Abstract 11441: Musclin, a Novel Skeletal Muscle Derived Myokine, Attenuates LV Dysfunction and Myocardial Fibrosis During Cardiac Cachexia.

Introduction: Cardiac cachexia is a strong independent risk factor for mortality in patients with chronic heart failure. However, the mechanism how skeletal muscle wasting adversely affects the course of heart failure during cardiac cachexia remains elusive. Here, we aim to determine whether skeletal muscle derived myokines are involved and whether they might be a therapeutic target to treat aggravated heart failure associated with cachexia. Methods Results: Transaortic constriction (TAC) for 12 weeks was used to induce severe long-term pressure overload and transition to heart failure with cardiac cachexia in C57/Bl6J mice. By RNAseq from quadriceps femoris muscle of cachectic mice, we identified a strongly reduced expression of Ostn , encoding the skeletal muscle derived and secreted protein musclin, which has been implicated in the control of natriuretic peptide (NP) signaling through binding to the NP clearance receptor Npr3. Compared to wild-type mice, skeletal muscle-restricted and tetracycline-inducible Ostn knock-out mice (Ostn flflHSA-rtTA/TRE-Cre) exhibited a marked deterioration of cardiac function and aggravated cardiac fibrosis after TAC. In turn, AAV6-mediated musclin overexpression in the quadriceps muscle and therefore restoration of musclin levels during wasting, ameliorated myocardial fibrotic remodeling, pulmonary congestion and LV-dysfunction compared to AAV6-control treated mice 12 weeks after TAC. Mechanistically, musclin enhanced C-type natriuretic peptide (CNP)- augmented contractility via a cGMP mediated inhibition of phosphodiesterase 3 (PDE3) and a subsequent rise in cAMP in isolated cardiomyocytes. Strikingly, the cardioprotective effects of musclin were blunted by administration of a selective Npr3 inhibitor, indicating that musclin mediates its effects at least in part via Npr3. Conclusions: Our data show that skeletal muscle-secreted musclin potently attenuates LV dysfunction following pressure overload through enhancement of CNP-cGMP-PDE3 dependent augmentation of cAMP signaling in the heart. Inter-tissue communication via AVV6-mediated overexpression of the myokine musclin could be a promising therapeutic strategy for treating heart failure progression during cardiac cachexia. [ABSTRACT FROM AUTHOR]