Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy

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.