Heterozygous loss of Rbm24 in the adult mouse heart increases sarcomere slack length but does not affect function

N. E. de Groot, M. M.G. van den Hoogenhof, A. Najafi, I. van der Made, J. van der Velden, A. Beqqali, Y. M. Pinto, E. E. Creemers

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Abstract

RNA-binding proteins are key regulators of post-transcriptional processes such as alternative splicing and mRNA stabilization. Rbm24 acts as a regulator of alternative splicing in heart and skeletal muscle, and is essential for sarcomere assembly. Homozygous inactivation of Rbm24 in mice disrupts cardiac development and results in embryonic lethality around E12.5. In the present study, we generated somatic Rbm24 knockout (KO) mice and investigated the effects of reduced levels of Rbm24 in the adult heart. Due to the embryonic lethality of Rbm24 KO mice, we examined cardiac structure and function in adult Rbm24 heterozygotes (HETs). Rbm24 protein expression was 40% downregulated in HET hearts compared to WT hearts. Force measurements on isolated membrane-permeabilized myocytes showed increased sarcomere slack length and lower myofilament passive stiffness in adult Rbm24 HET compared to wildtype cardiomyocytes. As a result of the differences in sarcomere slack length, the relations between force development and sarcomere length differed between WT and Rbm24 HET hearts. No differences in sarcomere structure and titin isoform composition were observed. Likewise, in vivo cardiac function and myocardial structure was unaltered in Rbm24 HET mice compared to WT, at baseline and upon pressure overload after transverse aortic constriction. In conclusion, we generated a somatic Rbm24 KO model and recapitulated the previously reported embryonic phenotype. In adult Rbm24 HET cardiomyocytes we observed increased sarcomere slack length, but no difference in sarcomere structure and cardiac function.

Original languageEnglish
Article number7687
Number of pages1
JournalScientific Reports
Volume10
Issue number1
DOIs
Publication statusPublished - 6 May 2020

Cite this

de Groot, N. E., van den Hoogenhof, M. M. G., Najafi, A., van der Made, I., van der Velden, J., Beqqali, A., ... Creemers, E. E. (2020). Heterozygous loss of Rbm24 in the adult mouse heart increases sarcomere slack length but does not affect function. Scientific Reports, 10(1), [7687]. https://doi.org/10.1038/s41598-020-64667-0