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 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.
From the Cardiovascular Research Group, Life Sciences Institute and.|Departments of Cellular and Physiological Sciences.
Michael J
MJ
Bround
From the Cardiovascular Research Group, Life Sciences Institute and.|the Department of Pathology and Laboratory Medicine, University of British Columbia and the Centre for Heart and Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6.
Rich
R
Wambolt
From the Cardiovascular Research Group, Life Sciences Institute and.|Departments of Cellular and Physiological Sciences.
Haoning
H
Cen
From the Cardiovascular Research Group, Life Sciences Institute and.|Departments of Cellular and Physiological Sciences.
Parisa
P
Asghari
Biochemistry and Molecular Biology, and.|the Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4.
Razvan F
RF
Albu
the University of Victoria-Genome British Columbia Proteomics Centre, Victoria, British Columbia V8Z 7X8, and.
Jun
J
Han
From the Cardiovascular Research Group, Life Sciences Institute and.|Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia V6T 1Z3.
Donald
D
McAfee
From the Cardiovascular Research Group, Life Sciences Institute and.|Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia V6T 1Z3.
Marc
M
Pourrier
Biochemistry and Molecular Biology, and.|the Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4.
Nichollas E
NE
Scott
the Department of Pathology and Laboratory Medicine, University of British Columbia and the Centre for Heart and Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6.
Lubos
L
Bohunek
Biochemistry and Molecular Biology, and.
Jerzy E
JE
Kulpa
the Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 2T9, Canada.
S R Wayne
SR
Chen
From the Cardiovascular Research Group, Life Sciences Institute and.|Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia V6T 1Z3.
David
D
Fedida
Biochemistry and Molecular Biology, and.
Roger W
RW
Brownsey
the University of Victoria-Genome British Columbia Proteomics Centre, Victoria, British Columbia V8Z 7X8, and.
Christoph H
CH
Borchers
Biochemistry and Molecular Biology, and.|the Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4.
Leonard J
LJ
Foster
Biochemistry and Molecular Biology, and.|the Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4.
Thibault
T
Mayor
From the Cardiovascular Research Group, Life Sciences Institute and.|Departments of Cellular and Physiological Sciences.
Edwin D W
ED
Moore
From the Cardiovascular Research Group, Life Sciences Institute and.|the Department of Pathology and Laboratory Medicine, University of British Columbia and the Centre for Heart and Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6.
Michael F
MF
Allard
From the Cardiovascular Research Group, Life Sciences Institute and james.d.johnson@ubc.ca.|Departments of Cellular and Physiological Sciences.
James D
http://orcid.org/0000-0002-7523-9433
JD
Johnson
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D020543:Proteome; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D011773:Pyruvates / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*
D020543:Proteome; D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates; D019837:Ryanodine Receptor Calcium Release Channel; C000592748:ryanodine receptor 2. mouse; D005947:Glucose; D002118:Calcium
calcium; calcium intracellular release; cardiac metabolism; cardiomyocyte; heart failure; intracellular calcium release; metabolism; metabolomics; mitochondria; mitochondrial metabolism; proteomics; ryanodine receptor; transcriptomics; tricarboxylic acid cycle (TCA cycle) (Krebs cycle)