Age-dependent biochemical and contractile properties in atrium of transgenic mice overexpressing junctin

• Published in: American journal of physiology. Heart and circulatory physiology 2004-11, Vol.287 (5), p.H2216-H2225
• Main Authors: Kirchhefer, Uwe, Baba, Hideo A, Hanske, Gabriela, Jones, Larry R, Kirchhof, Paulus, Schmitz, Wilhelm, Neumann, Joachim
• Format: Article
• Language: English
• Subjects: Aging - physiology; Animals; Atrial Function; Caffeine - pharmacology; Calcium - metabolism; Calcium-Binding Proteins - metabolism; Dogs; Electric Stimulation; Electrocardiography; Heart Atria - metabolism; Heart Rate; Homeostasis; In Vitro Techniques; Membrane Proteins - metabolism; Mice; Mice, Inbred Strains; Mice, Transgenic; Mixed Function Oxygenases - metabolism; Muscle Proteins - metabolism; Myocardial Contraction - drug effects; Myocardium - metabolism; Sarcoplasmic Reticulum - metabolism
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00137.2004

1 Institut für Pharmakologie und Toxikologie and 2 Medizinische Klinik und Poliklinik C, Westfälische Wilhelms-Universität, 48149 Münster; 3 Institut für Pathologie, Universität Essen, 45147 Essen, Germany; and 4 Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202 Submitted 13 February 2004 ; accepted in final form 13 June 2004 Junctin is a transmembrane protein of the cardiac junctional sarcoplasmic reticulum (SR) that binds to the ryanodine receptor, calsequestrin, and triadin 1. This quaternary protein complex is thought to facilitate SR Ca 2+ release. To improve our understanding of the contribution of junctin to the regulation of SR function, we examined the age-dependent effects of junctin overexpression in the atrium of 3-, 6-, and 18-wk-old transgenic mice. The ratio of atrial weight and body weight was unchanged between junctin-overexpressing (JCN) and wild-type (WT) mice at all ages investigated ( n = 6–8). The protein expression of triadin 1 was decreased starting in 3-wk-old JCN atria (by 69%), whereas the expression of the ryanodine receptor was diminished in 6- (by 48%) and 18-wk-old (by 57%) JCN atria compared with age-matched WT atria. Force of contraction was decreased by 35% in 18-wk-old JCN compared with age-matched WT left atrial muscle strips, which was accompanied by a prolonged time of relaxation (48.1 ± 0.9 vs. 44.2 ± 0.8 ms, respectively, n = 6–8, P < 0.05). The spontaneous beating rate of isolated right atria was higher in 18-wk-old JCN mice compared with age-matched WT mice (389 ± 10 vs. 357 ± 6 beats/min, respectively, n = 6–8, P < 0.05). Heart rate was lower by 9% in telemetric ECG recordings in 18-wk-old JCN mice during stress tests. Three-week-old JCN atria exhibited a higher potentiation of force of contraction at rest pauses of 30 s (by 13%) and of 300 s (by 35%), suggesting increased SR Ca 2+ content. This was consistent with the higher force of contraction in 3-wk-old JCN atria (by 29%) compared with age-matched WT atria (by 10%) under the administration of caffeine. We conclude that in 3-wk-old atria, junctin overexpression was associated with a reduced expression of triadin 1 resulting in a higher SR Ca 2+ load without changes in contractility or heart rate. In 6-wk-old JCN atria, the compensatory downregulation of the ryanodine receptor may offset the effects of junctin overexpression. Finally, the progressive decrease in ryanodine receptor densit