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

J Biol Chem. 2016 Nov 4;291(45):23490-23505. doi: 10.1074/jbc.M116.756973. Epub 2016 Sep 12.


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.

Keywords: 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).

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Signaling*
  • Gene Deletion
  • Glucose / metabolism*
  • Metabolome
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Contraction*
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Oxidation-Reduction
  • Proteome
  • Pyruvate Dehydrogenase Complex / metabolism*
  • Pyruvates / metabolism
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism*


  • Proteome
  • Pyruvate Dehydrogenase Complex
  • Pyruvates
  • Ryanodine Receptor Calcium Release Channel
  • ryanodine receptor 2. mouse
  • Glucose
  • Calcium