Skeletal muscle derived musclin as endocrine regulator of heart function

约20%的慢性心力衰竭患者发生骨骼肌萎缩。有趣的是，这种现象伴随着心脏功能下降，如果存在完全的心脏恶病质，死亡率明显升高。我们推测，在这些情况下，消耗过程中的骨骼肌可能直接导致心力衰竭的恶化。为了分析这一假设，我们开发了一种小鼠心脏恶病质模型，该模型基于实验性横向主动脉缩窄（TAC）诱导的长期压力超负荷。使用RNA测序对TAC诱导的消瘦小鼠与健康小鼠的四头肌肌肉转录组进行的整体分析显示，肌肉蛋白mRNA的强烈下调，肌肉蛋白mRNA编码一种内分泌主要是骨骼肌衍生的因子，该因子在心脏中不表达。Musclin与利钠肽（ANP，BNP，CNP）部分同源，来自其他组的数据表明，它通过与其清除受体NPR 3结合来减少其降解。肌肉素对心脏的影响在很大程度上仍不清楚。我们推测，在心脏恶病质期间骨骼肌中肌肉蛋白表达的减少需要增强保护性（收缩增强、抗肥大和抗纤维化）利钠肽的降解，从而促进心力衰竭进展，这将表明肌肉蛋白作为这些情况下的治疗靶点。因此，在这项提议中，我们希望分析通过基因治疗方法治疗性升高骨骼肌肌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，这是否是通过肌蛋白与NPR3受体结合而发生的。此外，我们的目的是研究内源性musclin的作用，心力衰竭的发展，通过检查骨骼肌特异性musclin基因敲除小鼠。在分离的心肌细胞中的收缩性，钙瞬变和细胞内cGMP和cAMP水平的分析将详细揭示肌肉蛋白如何作用于这些细胞。我们也将开始研究人类恶病质疾病中肌肉素的水平。

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.