Alternative splicing of TPM1 exon 9a, mediated by the splicing kinase SRPK3, drives myofilament disorder and diastolic dysfunction in HFpEF models.
Does alternative splicing of TPM1 mediated by SRPK3 drive cardiac diastolic dysfunction in HFpEF?
Alternative splicing of TPM1 exon 9a, mediated by SRPK3, drives myofilament disorder and diastolic dysfunction in HFpEF, suggesting SRPK3 as a novel therapeutic target.
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, a condition characterized by impaired diastolic function and elevated left ventricular stiffness. TPM1 (tropomyosin 1), a crucial part of the thin filament in cardiomyocytes, has multiple alternative exons. However, the impact of TPM1 alternative splicing (AS) in HFpEF remains unclear. METHODS: We examined cardiac myofiber disarray in HFpEF using transmission electron microscopy. Nanoindentation was used to detect myocardial compliance. Using genetically engineered (adenovirus-associated virus serotype 9) mouse models and human pluripotent stem cell-derived cardiomyocytes, we investigated the role of TPM1 isoforms and its upstream SRPK3 (serine/arginine rich protein kinase 3). Subsequently, the underlying mechanisms were investigated using RNA pulldown, mass spectrometry, AS analysis, and other molecular techniques. RESULTS: We identified unique myofilament disorders in HFpEF and observed upregulation of the TPM1b isoform, which skips exon 9a through AS, in both patients with HFpEF and mouse models. Cardiomyocyte-specific overexpression of distinct TPM1 isoforms showed that TPM1b (without exon 9a) exacerbated HFpEF phenotypes in mice and human pluripotent stem cell-derived cardiomyocytes. Furthermore, we found that the splicing kinase SRPK3 mediates the AS of TPM1 exon 9a. Cardiomyocyte-specific overexpression of SRPK3 induced myofiber disarray and diastolic dysfunction, whereas SRPK3 knockdown ameliorated these pathological phenotypes. Supplementation with TPM1 containing exon 9a partially rescued the diastolic dysfunction under conditions of SRPK3 overexpression. Preventive intervention experiments demonstrated that inactivating SRPK3 can alleviate diastolic dysfunction in the HFpEF mouse model. CONCLUSIONS: AS of TPM1 exon 9a is a critical pathogenic mechanism in myofilament disorder and diastolic dysfunction in HFpEF, which is dependent on the upstream splicing kinase SRPK3. SRPK3 may represent a novel therapeutic target for HFpEF.
Chen et al. (Tue,) conducted a other in Heart failure with preserved ejection fraction (HFpEF). SRPK3 modulation and TPM1 alternative splicing was evaluated on Cardiac diastolic dysfunction and myofiber disarray. Alternative splicing of TPM1 exon 9a, mediated by the splicing kinase SRPK3, drives myofilament disorder and diastolic dysfunction in HFpEF models.