Experimentally Increasing Titin's Compliance in a Mouse Model of Heart Failure with Preserved Ejection Fraction Ameliorates Diastolic Dysfunction

Increasing titin length in the heart through functional deletion of the RNA recognition motif (RRM) of RBM20 protein leads to a reduction of left ventricular (LV) chamber stiffness in sedentary mice. We tested the therapeutic effect of upregulating compliant titins by creating diastolic dysfunction in a mouse model with inducible RBM20 inhibition (MerCreMer;cRbm20ΔRRM). Under transcriptional control of an MHC6 promoter, RBM20 function of MerCreMer;cRbm20ΔRRM mice was inhibited in time- and cardiac-specific manners. Adult male MerCreMer;cRbm20ΔRRM mice had undergone transaortic constriction (TAC) surgery with Deoxycorticosterone acetate (DOCA) pellet implantation. Two weeks after TAC+DOCA surgery, mice developed LV hypertrophy and diastolic dysfunction as demonstrated by echocardiography. Four weeks after surgery, pressure volume analysis revealed that LV chamber stiffness was markedly increased in TAC+DOCA mice (140% increased versus sham). However, the TAC+DOCA mice with RBM20 inhibition developed less severe LV chamber stiffness (29% increased versus sham). Passive stiffness measurements showed a reduction of cardiomyocyte stiffness in TAC+DOCA mice with RBM20 inhibition. Inhibition of the RBM20-based splicing system results in expression of compliant mutant N2BA titin which consequently lead to reduction of cardiomyocyte stiffness and LV chamber stiffness in a mouse model with diastolic dysfunction.