201. Skeletal muscle derived Musclin protects the heart during pathological overload.
- Author
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Szaroszyk M, Kattih B, Martin-Garrido A, Trogisch FA, Dittrich GM, Grund A, Abouissa A, Derlin K, Meier M, Holler T, Korf-Klingebiel M, Völker K, Garfias Macedo T, Pablo Tortola C, Boschmann M, Huang N, Froese N, Zwadlo C, Malek Mohammadi M, Luo X, Wagner M, Cordero J, Geffers R, Batkai S, Thum T, Bork N, Nikolaev VO, Müller OJ, Katus HA, El-Armouche A, Kraft T, Springer J, Dobreva G, Wollert KC, Fielitz J, von Haehling S, Kuhn M, Bauersachs J, and Heineke J
- Subjects
- 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase genetics, 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase metabolism, Aged, Aged, 80 and over, Animals, Cachexia metabolism, Cachexia physiopathology, Cachexia prevention & control, Case-Control Studies, 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 metabolism, Endomyocardial Fibrosis physiopathology, Endomyocardial Fibrosis prevention & control, Female, Gene Expression Regulation, Heart Failure metabolism, Heart Failure physiopathology, Heart Failure prevention & control, Heart Function Tests, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle Proteins agonists, Muscle Proteins antagonists & inhibitors, Muscle Proteins deficiency, Muscular Atrophy metabolism, Muscular Atrophy physiopathology, Muscular Atrophy prevention & control, Myocardium metabolism, Myocardium pathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, Transcription Factors agonists, Transcription Factors antagonists & inhibitors, Transcription Factors deficiency, Cachexia genetics, Endomyocardial Fibrosis genetics, Heart Failure genetics, Muscle Proteins genetics, Muscle, Skeletal metabolism, Muscular Atrophy genetics, Transcription Factors genetics
- 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., (© 2022. The Author(s).)
- Published
- 2022
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