Knock out of the intracellular calcium conducting ion channel Mitsugumin 23 (MG23) protects against pressure overload induced left ventricular hypertrophy and cardiac dysfunction.
BackgroundIn cardiac dysfunction, intracellular Ca2+-dynamics are disrupted leading to leakage of Ca2+ from the sarcoplasmic reticulum (SR). This results in diminished cardiac contractility and impaired cardiac function. In cardiac tissue, the underlying molecular mechanisms responsible for RyR2-independent Ca2+ leak are poorly understood. Mitsugumin 23 (MG23) is an intracellular Ca2+-conducting ion channel located on ER/SR and nuclear membranes. We propose that MG23 contributes to regulation of intracellular Ca2+-homeostasis, and that altered MG23 function may drive progression of cardiac dysfunction. The aim of this research was to investigate the role of MG23 in SR Ca2+ leak, and whether knock out of Mg23 protects the heart against pressure-overload induced left ventricular hypertrophy. MethodsCardiac pressure-overload was induced in wild type (WT) and Mg23-knock out (KO) mice through subcutaneous Angiotensin II (AngII, 1.1 mg/kg/day) infusion via osmotic pump. After 10-days infusion, in vivo pressure-volume dynamics were measured by insertion of a pressure-volume catheter into the left ventricle. MG23 protein expression was assessed through Western blot analysis. Ventricular fibrosis and cardiomyocyte size were measured using histological and immunofluorescence approaches. Cardiomyocytes were isolated from WT and Mg23-KO hearts and intracellular Ca2+ dynamics assessed through live cell imaging using the Ca2+ indicator Fluo-4. ResultsAngII-induced cardiac pressure-overload increased expression of MG23 in WT mouse hearts. Knock out of Mg23 protected hearts against AngII-induced cardiac hypertrophy. Compared to WT animals, AngII treated Mg23-KO mice displayed a significant reduction in left ventricular fibrosis and displayed normal cardiac functioning. In Mg23-KO hearts, no alteration in expression of key Ca2+ handling proteins was identified, but cardiomyocytes displayed altered Ca2+ spark profiles consistent with a role for MG23 in SR Ca2+ leak. ConclusionMG23 plays a key role in driving Ca2+ dysregulation observed in the early pathological stages of pressure-overload induced heart failure.