Abstract 9065: Dose-Dependent Rescue Effects by a Desensitizing TnI Molecule in a RCM Mouse Model

Abstract

We have previously demonstrated that the R193H mutation of cardiac troponin I (cTnI) caused restrictive cardiomyopathy (RCM) and early death in transgenic mice (Du et al., 2006). RCM mutants are also characterized by increased myofilament Ca 2+ sensitivity and impaired cardiac relaxation (Gomes et al., 2005; Du et al., 2008). Restrictive cleavage of the N-terminal extension of cTnI has been shown to desensitize myofilament to Ca 2+ and enhance diastolic function in transgenic mice (Yu et al., 2001; Feng et al., 2008; McConnell et al., 2009). N-terminal truncated cTnI (cTnI-ND) also had the ability to correct the diastolic dysfunction and increase the lifespan of RCM mice expressing the cTnI R193H mutant in a wild type cTnI null background (Li et al, 2010). In the present study, we produced double transgenic mice (Double-TG) expressing different levels of mutant cTnI R193H and cTnI-ND to investigate the dose-dependent rescue effect of cTnI-ND and determine the mechanisms behind its protective role in young and aged RCM mice. In 2-month-old Double-TG mice, the rescue of these animals is secondary to the desensitization of their myofilament to Ca 2+ and the fixing of their cardiac relaxation impairment by cTnI-ND. The correction of the diastolic dysfunction by cTnI-ND occurs in a dose-dependent manner as evidenced by cell-based assays, measuring cardiac cell contractility of the various Double-TG mouse lines, and by echocardiography. In addition, in 8-10-month-old Double-TG mice, the rescue of RCM mice by cTnI-ND is characterized by both the restoration of their diastolic function and the amelioration of their systolic function, since both diastolic and systolic functions deteriorate in aged RCM mice. Thus, this study allows determining the efficiency of cTnI-ND in the treatment of RCM and evaluating how the dosage of RCM mutant proteins may influence the cardiac function. Also, consistent with the beneficial effect of cTnI-ND on the function of non-myopathic aging hearts (Biesiadescki et al., 2010), these data demonstrate the ability of cTnI-ND to rescue the RCM phenotype not only by correcting diastolic dysfunction in young RCM mice, but also by improving systolic function in aged RCM mice.