systolic Dysfunction
dc.typejournal article
dc.type.hasVersionAM
dc.volume.number125
dspace.entity.typePublication
relation.isAuthorOfPublication4072ae83-66a7-4959-ab38-1cae01035591
relation.isAuthorOfPublication.latestForDiscovery4072ae83-66a7-4959-ab38-1cae01035591
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