Skeletal muscle derived musclin as endocrine regulator of heart function

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，并且--如果完全心脏恶病质存在--死亡率显著升高。我们推测，在这种情况下，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，我们建立了一种心源性恶病质的小鼠模型，该模型基于实验性横动脉缩窄(TAC)引起的长期压力超负荷。使用RNA测序对TAC诱导的消瘦小鼠和健康小鼠的股四头肌转录组进行的全局分析显示，Musclin mRNA强烈下调，该基因编码一种内分泌主要是骨骼肌源性因子，而心脏不表达。Musclin与利钠肽(ANP、BNP、CNP)部分同源，来自其他组织的数据表明，它通过与它们的清除受体NPR3结合来减少它们的降解。肌抑素对心脏的影响在很大程度上仍不清楚。我们假设，心肌恶病质期间骨骼肌中Musclin蛋白表达的减少导致保护性(增强收缩、抗肥大和抗纤维化)钠尿肽的降解，从而促进心力衰竭的进展，这可能表明Musclin在这种情况下是治疗的靶点。因此，在这项建议中，我们希望分析通过基因治疗方法提高骨骼肌肌钙蛋白是否可以缓解心力衰竭和适应性不良的心脏重塑，如果是的话，这是否通过肌钙蛋白与NPR3受体的结合而发生。此外，我们的目标是通过检测骨骼肌特异性肌动蛋白基因敲除小鼠来研究内源性肌动蛋白在心力衰竭发生发展中的作用。对分离的心肌细胞的收缩能力、钙瞬变以及细胞内cGMP和cAMP水平的分析将详细揭示Musclin如何作用于这些细胞。我们还将开始研究在人类恶病质疾病中肌肉粘蛋白的水平。

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.