Impaired cardiomyocyte relaxation and diastolic function in transgenic mice expressing slow skeletal troponin I in the heart

1. To assess the specific functions of the cardiac isoform of troponin I (c TnI), we produced transgenic mice that expressed slow skeletal troponin I ( ssTnI) specifically in cardiomyocytes. Cardiomyocytes from these mice displ aced quantitative replacement of cTnI with transgene-encoded ssTnI. 2. The ssTnI transgenic mice were viable and fertile and did not display in creased mortality or detectable cardiovascular histopathology. They exhibit ed normal ventricular weights and heart rates. 3. Permeabilized transgenic cardiomyocytes demonstrated an increased Ca2+ s ensitivity of tension and a lack of contractile responsiveness to cAMP-depe ndent protein kinase (PKA). Isolated cardiomyocytes from transgenic mice ha d normal velocities of unloaded shortening but unlike wild-type controls ex hibited no enhancement of the velocity of shortening in response to treatme nt with isoprenaline. Transgenic cardiomyocytes exhibited greater extents o f shortening than non-transgenic cardiomyocytes at baseline and after treat ment with isoprenaline. 4. The rates or rise or intracellular [Ca2+] and the peak amplitudes of the intracellular [Ca2+] transients were similar in transgenic and wild-type m yocytes. However, the half-time of intracellular [Ca2+] decay was significa ntly greater in the transgenic myocytes. This change in decay of intracellu lar [Ca2+] was correlated with an increase in the re-lengthening time of th e transgenic cells. 5. These changes in cardiomyocyte function in vitro were manifested in vivo as impaired diastolic function both at baseline and after stimulation with isoprenaline. 6. Thus, cTnI has important roles in regulating the Ca2+ sensitivity of car diac myofibrils and controlling cardiomyocyte relaxation and cardiac diasto lic function. cTnI is also required for the normal responsiveness of cardio myocytes to beta-adrenergic receptor stimulation.