Skeletal muscle derived Musclin protects the heart during pathological overload

Malgorzata Szaroszyk,Katja Derlin,Katharina Völker,Abel Martín-Garrido ,Hugo A Katus,Gergana Dobreva,Michaela Kühn ,Badder Kattih,Aya Abouissa,Carolin Zwadlo,Gesine M Dittrich,Mortimer Korf‐Klingebiel ,Nadja I Bork ,Michael Boschmann,Felix A Trogisch,Julio Cordero,Michael Wagner,Martin Meier,Ali El‐Armouche ,Viacheslav O Nikolaev,Thomas Thum,Jens Fielitz,Cristina Pablo Tortola,Kai C Wollert,Tania Garfias Macedo,Johann Bauersachs,Nancy Ν Huang ,Theresia Kraft,Xiaojing Luo,Jochen Springer,Stephan Von Haehling,Tim Holler,Andrea Grund,Robert Geffers,Sándor Bátkai ,Oliver Müller ,Natali Froese,Mona Malek Mohammadi,Joerg Heineke

doi:10.1038/s41467-021-27634-5

Abstract

Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.

Highlights

Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood
WT mice subjected to transverse aortic constriction (TAC) for 12 weeks developed maladaptive cardiac hypertrophy, severe pulmonary congestion and a strongly reduced echocardiographic left ventricular ejection fraction, all indicative of advanced heart failure (Fig. 1b–d)
In line with reduced degradation of natriuretic peptides in response to Musclin overexpression, we detected a trend towards increased ANP levels and significantly increased mature C-type natriuretic peptide (CNP) levels in plasma of associated virus 6 (AAV6) Musclin treated mice (Supplementary Fig. 3r, Fig. 3q)

Summary

Introduction

Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. Heart failure is a systemic disease that is complicated by co-morbidities in patients In this regard, the existence of cardiac cachexia in CHF patients has been identified as a predictor of increased mortality[2,3]. We show that Musclin expression is reduced in mice and patients suffering from cardiac cachexia and that skeletal muscle-specific disruption of Musclin exaggerates the progression of heart failure in mice. We show that Musclin mainly enhances cardiomyocyte C-type natriuretic peptide (CNP)/NPR-B signaling to increase cardiomyocyte contractility and to inhibit fibroblast activation

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Conclusion