In the failing heart, Ca²⁺-cycling is profoundly altered leading to leak of Ca²⁺ from the sarcoplasmic reticulum (SR). Mitsugumin 23 (MG23) is a non-selective cation channel located with abundance on ER/SR membranes. Previously, we have suggested that MG23 mediated Ca²⁺-release in cardiac tissue becomes more apparent under pathophysiological conditions (Reilly O’Donnell 2017 JBC). This raises the question that MG23 may play a role in the progression of heart failure. The aim of this study was to investigate whether MG23 functions as Ca²⁺-leak channel and to probe its role in the failing heart.

Ca²⁺-store levels in fluo-4 loaded cardiomyocytes isolated from WT and MG23 KO hearts were assessed by the application of caffeine. To induce pressure-overload, MG23 knock out (KO) and wild type (WT) mice had Angiotensin II (1.1mg/kg/day) osmotic pumps implanted. Dynamic cardiac functions were measured in vivo using pressure-volume catheters placed in the left ventricle using a closed chest approach. Using histological approaches assessment of ventricular fibrosis following angiotensin treatment was made in WT and MG23 KO animals.

Cardiomyocytes isolated from MG23 KO animals had a reduced Ca²⁺-store load compared to WT controls. Knock out of MG23 protected hearts against angiotensin II induced hypertrophy. In contrast to WT hearts, MG23 KO hearts displayed no change in cardiac compliance following angiotensin II treatment. MG23 KO animals also had significantly reduced ventricular fibrosis compared to WT controls.

These data for the first time show that MG23 contributes to leakage of Ca²⁺ from SR stores and plays a key role in driving the early pathological stages of pressure-overload induced heart failure.