Hypoxia is an important environmental cue in heart development. Despite of extensive characterization of gain and loss of function models, there is disagreement about the impact of HIF1α elimination in cardiac tissue. Here, we used a new conditional knock out of Hif1a in NKX2.5 cardiac progenitors to assess the morphological and functional consequences of HIF1α loss in the developing heart. By combining histology, electron microscopy and high-throughout genomics, proteomics and metabolomics, we found that deletion of Hif1a leads to impaired embryonic glycolysis without influencing cardiomyocyte proliferation and results in an increased mitochondrial number, activation of a transient amino acid response and upregulation of HIF2α and ATF4 by E12.5. Hif1a mutants display normal fatty acid oxidation metabolic profile and do not show any sign of cardiac dysfunction in the adulthood. Our results demonstrate that HIF1 signaling is dispensable for heart development and reveal the metabolic flexibility of the embryonic myocardium, opening the potential application of alternative energy sources as therapeutic interventions during ischemic events.

中文翻译：

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响应心脏HIF1缺陷小鼠糖酵解受损而激活氨基酸代谢程序

缺氧是心脏发育的重要环境提示。尽管功能模型的获得和丧失具有广泛的特征，但是关于HIF1α消除在心脏组织中的影响尚存在分歧。在这里，我们使用了新的条件性敲除NKX2.5心脏祖细胞中的Hif1a，以评估发育中的心脏中HIF1α丢失的形态和功能后果。通过组织学，电子显微镜和高通量基因组学，蛋白质组学和代谢组学的结合，我们发现Hif1a的缺失会导致胚胎糖酵解受损而不影响心肌细胞的增殖，并导致线粒体数目增加，瞬时氨基酸反应的激活和HIF2α的上调和ETF的ATF4。Hif1a突变体显示正常的脂肪酸氧化代谢谱，在成年期未显示任何心脏功能障碍的迹象。我们的研究结果表明，HIF1信号对于心脏发育是必不可少的，并且揭示了胚胎心肌的代谢灵活性，从而开启了替代能源在缺血事件中作为治疗干预手段的潜在应用。