Mechanisms Connecting Dysregulated Branched-Chain Alpha-Ketoacid Metabolism to Cardiac Dysfunction

心脏代谢疾病状态的一个新特征，包括肥胖、糖尿病和心力衰竭， 代谢和随后的血浆支链氨基酸（BCAA;缬氨酸，亮氨酸， 异亮氨酸）和它们的同源α-酮酸（BCKA; KIV、KIC、KMV）。我们小组和其他人的工作揭示了 在这些病症中由于支链α-酮酸活性受损而引起血浆BCKA升高 在肝脏中的脱氢酶（BCKDH）复合物，由抑制性BCKDH激酶的更高表达引起， BDK，和较低的活化磷酸酶，PPM 1 K的表达。重要的是，全身操纵 通过BDK和PPM 1 K的药理学或遗传调节实现的BCKA代谢产生强大的影响 对心脏结构功能和新陈代谢的影响因此，靶向BCKA相关的新的治疗方法， 这些通路具有治疗心脏功能障碍的显著潜力。然而，目前尚不清楚是否 全身性BDK和PPM 1 K操作对心脏功能的体内效应是由于调节 心脏内的PPM 1 K和BDK活性或仅仅是心脏长期暴露于增加的 血浆BCKA。本提案中概述的工作将以我们先前的工作为基础，直接解决这一重要问题。 通过利用新开发的动物模型来弥补知识差距：1）确定肝脏特异性BDK的影响 2）扩展我们对BCKA介导的信号转导机制的理解 心脏中的通路;和3）定义PPM 1 K在心脏中的作用。从完成中获得的知识 预计该项目的研究将有助于开发用于治疗心脏病的BCKA相关治疗靶点。 广泛的心脏代谢疾病中的功能障碍。

An emerging feature of cardiometabolic disease states, including obesity, diabetes, and heart failure is perturbed metabolism and subsequent elevations of plasma branched-chain amino acids (BCAA; valine, leucine, isoleucine) and their cognate α-ketoacids (BCKA; KIV, KIC, KMV). Work from our group and others has revealed that elevated plasma BCKA arise in these conditions due to impaired activity of the branched chain a-ketoacid dehydrogenase (BCKDH) complex in liver, resulting from higher expression of the inhibitory BCKDH kinase, BDK, and lower expression of the activating phosphatase, PPM1K. Importantly, whole-body manipulation of BCKA metabolism achieved via pharmacologic or genetic modulation of BDK and PPM1K yields robust impacts on cardiac structure, function, and metabolism. Thus, novel therapeutic approaches targeting BCKA-related pathways hold significant potential for treatment of cardiac dysfunction. However, it remains unclear whether the in vivo effects of systemic BDK and PPM1K manipulation on cardiac function are due to modulation of PPM1K and BDK activity within the heart or simply the result of chronic exposure of the heart to increased plasma BCKA. The work outlined in this proposal will build upon our prior work to directly address this important knowledge gap by leveraging newly developed animal models to: 1) Determine the impact of liver-specific BDK modulation on cardiac function; 2) Extend our mechanistic understanding of BCKA-mediated signal transduction pathways in the heart; and 3) Define the role of PPM1K in the heart. The knowledge gained from the completion of this project is expected to aid in development of BCKA-related therapeutic targets for the treatment of cardiac dysfunction in a wide range of cardiometabolic diseases.