Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing triadin 1

Triadin 1 is a major transmembrane protein in cardiac junctional sarcoplasm ic reticulum (SR), which forms a quaternary complex with the ryanodine rece ptor (Ca2+ release channel), junctin, and calsequestrin. To better understa nd the role of triadin 1 in excitation-contraction coupling in the heart, w e generated transgenic mice with targeted overexpression of triadin 1 to mo use atrium and ventricle, employing the alpha -myosin heavy chain promoter to drive protein expression. The protein was overexpressed 5-fold in mouse ventricles, and overexpression was accompanied by cardiac hypertrophy. The levels of two other junctional SR proteins, the ryanodine receptor and junc tin, were reduced by 55% and 73%, respectively in association with triadin 1 overexpression, whereas the levels of calsequestrin, the Ca2+ binding pro tein of junctional SR, and of phospholamban and SERCA2a, Ca2+-handling prot eins of the free SR, were unchanged. Cardiac myocytes from triadin 1-over-e xpressing mice exhibited depressed contractility; Ca2+ transients decayed a t a slower rate, and cell shortening and relengthening were diminished. The extent of depression of cell shortening of triadin 1-overexpressing cardio myocytes was rate-dependent, being more depressed under low stimulation fre quencies (0.5 Hz), but reaching comparable levels at higher frequencies of stimulation (5 Hz). Spontaneously beating, isolated work-performing heart p reparations overexpressing triadin 1 also relaxed at a slower rate than con trol hearts, and failed to adapt to increased afterload appropriately. The fast time inactivation constant, tau (1), of the L-type Ca2+ channel was pr olonged in transgenic cardiomyocytes. Our results provide evidence for the coordinated regulation of junctional SR protein expression in heart indepen dent of free SR protein expression, and furthermore suggest an important ro le for triadin 1 in regulating the contractile properties of the heart duri ng excitation-contraction coupling.