Cardiac Ryanodine Receptor (Ryr2)-mediated Calcium Signals Specifically Promote Glucose Oxidation via Pyruvate Dehydrogenase
Cardiac Ryanodine Receptor (Ryr2)-mediated Calcium Signals Specifically Promote Glucose Oxidation via Pyruvate Dehydrogenase
复制标题
心脏Ryanodine受体（Ryr2）介导的钙信号通过丙酮酸脱氢酶特异性促进葡萄糖氧化
DOI：
10.1074/jbc.m116.756973
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发表时间：
2016-11-04
影响因子：
4.8
通讯作者：
Johnson, James D.
中科院分区：
文献类型：
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作者：
Bround, Michael J.;Wambolt, Rich;Johnson, James D.
心脏Ryanodine受体（Ryr 2）Ca2+释放通道和细胞代谢在心脏疾病中均被破坏。最近，我们证明Ryr2的完全缺失导致心肌细胞收缩功能障碍、心律失常和心率降低。急性总Ryr2消融也损害了代谢，但尚不清楚这是心力衰竭的原因还是后果。先前的体外研究表明，Ca2+流入线粒体有助于加快氧化代谢，但支持这一概念的体内证据有限。在这里，我们研究了心脏特异性，诱导型Ryr2单倍不足（cRyr250）小鼠，Ryr2蛋白稳定减少50%。这种操作降低了分离的心肌细胞中胞质和线粒体Ca2+信号的幅度和频率，而不改变心肌细胞收缩。值得注意的是，在灌流心脏的收缩功能保存良好的情况下，我们观察到葡萄糖氧化减少，但不是脂肪氧化，糖酵解增加。cRyr 250心脏表现出过度磷酸化和丙酮酸脱氢酶的抑制，丙酮酸脱氢酶是葡萄糖氧化的关键Ca 2+敏感守门人。代谢组学、蛋白质组学和转录组学分析揭示了该模型中与代谢改变相关的其他功能网络。这些结果表明，Ryr2控制线粒体Ca2+动力学，并在促进心肌细胞葡萄糖氧化中发挥特定的关键作用。我们的研究结果表明，部分RYR2损失足以导致心脏病中出现的代谢异常。
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 (cRyr250) 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. cRyr250 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.