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

心脏代谢性疾病状态的一个新特征，包括肥胖、糖尿病和心力衰竭 血浆支链氨基酸(支链氨基酸；缬氨酸、亮氨酸、 异亮氨酸)和它们的同源α-酮酸(BCKA；我们团队和其他人的工作揭示了 在这些情况下，由于支链a-酮酸的活性受损，导致血浆BCKA升高 肝脏中的脱氢酶复合体，是由于抑制BCKDH激酶的高表达而导致的， BDK，激活磷酸酶PPM1K的表达降低。重要的是，全身操作 通过BDK和PPM1K的药物或遗传调节实现的BCKA代谢产生强大的影响 心脏的结构、功能和新陈代谢。因此，针对BCKA相关的新的治疗方法 这些通路在心脏功能障碍的治疗方面具有巨大的潜力。然而，目前还不清楚是否 全身应用BDK和PPM1K对心功能的影响是通过调节 PPM1K和BDK在心脏内的活性或仅仅是心脏慢性暴露增加的结果 血浆BCKA。本提案中概述的工作将建立在我们先前工作的基础上，以直接解决这一重要问题 通过利用新开发的动物模型来确定肝脏特异性BDK的影响 对心脏功能的调节；2)扩大我们对BCKA介导的信号转导的机制的理解 心脏中的通路；以及3)定义PPM1K在心脏中的作用。从完成过程中获得的知识 这一项目的实施有望帮助开发BCKA相关的治疗靶点，用于治疗心脏病 多种心脏代谢性疾病的功能障碍。

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.