Our previous studies have demonstrated that the phenotype of the transgenic mouse hearts expressing a restrictive cardiomyopathy (RCM) cardiac troponin I (cTnI) C-terminal mutation (R193H) is characterized by a diastolic dysfunction and sudden cardiac death (SCD) (Du et al, 2006, 2008). We have also observed that restrictive cleavage of the N-terminal extension of cTnI (cTnI-ND) that occurs in physiological and pathological adaptations (Yu et al., 2001; Feng et al, 2008; McConnell et al., 2009) desensitizes myofibril sensitivity for Ca2+ and enhances diastolic function in transgenic mice expressing cTnI-ND (Li et al, 2010). In the present study, we generated 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 the mechanisms underlying the protective role of cTnI-ND in young and aged RCM mice. In 2-month-old Double-TG mice, cTnI-ND rescues RCM mice by correcting diastolic dysfunction caused by cTnI R193H mutation in the heart. The rescue effect of cTnI-ND shows a dose-dependent manner. In 8-10-month-old Double-TG mice, echocardiography and Doppler data indicate that cTnI-ND rescues RCM mice not only by reversing the diastolic dysfunction, but also by improving systolic function in the heart, since both diastolic and systolic functions are deteriorated in aged RCM mice. Cell-based assays measuring cardiac cell contractility further confirm the dose-dependent protective effect of cTnI-ND in correcting the impaired relaxation in isolated cardiac myocytes from various Double-TG mouse lines. Consistent with the beneficial effect of cTnI-ND on the function of non-myopathic aging hearts (Biesiadescki et al., 2010), these data demonstrate that cTnI-ND can rescue RCM phenotype not only by correcting diastolic dysfunction in young RCM mice but also by improving systolic function in aged RCM mice.