TY - THES AB - Mutations in the myosin binding protein C gene (MYBPC3) are a frequent cause of hypertrophic cardiomyopathy (HCM) and calcineurin plays a major role in hypertrophic remodelling. However, a functional link between MYBPC3 mutations and calcineurin has not been investigated. Mybpc3 knock out (KO) mice were generated and an increase in the regulator of calcineurin 1 (Rcan1) mRNA expression was detected, indicating an increase in calcineurin activity (Knöll et al. unpublished data). Accordingly, it was hypothesised that calcineurin, particularly its major β-isoform (CnAβ), plays a role in the pathogenesis of these mice. Therefore we investigated Mybpc3/CnAβ double KO (dKO) mice. Our results confirmed that the severe heart failure (HF) phenotype observed in Mybpc3 KO mice is completely rescued by additional ablation of CnAβ as judged by echocardiography, gravimetric analysis, histology and electron microscopy studies. We also have measured muscle contractility in skinned cardiac trabeculae from dKO mice and demonstrated that the rescue was present at the level of the contractile apparatus. Moreover, this rescue was specific to Mybpc3 KO mice as the phenotype of a mouse model expressing the apical hypertrophic cardiomyopathy-causing mutation ACTC E99K actin was more severe in ACTC E99K/ CnAβ double transgenic (dTG) mice.Crucially, it was found that ventricular myosin light chain (MLC2v) was hyperphosphorylated in the Mybpc3/CnAβ dKO mice. Furthermore, calcineurin was shown to dephosphorylate MLC2v in vitro. We therefore investigated whether MLC2v hyperphosphorylation per se could rescue the Mybpc3 KO phenotype. Mybpc3 KO mice were injected with AAV9 overexpressing pseudophosphorylated MLC2v (S14/15D; AAV9-pMLC2v), cardiomyocytes were transfected with adv-pMLC2v, and a construct to create a TG mice overexpressing pMLC2v was made.The AAV9-pMLC2v injected mice were studied in detail. A maximal improvement in cardiac function was observed AU - Abou,Al Saud S PY - 2016/// TI - Investigation of Phenotypic Rescue of Mybpc3 Deficient Mouse ER -