Key result
Deleting the cardiac mitochondrial calcium uniporter reduces high-fat diet-induced VT inducibility by ~83% in mice.
Why the study?
Obesity and diabetes increase arrhythmia and sudden cardiac death risk, but the molecular mechanisms underlying metabolic arrhythmia are not well understood.
Does genetic deletion of MCU or inhibition of CaMKII prevent high-fat diet-induced ventricular arrhythmias and mitochondrial dysfunction in mice?
Does genetic deletion of MCU or inhibition of CaMKII prevent high-fat diet-induced ventricular arrhythmias and mitochondrial dysfunction in mice?
Absolute Event Rate: 16.7% vs 100%
p-value: p=0.0018
Mitochondrial calcium overload and subsequent CaMKII activation are key mechanisms of high-fat diet-induced arrhythmias, suggesting MCU and CaMKII as potential therapeutic targets.
Obesity and diabetes increase the risk of arrhythmia and sudden cardiac death. However, the molecular mechanisms of arrhythmia caused by metabolic abnormalities are not well understood. We hypothesized that mitochondrial dysfunction caused by high fat diet (HFD) promotes ventricular arrhythmia. Based on our previous work showing that saturated fat causes calcium handling abnormalities in cardiomyocytes, we hypothesized that mitochondrial calcium uptake contributes to HFD-induced mitochondrial dysfunction and arrhythmic events. For experiments, we used mice with conditional cardiac-specific deletion of the mitochondrial calcium uniporter (Mcu), which is required for mitochondrial calcium uptake, and littermate controls. Mice were used for in vivo heart rhythm monitoring, perfused heart experiments, and isolated cardiomyocyte experiments. MCU KO mice are protected from HFD-induced long QT, inducible ventricular tachycardia, and abnormal ventricular repolarization. Abnormal repolarization may be due, at least in part, to a reduction in protein levels of voltage gated potassium channels. Furthermore, isolated cardiomyocytes from MCU KO mice exposed to saturated fat are protected from increased reactive oxygen species (ROS), mitochondrial dysfunction, and abnormal calcium handling. Activation of calmodulin-dependent protein kinase (CaMKII) corresponds with the increase in arrhythmias in vivo. Additional experiments showed that CaMKII inhibition protects cardiomyocytes from the mitochondrial dysfunction caused by saturated fat. Hearts from transgenic CaMKII inhibitor mice were protected from inducible ventricular tachycardia after HFD. These studies identify mitochondrial dysfunction caused by calcium overload as a key mechanism of arrhythmia during HFD. This work indicates that MCU and CaMKII could be therapeutic targets for arrhythmia caused by metabolic abnormalities.
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Joseph et al. (2021) studied Arrhythmia caused by high-fat diet. Cardiac-specific deletion of mitochondrial calcium uniporter (MCU KO) vs. Littermate controls (WT) was evaluated on Inducible ventricular tachycardia (VT) (p=0.0018). Cardiac-specific deletion of the mitochondrial calcium uniporter protected mice from high-fat diet-induced ventricular tachycardia, reducing inducibility from 100% in controls to 16.7%.
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