TY  - JOUR
A1  - Ortiz-Sánchez, Paula
A1  - Villalba-Orero, María
A1  - López-Olañeta, Marina M.
A1  - Larrasa-Alonso, Javier
A1  - Sánchez-Cabo, Fátima
A1  - Martí-Gómez, Carlos
A1  - Camafeita, Emilio
A1  - Gómez-Salinero, Jesús M.
A1  - Ramos-Hernández, Laura
A1  - Nielsen, Peter J.
A1  - Vázquez, Jesús
A1  - Müller-McNicoll, Michaela
A1  - García-Pavía, Pablo
A1  - Lara-Pezzi, Enrique
T1  - Loss of SRSF3 in cardiomyocytes leads to decapping of contraction-related mRNAs and severe systolic dysfunction
T2  - Circulation research
N2  - Rationale: 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.
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/53281
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-532811
SN  - 0009-7330
SN  - 0931-6876
VL  - 125
IS  - No. 2
SP  - 170
EP  - 183
PB  - Lippincott Williams & Wilkins
CY  - Baltimore, Md.
ER  -