Reducing RBM20 activity by approximately 50% restored diastolic filling and ameliorated cardiac atrophy in a titin N2B-deficient mouse model of diastolic dysfunction.
Does reducing RBM20 activity improve diastolic dysfunction and cardiac atrophy in a titin N2B-deficient mouse model?
Reducing RBM20 activity improves diastolic filling and reverses cardiac atrophy in a mouse model of HFpEF, highlighting cardiac splicing as a potential therapeutic target.
Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin's elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness. A ~50 % reduction of RBM20 activity does not only maintain cardiac filling in diastole but also ameliorates cardiac atrophy and thus improves cardiac function in the N2B-deficient heart. Reduced RBM20 activity partially normalized gene expression related to muscle development and fatty acid metabolism. The adaptation of cardiac growth was related to hypertrophy signaling via four-and-a-half lim-domain proteins (FHLs) that translate mechanical input into hypertrophy signals. We provide a novel link between cardiac isoform expression and trophic signaling via FHLs and suggest cardiac splicing as a therapeutic target in diastolic dysfunction. KEY MESSAGE: Increasing the length of titin isoforms improves ventricular filling in heart disease. FHL proteins are regulated via RBM20 and adapt cardiac growth. RBM20 is a therapeutic target in diastolic dysfunction.
Hinze et al. (Sat,) conducted a other in Diastolic dysfunction and cardiac atrophy. Reduced RBM20 activity (heterozygous RBM20 deletion) vs. Titin N2B knockout (N2B-KO) and Wildtype (WT) was evaluated on Diastolic function (E/A ratio and EDPVR) and cardiac dimensions. Reducing RBM20 activity by approximately 50% restored diastolic filling and ameliorated cardiac atrophy in a titin N2B-deficient mouse model of diastolic dysfunction.