Effect Of MG53 On ECG Stability Of Cardiomyocytes

Background:Mitsugumin 53(MG53)is a muscle-specific RBCC/TRIM family member,also named TRIM72.It is known that RBCC/TRIM family proteins share the highly conserved tripartite motif in the N-terminal regions which composed of Ring finger,B-box and Coiled domains.MG53,predominantly localized on intracellular vesicles and specifically expressed in striated muscle such as skeletal muscle and cardiac muscle.Several studies show that MG53 is involved in repair of injured plasma membrane.By usingadenovirusmediated infection of MG53 in the cardiomycytes,we find out that MG53 over-expression can enhance vesicle transport,budding and exocytose.Also in the MG53 knockout mice,the mice show muscular dystrophy and muscular dystrophy which is strongly associated with membrane repair function.Once plasma membrane is injured,MG53 which interacting with caveolin-3 recruits MG53-containing vesicle to the injury sites and bud form the cell membrane for membrane-patch formation by sensing the extracellular oxidative environment.All these evidence shows that MG53 is also associated with the ECG stability.Numerous studies have reported that MG53 can act as a cardioprotection role by repairing damaged cell membrane in the myocardial ischemia/reperfusion injury process and also plays an impotent role in ischemic preconditioning.Also it been show that upregulation of MG53 will induces diabetic cardiomyopathy,however few studies also reported the role of MG53 with calcium signaling and ion channel remodeling.Method and results:Experiments were performed on cultured neonatal rat ventricular myocytes,cultured adult rat ventricular myocytes and MG53 knockout mice ventricular myocytes.We use adenovirus to regulate MG53 expression to investigate the rules of MG53 in modulation of calcium signaling and action potential remodeling,if any.Our data clearly show that overexpression of MG53 will significantly increased the incidences of spontaneous Ca2+sparks.Also we find out that overexpression of MG53 could shorten APD.Simultaneously MG53 knockdown will significantly prolong APD and also significantly decreased the incidences of spontaneous Ca2+ sparks and Ik1 current density.Compare to the Wildtype mouse,MG53 knockout mice significantly prolong APD and significantly decreased IKs1 and Iks2 current density.Conclusion:Our data clearly show that by regulating MG53 expression there is significant and positive change in spontaneous Ca2+ sparks without affecting other calcium signal,so we suspect that MG53 can modified Ry R function therefore,modify calcium sparks.Also MG53 will strongly mediated action potential remodeling,so MG53 could be a new therapeutic target for Arrhythmia.