Ablation of junctin in mice enhanced cardiac contractility but caused aberrant calcium homeostasis leading to fatal arrhythmias, with 25% of junctin-null mice dying by 3 months of age.
Junctin is an essential regulator of sarcoplasmic reticulum calcium release, and its deficiency in mice leads to aberrant calcium homeostasis and fatal ventricular arrhythmias.
BACKGROUND: Abnormal sarcoplasmic reticulum calcium (Ca) cycling is increasingly recognized as an important mechanism for increased ventricular automaticity that leads to lethal ventricular arrhythmias. Previous studies have linked lethal familial arrhythmogenic disorders to mutations in the ryanodine receptor and calsequestrin genes, which interact with junctin and triadin to form a macromolecular Ca-signaling complex. The essential physiological effects of junctin and its potential regulatory roles in sarcoplasmic reticulum Ca cycling and Ca-dependent cardiac functions, such as myocyte contractility and automaticity, are unknown. METHODS AND RESULTS: The junctin gene was targeted in embryonic stem cells, and a junctin-deficient mouse was generated. Ablation of junctin was associated with enhanced cardiac function in vivo, and junctin-deficient cardiomyocytes exhibited increased contractile and Ca-cycling parameters. Short-term isoproterenol stimulation elicited arrhythmias, including premature ventricular contractions, atrioventricular heart block, and ventricular tachycardia. Long-term isoproterenol infusion also induced premature ventricular contractions and atrioventricular heart block in junctin-null mice. Further examination of the electrical activity revealed a significant increase in the occurrence of delayed afterdepolarizations. Consistently, 25% of the junctin-null mice died by 3 months of age with structurally normal hearts. CONCLUSIONS: Junctin is an essential regulator of sarcoplasmic reticulum Ca release and contractility in normal hearts. Ablation of junctin is associated with aberrant Ca homeostasis, which leads to fatal arrhythmias. Thus, normal intracellular Ca cycling relies on maintenance of junctin levels and an intricate balance among the components in the sarcoplasmic reticulum quaternary Ca-signaling complex.
Yuan et al. (Tue,) conducted a other in Junctin deficiency and ventricular arrhythmias. Junctin deficiency (gene ablation) vs. Normal hearts (wild-type) was evaluated on Mortality and arrhythmias. Ablation of junctin in mice enhanced cardiac contractility but caused aberrant calcium homeostasis leading to fatal arrhythmias, with 25% of junctin-null mice dying by 3 months of age.