Skeletal muscle derived musclin as endocrine regulator of heart function

骨骼肌衍生的肌蛋白作为心脏功能的内分泌调节剂

• 批准号: 425476152
• 负责人: Professor Dr. Jörg Heineke
• 金额: --
• 依托单位: European Center for Angioscience (ECAS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/425476152?language=en
• 关键词: Skeletal; muscle; derived; musclin; endocrine

About 20% of patients with chronic heart failure develop skeletal muscle wasting. Interestingly, this phenomenon is accompanied by decreased cardiac function, and –if full cardiac cachexia exists- by markedly elevated mortality. We hypothesize that the skeletal muscle during wasting might directly contribute to worsening of heart failure under these circumstances. To analyze this hypothesis we developed a murine model of cardiac cachexia, which is based on long-term pressure overload induced by experimental transverse aortic constriction (TAC). A global analysis of the quadriceps muscle transcriptome in TAC induced wasting versus healthy mice using RNA-sequencing revealed a strong downregulation of musclin mRNA, which encodes an endocrine mainly skeletal muscle derived factor that is not expressed in the heart. Musclin is partially homologous to natriuretic peptides (ANP, BNP, CNP) and data from other groups suggest that it reduces their degradation by binding to their clearance-receptor NPR3. The effects of musclin on the heart remains largely unclear. We hypothesize that the reduced musclin protein expression in skeletal muscle during cardiac cachexia entails enhanced degradation of protective (contractility enhancing, anti-hypertrophic and anti-fibrotic) natriuretic peptides and thereby promote heart failure progression, which would suggest musclin as therapeutic target under these circumstances. In this proposal, we therefore want to analyze whether a therapeutic elevation of skeletal muscle musclin by a gene-therapeutic approach would alleviate heart failure and maladaptive cardiac remodeling, and if so, whether this occurs through binding of musclin to the NPR3 receptor. Furthermore, we aim to study the role of endogenous musclin for the development of heart failure by examining skeletal muscle specific musclin knock-out mice. Analyses of contractility, calcium transients and of intracellular cGMP and cAMP levels in isolated cardiomyocytes will reveal in detail how musclin acts on these cells. We will also start to investigate the levels of musclin in human cachectic diseases.

大约 20% 的慢性心力衰竭患者会出现骨骼肌萎缩，这种现象伴随着心脏功能下降，并且如果存在完全的心脏恶病质，我们发现骨骼肌萎缩可能直接导致死亡率升高。为了分析这一假设，我们开发了一种心脏恶病质的小鼠模型，该模型基于实验性横主动脉缩窄（TAC）引起的长期压力超负荷。使用 RNA 测序对 TAC 诱导消瘦小鼠和健康小鼠的股四头肌转录组进行分析，结果显示 Musclin mRNA 强烈下调，该基因编码一种主要由骨骼肌衍生的内分泌因子，该因子在心脏中不表达，与利尿钠肽 (ANP) 部分同源。 、BNP、CNP）和其他组的数据表明，它通过结合其清除受体 NPR3 来减少其降解。肌肉蛋白对心脏的影响仍然很大。我们还不清楚，心脏恶病质期间骨骼肌中肌肉蛋白表达的减少会导致保护性（增强收缩性、抗肥厚性和抗纤维化）利尿钠肽的降解增强，从而促进心力衰竭的进展，这表明肌肉蛋白可以作为治疗靶点。因此，在这种情况下，我们想要分析通过基因治疗方法提高骨骼肌肌肉蛋白是否会减轻心力衰竭和适应不良的心脏重塑。如果是这样，这是否是通过肌肉蛋白与 NPR3 受体的结合而发生的。此外，我们的目的是通过检查骨骼肌特异性肌肉蛋白敲除小鼠的收缩性、钙瞬变来研究内源性肌肉蛋白在心力衰竭发展中的作用。分离心肌细胞中的细胞内 cGMP 和 cAMP 水平的研究将详细揭示肌肉蛋白如何作用于这些细胞。我们还将开始研究肌肉蛋白在人类恶病质疾病中的水平。