Roles of SARM1 NAD hydrolase in metabolic cardiomyopathy

在包括心力衰竭和代谢性心肌病在内的疾病中观察到NAD+耗竭。维护 通过激活NAD+合成途径实现NAD+动态平衡已显示出治疗疾病的巨大前景。我们 在这里，探索抑制NAD+的摄入将防止NAD+的消耗，并改善心脏病。NAD+ 水解酶催化NAD+降解形成烟酰胺和ADPR。Sarm1是一种细胞内NAD+ 一种水解酶，被认为是轴突变性的执行者，促进线粒体功能障碍。 最近的研究表明，Sarm1是通过增加NMN/NAD+比值和Sarm1的磷酸化而激活的。 然而，Sarm1在代谢性心肌病中的作用从未被报道过，以及Sarm1是如何 激活导致线粒体功能障碍的原因尚不清楚。这个项目的总体目标是调查 Sarm1如何在代谢性心肌病中促进NAD+下降和调节有丝分裂。进一步 了解心脏中的Sarm1将为心脏病的治疗开发提供新的靶点。 在我们的实验数据中，我们发现Sarm1-KO小鼠和新发现的Sarm1缺乏 心肌细胞特异性Sarm1-KO小鼠(Sarm1-CKO)对代谢应激诱导的保护作用 心肌病，为Sarm1在导致糖尿病心脏功能障碍中的作用提供了第一个证据。 实验数据进一步表明，NAD+代谢和JNK1磷酸化信号可能激活SARM1， 而Sarm1促进糖尿病心脏的有丝分裂。基于这些结果，我们建议剖析 Sarm1在代谢性心肌病中的致病机制具有三个目的。《特定目标1》将使用 Sarm1-CKO小鼠确定心肌细胞Sarm1缺乏对1型糖尿病(T1D)的影响- 诱导性和饮食诱导性肥胖(DIO)诱发的心肌病。针对已知目标的多组学分析 糖尿病心脏的机械通路将被用来确定心肌细胞Sarm1缺陷是如何 保护心脏免受两种类型的代谢压力。特定目标2将了解新陈代谢是如何 应激激活Sarm1，导致脑室NAD+下降。我们将操纵NAD+代谢和JNK1- Sarm1磷酸化信号以确定两条通路如何激活Sarm1导致NAD+下降 在线粒体或细胞质中使用隔室特异性NAD+生物传感器。具体目标3将决定如何 Sarm1促进糖尿病心脏的丝裂原吞噬。代谢应激和Sarm1对有丝分裂通透性的影响 缺陷将通过Mito-Keima小鼠进行测量。Sarm1如何通过传统的PINK1促进有丝分裂 Parkin和/或替代的Ulk1-Rab9通路将在糖尿病心脏中进行检查。该项目将建立 Sarm1作为促进NAD+减少线粒体功能障碍和代谢性心肌病的新靶点。 该项目的结果将确定与Sarm1依赖机制相关的新的治疗靶点。

NAD+ depletion is observed in diseases including heart failure and metabolic cardiomyopathy. Maintaining NAD+ homeostasis by activating NAD+ synthesis pathways has shown great promise to treat diseases. We here explore that inhibiting NAD+ consumption will prevent NAD+ depletion and ameliorate heart disease. NAD+ hydrolases catalyze NAD+ degradation to form nicotinamide and ADPR. SARM1 is an intracellular NAD+ hydrolase that is known as an executer of axonal degeneration and promotes mitochondrial dysfunction. Recent studies showed that SARM1 is activated by increased NMN/NAD+ ratio and SARM1 phosphorylation. However, the role of SARM1 in metabolic cardiomyopathy has never been reported, and how SARM1 is activated to cause mitochondrial dysfunction is not known. The overall objective of this project is to investigate how SARM1 promotes NAD+ decline and regulates mitophagy during metabolic cardiomyopathy. Further understanding of SARM1 in the heart will lead to a new target for therapeutic development of heart disease. In our pilot data, we showed that SARM1 deficiency in SARM1-KO mice and in newly developed cardiomyocyte-specific SARM1-KO mice (SARM1-cKO) protected against metabolic stress-induced cardiomyopathy, providing the first evidence on the role of SARM1 in causing dysfunction of diabetic hearts. Pilot data further suggested that NAD+ metabolic and JNK1 phosphorylation signaling may activate SARM1, and SARM1 promotes mitophagy in diabetic hearts. Based on these results, we propose to dissect the pathogenic mechanisms of SARM1 in metabolic cardiomyopathy with the three aims. Specific Aim 1 will use SARM1-cKO mice to determine the impact of cardiomyocyte SARM1 deficiency on type 1 diabetes (T1D)- induced and diet-induced obesity (DIO)-induced cardiomyopathy. Multi-omics analyses targeting known mechanistic pathways of diabetic hearts will be performed to identify how cardiomyocyte SARM1 deficiency protects hearts against the two types of metabolic stresses. Specific Aim 2 will understand how metabolic stress activates SARM1 to cause compartmental NAD+ decline. We will manipulate NAD+ metabolic and JNK1- SARM1 phosphorylation signaling to establish how the two pathways activate SARM1 to cause NAD+ decline in mitochondria or cytosol using compartment-specific NAD+ biosensors. Specific Aim 3 will determine how SARM1 promotes mitophagy in diabetic hearts. Mitophagy flux impacted by metabolic stress and SARM1 deficiency will be measured by mito-Keima mice. How SARM1 promotes mitophagy via traditional PINK1- Parkin and/or alternative Ulk1-Rab9 pathways will be examined in diabetic hearts. This project will establish SARM1 as a new target to promote NAD+ decline mitochondrial dysfunction and metabolic cardiomyopathy. The results from this project will identify new therapeutic targets linked to SARM1-dependent mechanisms.