Delineating SLM2's Regulatory Role in Cardiac Stress and Splicing Homeostasis

Mathieu Klop (Heidelberg)1, S. Herch (Heidelberg)1, J. Haas (Heidelberg)1, R. Eghbalian (Heidelberg)1, J. Kölemen (Heidelberg)1, F. Sedaghat-Hamedani (Heidelberg)1, E. Kayvanpour (Heidelberg)1, K. Frese (Heidelberg)1, B. Meder (Heidelberg)1

1Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland



Dilated Cardiomyopathy (DCM) is characterized by significant alterations of the cardiac transcriptome and isoform expression. Alternative splicing, as one mechanism of transcriptome diversification, is often associated with the development and progression of DCM. We have shown in previous work that alternative splicing of sarcomeric genes, pivotal for cardiac function, is profoundly modulated by the RNA-binding protein SLM2. Although SLM2's upregulation in dilated cardiomyopathy (DCM) suggests a therapeutic target, particularly in the context of cardiomyopathy, its functional in-vivo roles remain underexplored. This study investigates the impact of SLM2 knockout on cardiac physiology and splicing regulation in the murine heart, aiming to fill the knowledge gap and validate its therapeutic potential.


We established a heart-specific, tamoxifen-inducible SLM2 knockout (KO) mouse model to investigate the in vivo role of SLM2. Cardiac function was assessed through echocardiography, and transcriptomic changes were probed via RNA sequencing to evaluate alternative splicing modifications. To induce cardiac stress and pressure overload, standardized O-ring aortic banding (ORAB) surgery was performed, allowing us to precisely investigate the stress-adaptive capacity of the heart in the absence of SLM2.


At eight weeks post-induction, SLM2 KO mice exhibited no significant change in cardiac morphology or function. Since this was surprising, we performed in-depth transcriptome sequencing, which showed no relevant changes in myocardial gene expression. However, when investigating alternative splicing, we found that upon SLM2 depletion the pathways for cardiac muscle tissue development and cellular stress response were markedly altered (up to 2.5-fold enrichment, p<0.05). Specifically, the KO mice exhibited marked changes (p-val < 0.05) in exon usage in genes central to cardiac function, including differential splicing in titin (Ttn), myosn light chain 2 (Myl2), and troponin T2 (Tnnt2). Hence, we considered performing cardiac stress by ORAB surgery in SLM2 K.O. and controls. KO mice displayeda pronounced decline in Ejection Fraction (EF) 1 week post ORAB surgery (29% (KO) vs 51% (Ctr)) and other morphofunctional paramters. Survival was reduced strongly and mice suffered from heart failure, indicating a crucial role of SLM2-mediated splicing during stress response.


The absence of SLM2 alters the splicing pattern of key sarcomeric genes, which may increase vulnerability to cardiac dysfunction under stress. Our results support the exploration of SLM2 as a therapeutic target in DCM and open new avenues for understanding the molecular compensatory mechanisms in cardiac physiology.

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