Mutations of Cardiac Troponin I cause Restrictive Cardiomyopathy; is cTnI N-terminal deletion an effective rescuing approach ?

Cardiomyopathy is a disorder which affects the heart muscle and causes varied physiological dysfunctions. Restrictive cardiomyopathy RCM is a cardiac muscle disorder in which the left ventricle becomes stiff, due to relaxation impairment. Mutations of the sarcomeric protein cardiac troponin I cTnI gene is found to cause idiopathic RCM. These mutations of cTnI are located in the C-terminus and affect cardiac relaxation. Transgenic mouse models presenting the pathology observed in clinical patients with RCM have been generated by expressing the mutant cTnI in the heart. RCM-linked mutations increase cardiac myofilament Ca2 sensitivity and promote diastolic dysfunction in the heart. In our laboratory, we have generated double transgenic mice cTnI R193H/ND/KO by crossing the cTnI R193H mice with transgenic cTnI-N terminal truncated mice cTnI-ND. Previous studies using the double transgenic mice showed that ventricular relaxation is enhanced in these mice. This study’s aim is to investigate whether or not the cardiac troponin I N-terminal deletion cTnI-ND corrects the debilitating effects caused by the cTnI R193H high expression in the heart. In doing so, we have first confirmed the genetypes of each experimental group. Echocardiography measurements have been performed on the animals at age 19-21 days. Our data indicate that cTnI R193H/KO showed a significant diastolic dysfunction, whereas the cardiac function in double transgenic mice did not show any difference compared to that in the wild type group, suggesting a functional correction by cTnI-ND in RCM phenotype.
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