MCU Overexpression Rescues Inotropy and Reverses Heart Failure by Reducing SR Ca²⁺Leak

Rationale: In heart failure (HF), impaired sarcoplasmic reticulum (SR) Ca2+ release and cytosolic Na+ overload depress mitochondrial Ca2+ (mCa2+) signaling, resulting in a diminished ability to maintain matrix NAD(P)H redox potential, leading to increased oxidative stress when workload increases. Enhancing mCa2+ can reverse this defect but could potentially increase the likelihood of mCa2+ overload. Objective: To determine if moderate mCa2+ uniporter (MCU) overexpression has beneficial or detrimental effects on the development of HF and incident arrythmias in a guinea pig model (ACi) of HF and sudden cardiac death. Methods and Results: In vivo viral gene transfer was used to increase MCU levels by ≈57% in ACi hearts. Left ventricular myocytes from hearts with MCU overexpression (ACi+MCU) displayed enhanced mCa2+ uptake, decreased oxidative stress, and increased β-adrenergic- and frequency-dependent augmentation of Ca2+ transients and contractions, compared with myocytes from ACi hearts. MCU overexpression decreased SR Ca2+ leak in the ACi group and mitigated the elevated RyR (ryanodine receptor) disulfide crosslinks in HF. β-Adrenergic responses were blunted in isolated perfused ACi hearts, and these deficiencies were normalized in ACi+MCU hearts. To examine the in vivo effects of MCU overexpression, ACi hearts were transduced with the MCU virus 2 to 3 weeks after aortic constriction, at the onset of cardiac decompensation. Two weeks later, cardiac function worsened in the untreated ACi group (fractional shortening: 39±1% at 2 weeks and 32±1% at 4 weeks), whereas MCU overexpression significantly improved cardiac function (36±1% at 2 weeks and 42±2% at 4 weeks). MCU overexpression in the decompensating ACi heart also attenuated pulmonary edema and interstitial fibrosis and prevented triggered arrhythmias. Conclusions: Moderate MCU overexpression in failing hearts enhances contractility and responses to β-adrenergic stimulation in isolated myocytes and perfused hearts by inhibiting mitochondrial oxidative stress-induced SR Ca2+ leak. MCU overexpression also reversed HF and inhibited ectopic ventricular arrhythmias.