Submitted on July 10, 2007
Accepted on September 17, 2007
Triadin is a critical determinant of cellular Ca cycling and contractility in the heart
Uwe Kirchhefer1*, Jan Klimas2, Hideo A Baba3, Igor B Buchwalow4, Larissa Fabritz5, Marion Huls5, Marek Matus1, Frank U Muller1, Wilhelm Schmitz1, and Joachim Neumann6
1 University of Muenster, Muenster, Germany
2 Comenius University Bratislava, Bratislava, Slovakia
3 University of Essen, Essen, Germany
4 Institute of Pathology Muenster, Muenster, Germany
5 University hospital Muenster, Muenster, Germany
6 University of Halle-Wittenberg, Halle, Germany
* To whom correspondence should be addressed. E-mail: kirchhef{at}uni-muenster.de.
Triadin is involved in the regulation of cardiac excitation-contraction coupling. However, the extent of its contribution to the regulation of sarcoplasmic reticulum (SR) Ca release remains unclear because overexpression of triadin in single transgenic mice was associated with the down-regulation of its homologue protein, junctin. In the present study, this problem was circumvented by cross-breeding of mice with heart-directed overexpression of triadin and junctin (JxT). This resulted in a stable ~3-fold expression of total triadin but unchanged junctin protein. Transgenic mice exhibited cardiac hypertrophy and structural abnormalities of myofibrils. Measurement of cardiac function by echocardiography and edge detection in myocytes revealed an impaired relaxation in JxT mice. The stimulation of 
-adrenergic receptors resulted in a depressed contractility and an impaired relaxation in catheterized hearts and myocytes of JxT mice. The use of a maximum stimulation frequency (5 Hz) was associated with both a lower shortening and relengthening in isolated myocytes of JxT mice. The contractile effects in JxT myocytes were paralleled by similar changes of the [Ca]i peak amplitude and Ca transient decay kinetics at basal conditions, under administration of isoproterenol, and high-frequency stimulation. Finally, we found a higher caffeine-induced [Ca]i peak amplitude in JxT myocytes. Our data show that the stable expression of triadin, independent of junctin expression, resulted in cardiac hypertrophy, prolonged basal relaxation, a depressed response to beta-adrenergic agonists, and altered Ca transients. Thus, the maintenance of triadin expression is essential for normal SR Ca cycling and contractile function.
