Cardiac calsequestrin (Casq2) is thought to be the key sarcoplasmic reticulum (SR) Ca 2+ storage protein essential for SR Ca 2+ release in mammalian heart. Human CASQ2 mutations are associated with catecholaminergic ventricular tachycardia. However, homozygous mutation carriers presumably lacking functional Casq2 display surprisingly normal cardiac contractility. Here we show that Casq2-null mice are viable and display normal SR Ca 2+ release and contractile function under basal conditions. The mice exhibited striking increases in SR volume and near absence of the Casq2-binding proteins triadin-1 and junctin; upregulation of other Ca 2+ -binding proteins was not apparent. Exposure to catecholamines in Casq2-null myocytes caused increased diastolic SR Ca 2+ leak, resulting in premature spontaneous SR Ca 2+ releases and triggered beats. In vivo, Casq2-null mice phenocopied the human arrhythmias. Thus, while the unique molecular and anatomic adaptive response to Casq2 deletion maintains functional SR Ca 2+ storage, lack of Casq2 also causes increased diastolic SR Ca 2+ leak, rendering Casq2-null mice susceptible to catecholaminergic ventricular arrhythmias.

Heart muscle excitation-contraction (E-C) coupling is governed by Ca 2؉ release units (CRUs) whereby Ca 2؉ influx via L-type Ca 2؉ channels (Cav1.2) triggers Ca 2؉ release from juxtaposed Ca 2؉ release channels (RyR2) located in junctional sarcoplasmic reticulum (jSR). Although studies suggest that the jSR protein triadin anchors cardiac calsequestrin (Casq2) to RyR2, its contribution to E-C coupling remains unclear. Here, we identify the role of triadin using mice with ablation of the Trdn gene (Trdn ؊/؊ ). The structure and protein composition of the cardiac CRU is significantly altered in Trdn ؊/؊ hearts. jSR proteins (RyR2, Casq2, junctin, and junctophilin 1 and 2) are significantly reduced in Trdn ؊/؊ hearts, whereas Cav1.2 and SERCA2a remain unchanged. Electron microscopy shows fragmentation and an overall 50% reduction in the contacts between jSR and T-tubules. Immunolabeling experiments show reduced colocalization of Cav1.2 with RyR2 and substantial Casq2 labeling outside of the jSR in Trdn ؊/؊ myocytes. CRU function is impaired in Trdn ؊/؊ myocytes, with reduced SR Ca 2؉ release and impaired negative feedback of SR Ca 2؉ release on Cav1.2 Ca 2؉ currents (ICa). Uninhibited Ca 2؉ influx via ICa likely contributes to Ca 2؉ overload and results in spontaneous SR Ca 2؉ releases upon ␤-adrenergic receptor stimulation with isoproterenol in Trdn ؊/؊ myocytes, and ventricular arrhythmias in Trdn ؊/؊ mice. We conclude that triadin is critically important for maintaining the structural and functional integrity of the cardiac CRU; triadin loss and the resulting alterations in CRU structure and protein composition impairs E-C coupling and renders hearts susceptible to ventricular arrhythmias.cardiac muscle ͉ sarcoplasmic reticulum ͉ calsequestrin ͉ Cav1.2 ͉ RyR2

Bone turnover markers of resorption and formation are released during the process of bone remodelling. These markers have been extensively studied in a number of therapeutic trials of osteoporosis during the past decade. This has led to better understanding of their physiology, clinical applications and possible ways to optimize analytical techniques. Bone markers can complement the results of bone mineral density in the management of osteoporosis, but their use in clinical practice is challenged by pre-analytical and analytical variability. This review will discuss different types of bone markers, their limitations, use in different metabolic bone diseases and current recommendations from the International Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine bone marker standards working group.

Abstract-Cardiac calsequestrin-null mice (Casq2 Ϫ/Ϫ ) display catecholaminergic ventricular tachycardia akin to humans with CASQ2 mutations. However, the specific contribution of Casq2 deficiency to the arrhythmia phenotype is difficult to assess because Casq2 Ϫ/Ϫ mice also show significant reductions in the sarcoplasmic reticulum (SR) proteins junctin and triadin-1 and increased SR volume. Furthermore, it remains unknown whether Casq2 regulates SR Ca 2ϩ release directly or indirectly by buffering SR luminal Ca 2ϩ . To address both questions, we examined heterozygous (Casq2 ϩ/Ϫ ) mice, which have a 25% reduction in Casq2 but no significant decrease in other SR proteins. Casq2