Understanding the multifaceted functions of MG53 in heart failure pathogenesis

心力衰竭是老年退伍军人最常见的健康问题。在细胞和分子水平上，心脏 衰竭是由于心脏兴奋-收缩（E-C）受损导致的心肌细胞收缩衰竭的结果 耦合过程E-C偶联是控制心肌细胞收缩的中心机制。一个关键 E-C偶联的结构成分是肌细胞横（T）小管系统。T管排列整齐 表面膜内陷进入细胞内部，对于快速电激发至关重要， 同步触发肌浆网Ca 2+释放，因此，协调收缩每个 整个肌细胞的收缩单位。在动物模型和人类患者的衰竭肌细胞中， 和其他人已经表明，规则排列的T-小管系统经历破坏性重塑，导致 异常的细胞内Ca 2+释放和受损的肌细胞收缩性。我研究的一个长期目标 该计划旨在更好地了解不同类型T小管损伤的机制 心脏病，并确定新的策略，可以恢复或修复T-小管的完整性，从而改善 甚至挽救心脏功能。为了确定T-小管修复的假定机制，我们有 检测到Mitsugumin 53（MG 53，也称为TRIM 72）在人类衰竭心脏中的表达增加， 慢性心力衰竭动物模型。MG 53是一种新的肌特异性蛋白，参与膜囊泡的形成 急性损伤后的运输和膜修复。我们的试验数据表明，外源性MG 53 短期过度表达可保护T-小管损伤，但长期过度表达MG 53 导致严重的T-小管破坏。这些看似相反的数据导致了一种假设，即MG 53介导的 膜修复是必要的，在短期内，以防止T-小管损伤，以应对心脏 应激，而MG 53的慢性长期上调导致肌细胞T-小管膜损伤和E- C偶联功能障碍代替膜修复。我们将在三个目标中测试这个假设：1）确定 MG 53上调在心肌病中T-小管完整性和心力衰竭进展中的作用; 2）确定MG 53上调在心肌病中的作用。 MG 53调节心肌细胞中T-小管完整性的机制;以及3）确定MG 53调节心肌细胞中T-小管完整性的分子机制。 心力衰竭中MG 53上调的机制。我们的研究将确定长期上调的作用， 膜修复蛋白MG 53在人和小鼠T-小管膜结构损伤中的作用 模型，这是一个完全未研究的领域。了解这些分子机制将提供新的 平台，并指导我们设计更好的MG 53/T-小管靶向治疗心力衰竭的治疗方法， 促进修复同时避免副作用。

Heart failure is the most common health concern for aging veterans. At the cellular and molecular level, heart failure is the result of cardiomyocyte contractile failure due to impairment of cardiac excitation-contraction (E-C) coupling process. E-C coupling is the central mechanism governing cardiomyocyte contraction. One critical structural component of E–C coupling is the myocyte transverse (T)-tubule system. T-tubules are orderly invaginations of surface membrane into the cell interior and are critical for rapid electric excitation and synchronous triggering of sarcoplasmic reticulum Ca2+ release, and therefore, coordinated contraction of each contractile unit throughout the entire myocyte. In failing myocytes from animal models and human patients, we and others have shown that the regularly arrayed T-tubule system undergoes disruptive remodeling, leading to aberrant intracellular Ca2+ release and compromised myocyte contractility. A long-term goal of my research program is to achieve a better understanding of the mechanisms underlying T-tubule damage in different types of heart disease, and to identify new strategies that can restore or repair T-tubule integrity and thereby improve or even rescue cardiac function. Towards identifying putative mechanisms for T-tubule repair, we have detected increased expression of Mitsugumin 53 (MG53, also known as TRIM72) in human failing hearts and animal models of chronic heart failure. MG53 is a novel muscle-specific protein involved in membrane vesicle trafficking and membrane repair following acute injury. Our pilot data showed that exogenous MG53 overexpression in short term protects against T-tubule damage, but chronic long-term overexpression of MG53 results in severe T-tubule disruption. These seemingly opposite data led to the hypothesis that MG53-mediated membrane repair is necessary in the short term to protect against T-tubule damage in response to cardiac stress, whereas chronic long-term upregulation of MG53 leads to myocyte T-tubule membrane damage and E- C coupling dysfunction instead of membrane repair. We will test this hypothesis in three aims: 1) Determine the role of MG53 upregulation in T-tubule integrity and heart failure progression in cardiomyopathy; 2) Define the mechanisms by which MG53 regulates T-tubule integrity in cardiomyocytes; and 3) Determine the molecular mechanism of MG53 upregulation in heart failure. Our study will define the role for long-term upregulation of the membrane repair protein, MG53, in damage of the T-tubule membrane structure in human and mouse models, which is a completely unstudied area. Understanding these molecular mechanisms will provide a new platform and guide us to design better MG53/T-tubule-targeted therapeutics for heart failure treatment by promoting repairs while avoiding the side effects.