Skeletal muscle derived musclin as endocrine regulator of heart function

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

Musclin is a secreted protein, which is predominantly expressed in skeletal muscle, but not in heart or adipose tissue. We have recently shown that patients suffering from systolic heart failure (HFrEF) exert markedly reduced Musclin expression in skeletal muscle as well as reduced Musclin serum concentrations. In addition, we revealed that skeletal muscle derived Musclin protects the heart from systolic dysfunction and fibrosis during transverse aortic constriction (TAC) induced HFrEF in mice. Heart failure with preserved ejection fraction (HFpEF) has a high prevalence in our society and is associated with a similar high mortality as HFrEF, in part due to insufficient treatment options. The co-existence of HFpEF and obesity is associated with a particular unfavorable prognosis, although the underlying mechanisms remain unknown. In this proposal, we aim to decipher the role of Musclin in obesity associated HFpEF. In addition, we will investigate whether Musclin abundance is de-regulated in mice and patients with HFpEF. Our preliminary data from skeletal muscle specific Musclin knock-out mice suggest that endogenous Musclin protects from diastolic dysfunction and obesity in a mouse HFpEF model (administration of high fat diet feeding + L-Name). In this proposal, we will investigate by which molecular mechanisms Musclin acts in HFpEF in vivo, and whether therapeutic Musclin overexpression improves diastolic dysfunction and remodeling as well as obesity under these circumstances. We will therefore decipher the impact of Musclin on cardiac lipid deposition and gene-expression in whole hearts and cardiac fibroblasts at different time-points in the disease and will also delineate in mice whether Musclin in HFpEF acts via its putative receptor NPR3. On the other hand, we will investigate how Musclin acts on skeletal muscle and adipose tissue and how it thereby affects systemic metabolism, e.g. in order to suppress obesity. Furthermore, we are interested to see whether Musclin regulates endocrine signals from adipose tissue that could affect the heart and its function. For this purpose, we will analyze the transcriptome of adipose tissue and skeletal muscle in Musclin knock-out and overexpression conditions and will also clarify whether NPR3 is involved in the observed Musclin dependent effects. Data integration will help to decipher general and cell- or tissue specific Musclin dependent pathways and will identify possible new therapeutic targets for obesity associated HFpEF.

• DFG Programme: Research Grants