Deregulation of alternative splicing of sarcomeric genes is a hallmark of heart failure. To better understand the cardiac splicing dynamics, we aimed to determine the in vivo function of Sam68-Like mammalian protein 2 (SLM2) splicing factor, that we have previously discovered to oppose cardiac RBM20 splicing. Here, we utilized a mouse model of inducible cardiomyocyte specific gene deletion of SLM2. We show that the alternative splicing patterns of mRNAs display differences in SLM2-KO that have undergone O -Ring Aortic Banding (ORAB) surgery suggesting that SLM2 affects sarcomere gene splicing under stress conditions and SLM2 deficiency leads to cardiac vulnerability in a pressure overload model of heart failure. Interestingly, we observed significant overexpression of SLM2 and Sam68 in heart tissue upon ORAB surgery, suggesting a compensatory function of these splicing factors in our pressure overload mouse model. Through long read RNA sequencing, we observed significant alterations in the expression of TTN transcript and its alternative splicing isoforms in mouse heart tissue. In conclusion, our data demonstrates that the alternative splicing patterns of mRNAs display differences in SLM2 knockout mice that have undergone ORAB surgery.

ORAB surgery in SLM2 heart specific KO mice leads to altered expression of splicing factors which leads to altered alternative splicing pattern in targeted mRNAs determined by Long-read RNASeq analysis.