Increased Cardiac PFK-2 Protects Against High-Fat Diet-Induced Cardiomyopathy and Mediates Beneficial Systemic Metabolic Effects

Abstract. The healthy heart adapts to changes in nutrient availability and energy demands. In metabolic diseases like type 2 diabetes (T2D), increased reliance on fatty acids for energy production contributes to mitochondrial dysfunction and cardiomyopathy. A principal regulator of cardiac metabolism is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2), which is a central driver of glycolysis. We hypothesized that increasing PFK-2 activity could mitigate cardiac dysfunction induced by high fat diet (HFD). Wild type (WT) and cardiac-specific transgenic mice expressing PFK-2 (Glyco^Hi) were fed a low fat or HFD for 16-weeks to induce metabolic dysfunction. Metabolic phenotypes were determined by measuring mitochondrial bioenergetics and performing targeted quantitative proteomic and metabolomic analysis. Increasing cardiac PFK-2 had beneficial effects on cardiac and mitochondrial function. Unexpectedly, Glyco^Hi mice also exhibited sex-dependent systemic protection from HFD, including increased glucose homeostasis. These findings support improving glycolysis via PFK-2 activity can mitigate mitochondrial and functional changes that occur with metabolic syndrome. There are two types of data in this upload, proteomics and metabolomics. The proteomics data are raw files acquired on a tsq quantiva triple quadrupole mass spectrometer in the SRM mode at OMRF. Each file is panel of protein assays. Please contact Mike Kinter with questions. The metabolomics data are more processed data files as described in the paper. Please contact Haiwei Gu with questions.摘要：健康心脏可适应营养供给与能量需求的动态变化。在2型糖尿病（type 2 diabetes, T2D）这类代谢性疾病中，机体对脂肪酸供能的依赖程度升高，可诱发线粒体功能障碍与心肌病。6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶（PFK-2）是心脏代谢的核心调控因子，同时也是糖酵解的关键驱动因子。我们提出假说：增强PFK-2活性可改善高脂饮食（high fat diet, HFD）诱导的心脏功能障碍。本研究将野生型（WT）小鼠与表达PFK-2的心脏特异性转基因小鼠（Glyco^Hi）分别饲喂低脂饮食或高脂饮食，持续16周以诱导代谢功能障碍。通过检测线粒体生物能学特征，并开展靶向定量蛋白质组学与代谢组学分析，以明确代谢表型。实验结果显示，增强心脏PFK-2活性对心脏与线粒体功能具有改善作用。出乎意料的是，Glyco^Hi小鼠还表现出性别依赖性的全身抗高脂饮食损伤效应，包括葡萄糖稳态的改善。本研究结果证实，通过增强PFK-2活性以优化糖酵解水平，可缓解代谢综合征相关的线粒体与功能异常。本次上传包含两类数据：蛋白质组学数据与代谢组学数据。蛋白质组学数据为在OMRF使用TSQ Quantiva三重四极杆质谱仪，以选择反应监测（Selected Reaction Monitoring, SRM）模式采集得到的原始文件，每个文件对应一套蛋白质检测组合。如有相关疑问，请联系Mike Kinter。代谢组学数据为经进一步处理的数据文件，具体说明详见论文。如有相关疑问，请联系Haiwei Gu。