Cardiac Ryanodine Receptor (Ryr2)-mediated Calcium Signals Specifically Promote Glucose Oxidation via Pyruvate Dehydrogenase

Cardiac ryanodine receptor (Ryr2) Ca2+ release channels and cellular metabolism are both disrupted in heart disease. Recently, we demonstrated that total loss of Ryr2 leads to cardiomyocyte contractile dysfunction, arrhythmia, and reduced heart rate. Acute total Ryr2 ablation also impaired metabolis...

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Published in:The Journal of biological chemistry 2016-11, Vol.291 (45), p.23490-23505
Main Authors: Bround, Michael J., Wambolt, Rich, Cen, Haoning, Asghari, Parisa, Albu, Razvan F., Han, Jun, McAfee, Donald, Pourrier, Marc, Scott, Nichollas E., Bohunek, Lubos, Kulpa, Jerzy E., Chen, S. R. Wayne, Fedida, David, Brownsey, Roger W., Borchers, Christoph H., Foster, Leonard J., Mayor, Thibault, Moore, Edwin D.W., Allard, Michael F., Johnson, James D.
Format: Article
Language:English
Subjects:
Animals
calcium
Calcium - metabolism
calcium intracellular release
Calcium Signaling
cardiac metabolism
cardiomyocyte
Gene Deletion
Glucose - metabolism
heart failure
intracellular calcium release
Metabolism
Metabolome
metabolomics
Mice
Mice, Inbred C57BL
mitochondria
mitochondrial metabolism
Myocardial Contraction
Myocardium - cytology
Myocardium - metabolism
Myocardium - pathology
Myocytes, Cardiac - cytology
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Oxidation-Reduction
Proteome
proteomics
Pyruvate Dehydrogenase Complex - metabolism
Pyruvates - metabolism
ryanodine receptor
Ryanodine Receptor Calcium Release Channel - genetics
Ryanodine Receptor Calcium Release Channel - metabolism
transcriptomics
tricarboxylic acid cycle (TCA cycle) (Krebs cycle)
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Summary:Cardiac ryanodine receptor (Ryr2) Ca2+ release channels and cellular metabolism are both disrupted in heart disease. Recently, we demonstrated that total loss of Ryr2 leads to cardiomyocyte contractile dysfunction, arrhythmia, and reduced heart rate. Acute total Ryr2 ablation also impaired metabolism, but it was not clear whether this was a cause or consequence of heart failure. Previous in vitro studies revealed that Ca2+ flux into the mitochondria helps pace oxidative metabolism, but there is limited in vivo evidence supporting this concept. Here, we studied heart-specific, inducible Ryr2 haploinsufficient (cRyr2Δ50) mice with a stable 50% reduction in Ryr2 protein. This manipulation decreased the amplitude and frequency of cytosolic and mitochondrial Ca2+ signals in isolated cardiomyocytes, without changes in cardiomyocyte contraction. Remarkably, in the context of well preserved contractile function in perfused hearts, we observed decreased glucose oxidation, but not fat oxidation, with increased glycolysis. cRyr2Δ50 hearts exhibited hyperphosphorylation and inhibition of pyruvate dehydrogenase, the key Ca2+-sensitive gatekeeper to glucose oxidation. Metabolomic, proteomic, and transcriptomic analyses revealed additional functional networks associated with altered metabolism in this model. These results demonstrate that Ryr2 controls mitochondrial Ca2+ dynamics and plays a specific, critical role in promoting glucose oxidation in cardiomyocytes. Our findings indicate that partial RYR2 loss is sufficient to cause metabolic abnormalities seen in heart disease.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M116.756973