Reciprocal Adaptations in Sarcomere Sensitivity and Metabolic Phenotype

项目3研究肌节重塑后收缩功能代谢支持的适应性变化。该项目涉及该项目的中心主题，通过研究心脏中的代谢重塑，改变肌丝对Ca[2+]的敏感性，以及通过改变代谢信号传导来间接影响肌丝活性的潜力。总体目标是确定肌丝修饰是否诱导代谢调节的适应性、适应不良和/或心脏保护性转变。 途径。这项工作研究了病理生理应激是否诱导代谢活性的相互变化，通过AMPK连接的底物氧化竞争模式的转变，用于能量生产，和收缩功能，通过酰基衍生物对收缩功能的影响，通过磷酸化的肌节蛋白。主要假设是：收缩/调节蛋白的化学修饰，特别是肌钙蛋白和可能的调节肌球蛋白轻链，影响代谢表型，通过改变细胞质的化学环境来间接影响肌节活性。我们提出了三个具体的目标：1）确定压力超载，转基因小鼠心脏表达的胎儿/新生儿肌钙蛋白I，ssTnl亚型，应激抗性的一个明显的模型，并测试在压力超载心脏发生的氧化代谢的潜在适应不良的变化的衰减脂肪酸氧化和存储之间的平衡。2)阐明基线和B-肾上腺素能应激期间收缩功能代谢支持的改变， 肌丝修饰的小鼠心脏模型，其将或将不发展为家族性肥厚型心肌病（FHC），并且还显示出改变的AMPK活化3）通过与脱敏肌丝的小鼠心脏模型杂交，确定对拯救来自具有高Ca[2+]敏感性和FHC的TG小鼠的心脏的代谢反应。这些目标将通过一种独特的方法来实现，将代谢通量和酶表达的NMR测定与肌丝功能实验相结合， 蛋白质组学该实验计划将能够研究心肌病发病机制中肌节的代谢通量、AMPK激活和Ca[2+]敏感性之间的三方联系。

Project 3 examines adaptive changes in the metabolic support of contractile function subsequent to sarcomere remodeling. This project relates to the central theme of the program project, by investigating metabolic remodeling in hearts with altered myofilament sensitivity to Ca[2+], and the potential to reciprocally influence myofilament activity through altered metabolic signaling. The overall objective is to determine if myofilament modifications induce adaptive, maladaptive, and/or cardioprotective shifts in metabolic pathways. The work examines whether the pathophysiological stress induces reciprocal changes in both metabolic activity, through AMPK-linked shifts in competing modes of substrate oxidation for energy production, and contractile function, through resulting affects of acyl-derivatives on contractile function via phosphorylation of sarcomeric proteins. The primary hypothesis is that: Chemical modifications of the contractile/regulatory proteins, specifically within troponin and possibly the regulatory myosin light chain, influence metabolic phenotype which reciprocally effects sarcomere activity by altering the chemical environment of the cytosol. We propose three specific aims: 1) Determine the balance between fatty acid oxidation and storage in pressure overloaded, transgenic mouse hearts that express the fetal/neonatal isoform of troponin I, ssTnl, an apparent model of stress resistance, and test for attenuation of potentially maladaptive changes in oxidative metabolism that occur during pressure overload cardiac. 2) Elucidate alterations in the metabolic support of contractile function at baseline and during B-adrenergic stress, in mouse heart models of myofilament modifications that will or will not develop familial hypertrophic cardiomyopathy (FHC), and also display altered AMPK activation 3) Determine the metabolic responses to rescue of hearts from TG mice with high Ca[2+] sensitivity and FHC, by crossing with a mouse heart model of desensitized myofilaments. These aims will be accomplished though a unique approach, combining NMR determinations of metabolic flux and enzyme expression with experiments on myofilament function and proteomics. The experimental plan will enable study of the three-way link between metabolic flux, AMPK activation, and Ca[2+] sensitivity of the sarcomeres in the pathogenesis of cardiomyopathy.