Journal Article

Skeletal muscle derived Musclin protects the heart during pathological overload

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

2022

Overview

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. Cachexia is associated with poor prognosis in heart failure. Here the authors show that mice and patients with cardiac cachexia display reduced skeletal muscle expression and circulating levels of Musclin. Musclin ablation in skeletal muscle worsens, while its muscle-specific overexpression ameliorates heart failure in mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 14/63 / 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase - genetics / 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase - metabolism / 38 / 38/89 / 38/90 / 38/91 / 42/41 / 42/44 / 59/57 / 64/60 / 692/308/1426 / 692/4019/592 / 82/80 / 96/1 / Ablation / Aged / Aged, 80 and over / Animals / C-Type natriuretic peptide / Cachexia / Cachexia - genetics / Cachexia - metabolism / Cachexia - physiopathology / Cachexia - prevention & control / Cardiac muscle / Cardiomyocytes / Case-Control Studies / Congestive heart failure / Cyclic AMP-Dependent Protein Kinases - genetics / Cyclic AMP-Dependent Protein Kinases - metabolism / Cyclic GMP-Dependent Protein Kinases - genetics / Cyclic GMP-Dependent Protein Kinases - metabolism / Disease Models, Animal / Endomyocardial Fibrosis - genetics / Endomyocardial Fibrosis - metabolism / Endomyocardial Fibrosis - physiopathology / Endomyocardial Fibrosis - prevention & control / Female / Fibrosis / Gene Expression Regulation / Gene sequencing / Heart failure / Heart Failure - genetics / Heart Failure - metabolism / Heart Failure - physiopathology / Heart Failure - prevention & control / Heart Function Tests / Humanities and Social Sciences / Humans / Kinases / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Muscle contraction / Muscle Proteins - agonists / Muscle Proteins - antagonists & inhibitors / Muscle Proteins - deficiency / Muscle Proteins - genetics / Muscle, Skeletal - metabolism / Muscles / Muscular Atrophy - genetics / Muscular Atrophy - metabolism / Muscular Atrophy - physiopathology / Muscular Atrophy - prevention & control / Musculoskeletal system / Myocardium - metabolism / Myocardium - pathology / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Overloading / Peptides / Prognosis / Protein kinase A / Protein kinase G / Proteins / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Signaling / Skeletal muscle / Transcription Factors - agonists / Transcription Factors - antagonists & inhibitors / Transcription Factors - deficiency / Transcription Factors - genetics