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The effects of RYR2 gene deletion on cardiac function and metabolism

University of British Columbia

The cardiac ryanodine receptor 2 (RYR2) is a sarcoplasmic reticulum Ca²⁺ release channel central to cardiomyocyte biology. RYR2 Ca²⁺ release has a well-established role in activating cardiomyocyte motor proteins during excitation-contraction coupling and is therefore critical for heart function. RYR2 is also poised to have other important cardiac functions such as setting heart rate, stimulating ATP metabolism, regulating cardiac hypertrophy, and controlling cardiomyocyte survival. In addition, there is evidence that RYR2 dysfunction occurs during heart disease, suggesting that RYR2 may be a driver of cardiac pathology. The research in this thesis seeks to test which aspects of cardiomyocyte biology are regulated by RYR2 signaling and whether RYR2 loss-of-function is pathogenic. Using a heart-specific, inducible gene deletion system in mice we were able to show that loss of Ryr2 caused heart failure and reduced cardiac contraction. In addition, we saw that Ryr2 deletion lead to reduced heart rate, tachycardic arrhythmia, diminished oxidative metabolism, increased cardiac hypertrophy, and increased cell death via a novel mechanism. To test whether the metabolic and heart rate effects persist in the absence of heart failure, we used an inducible, heart-specific 50% Ryr2 deletion model. In this context we did not see heart failure or decreased cardiac function, but still observed a decrease in heart rate and altered oxidative metabolism. Unlike complete Ryr2 knockout, the 50% Ryr2 ablation model did not display a general decrease in oxidative ATP metabolism, but instead a specific decrease in glucose oxidation. This was associated with reduced mitochondrial Ca²⁺ uptake and decreased activation of the pyruvate dehydrogenase complex, a Ca²⁺ sensitive gatekeeper of glucose oxidation. Collectively, these results provide compelling evidence that RYR2 is an essential component of excitation-contraction coupling and a critical driver of cardiac pacemaking. These results also demonstrate that RYR2 is critical for mitochondrial Ca²⁺ uptake and stimulating oxidative metabolism and strongly suggest that RYR2 has a specific role in activating glucose oxidation. This research also shows that loss of Ryr2 recapitulates heart failure and suggests RYR2 may be involved in hypertrophy and cell death. This suggests a model where RYR2 simultaneously regulates a several facets of cardiomyocyte biology.

Text

2016-04-14

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/57589

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/