Knockout of the Intracellular Calcium Conducting Ion Channel Mitsugumin 23 ( <scp>MG23</scp> ) Protects Against Pressure Overload Induced Left Ventricular Hypertrophy and Cardiac Dysfunction

In 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 endoplasmic/sarcoplasmic reticulum (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 knockout of Mg23 protects the heart against pressure-overload induced left ventricular hypertrophy. Cardiac pressure-overload was induced in wild type (WT) and Mg23-knockout (KO) mice through subcutaneous Angiotensin II (AngII, 1.1 mg/kg/day) infusion via osmotic pump. After 10-day 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. AngII-induced cardiac pressure-overload increased expression of MG23 in WT mouse hearts. Knockout 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. Overexpression of MG23 in the ventricular cell line H9C2, resulted in reduced SR Ca²⁺ store levels. 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. MG23 plays a key role in driving Ca²⁺-dysregulation observed in the early pathological stages of pressure-overload induced heart failure.