Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice
Myc controls transcriptional regulation of cardiac metabolism and mitochondrial biogenesis in response to pathological stress in mice
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DOI：
10.1172/jci38331
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发表时间：
2010-05-01
影响因子：
15.9
通讯作者：
MacLellan, W. Robb
中科院分区：
文献类型：
--
作者：
Ahuja, Preeti;Zhao, Peng;MacLellan, W. Robb
在成人心脏中，脂肪酸氧化和线粒体基因的调控是由PPAR γ共激活因子-1 （PGC-1）转录共激活因子家族控制的。然而，在血流动力学负荷或缺血等病理性应激源的作用下，心肌细胞会下调PGC-1活性和脂肪酸氧化基因，而不是下调葡萄糖代谢途径。有趣的是，尽管PGC-1活性降低，但这些病理性应激源与线粒体生物发生有关，至少在最初是这样。在PGC-1减少的情况下，调控这些变化的转录因子尚不清楚，但Myc可以调节癌细胞细胞增殖和肿瘤发生过程中的葡萄糖代谢和线粒体生物发生。在这里，我们已经证明Myc在成年小鼠心肌中的激活增加了葡萄糖的摄取和利用，通过降低PGC-1 α水平下调脂肪酸氧化，并诱导线粒体生物发生。Myc在成人心肌中的失活可减轻肥厚生长，降低糖酵解和线粒体生物发生基因的表达，以响应血流动力学负荷。令人惊讶的是，myc介导的代谢改变与心脏功能的保存和缺血恢复的改善有关。我们的数据表明，Myc直接调节心肌细胞的葡萄糖代谢和线粒体生物发生，是心脏对病理应激反应中能量代谢的重要调节因子。
In the adult heart, regulation of fatty acid oxidation and mitochondrial genes is controlled by the PPAR gamma coactivator-1 (PGC-1) family of transcriptional coactivators. However, in response to pathological stressors such as hemodynamic load or ischemia, cardiac myocytes downregulate PGC-1 activity and fatty acid oxidation genes in preference for glucose metabolism pathways. Interestingly, despite the reduced PGC-1 activity, these pathological stressors are associated with mitochondrial biogenesis, at least initially. The transcription factors that regulate these changes in the setting of reduced PGC-1 are unknown, but Myc can regulate glucose metabolism and mitochondrial biogenesis during cell proliferation and tumorigenesis in cancer cells. Here we have demonstrated that Myc activation in the myocardium of adult mice increases glucose uptake and utilization, downregulates fatty acid oxidation by reducing PGC-1 alpha levels, and induces mitochondrial biogenesis. Inactivation of Myc in the adult myocardium attenuated hypertrophic growth and decreased the expression of glycolytic and mitochondrial biogenesis genes in response to hemodynamic load. Surprisingly, the Myc-orchestrated metabolic alterations were associated with preserved cardiac function and improved recovery from ischemia. Our data suggest that Myc directly regulates glucose metabolism and mitochondrial biogenesis in cardiac myocytes and is an important regulator of energy metabolism in the heart in response to pathologic stress.