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。有趣的是，这种现象伴随着心功能下降，如果存在完全的心脏恶病质，则死亡率显著升高。我们推测，在这种情况下，骨骼肌萎缩可能直接导致心力衰竭的恶化。为了分析这一假设，我们建立了一种基于实验性主动脉横缩（TAC）引起的长期压力过载的小鼠心脏恶病质模型。使用rna测序对TAC诱导的消瘦小鼠与健康小鼠的股四头肌转录组进行了全面分析，发现肌肉蛋白mRNA的强烈下调，该mRNA编码一种在心脏中不表达的内分泌主要骨骼肌衍生因子。Musclin与利钠肽（ANP， BNP， CNP）部分同源，其他研究小组的数据表明，它通过与利钠肽的清除受体NPR3结合来减少利钠肽的降解。肌肉素对心脏的影响在很大程度上仍不清楚。我们假设，在心脏恶病质期间骨骼肌中肌肉蛋白表达的减少导致保护性（增强收缩力、抗肥厚和抗纤维化）利钠肽的降解增强，从而促进心力衰竭的进展，这表明肌肉蛋白是这种情况下的治疗靶点。因此，在本研究中，我们想分析通过基因治疗方法提高骨骼肌肌素的治疗性水平是否会减轻心力衰竭和心脏重构的不适应性，如果是这样，是否通过肌素与NPR3受体的结合来实现。此外，我们旨在通过检测骨骼肌特异性肌肉蛋白敲除小鼠来研究内源性肌肉蛋白在心力衰竭发展中的作用。分析离体心肌细胞的收缩力、钙瞬变、细胞内cGMP和cAMP水平将详细揭示肌素如何作用于这些细胞。我们也将开始研究肌肉素在人类病毒性疾病中的水平。