Background: Maladaptive remodeling during chronic heart failure is characterized by the activation of different neurohormonal systems. While chronic activation of the sympathetic nervous system is harmful, increased natriuretic peptide (NP) level are in principal beneficial, although their effectiveness is strongly impaired in heart failure, in part due to their rapid degradation. Musclin, a novel skeletal muscle-derived, secreted myokine is a specific ligand of the NP clearance receptor (Npr3), thereby inhibiting the degradation of natriuretic peptides (ANP, BNP, CNP).

Methods: Transaortic constriction (TAC) was used to induce long-term pressure overload and transition to heart failure with muscle wasting in C57/Bl6 mice. RNAseq in wasting skeletal muscle 12 weeks after TAC revealed a 3.5-fold reduction in Musclin expression, which was confirmed by qPCR analysis. Because Musclin as potential cardioprotective myokine is downregulated in skeletal muscle during heart failure, we assessed the functional consequence of Musclin overexpression in murine skeletal muscle as therapeutic approach.

Results: AAV6-mediated skeletal muscle specific overexpression of Musclin ameliorated myocardial fibrotic remodeling (Sirius red staining) and pulmonary congestion (lung weight/body weight ratio) compared to AAV6-Control treated mice 12 weeks after TAC. These beneficial effects were accompanied by improved cardiac function (echocardiography) 6, 9 and 12 weeks after TAC in mice treated with AAV6-Musclin. Improved systolic contractility and diastolic relaxation was also demonstrated in the AAV6-Musclin group by intraventricular pressure/volume analysis. Furthermore, we investigated the impact of Musclin overexpression on cardiomyocyte contractility in isolated cardiomyocytes. Indeed, adult murine cardiomyocytes isolated from mice 8 week after TAC and AAV6-Musclin administration (vs. TAC and AAV6-Control) exhibited improved contractility at baseline and during β1-AR-stimulation (Isoproterenol). While NP production (qPCR and Western blot analysis) in murine hearts was not different in AAV6-Musclin vs. AAV6-Control treated mice subjected to TAC, ANP plasma levels tended to be higher in AAV6-Musclin treated mice, suggesting less degradation of NPs. Administration of a selective Npr3 antagonist (AP-811) via osmotic pumps for 4 weeks partially blunted the Musclin induced increase in cardiac function, indicating that Musclin mediates its effects at least in part via preventing the degradation of NPs.

Conclusion:  Our data show that Musclin potently attenuates LV dysfunction following pressure overload at least in part through enhancement of natriuretic peptide (NP) signaling. Preventing disease progression in chronic heart failure by inter-tissue communication via AVV6-mediated overexpression of the myokine Musclin could be a promising therapeutic strategy for the treatment of chronic heart failure.