Skeletal muscle derived musclin as endocrine regulator of heart function

• Applicant: Professor Dr. Jörg Heineke
• Subject Area: Cardiology, Angiology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 425476152

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.

• DFG Programme: Research Grants