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Skeletal muscle derived Musclin protects the heart during pathological overload

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Item Type:Article
Title:Skeletal muscle derived Musclin protects the heart during pathological overload
Creators Name:Szaroszyk, M., Kattih, B., Martin-Garrido, A., Trogisch, F.A., Dittrich, G.M., Grund, A., Abouissa, A., Derlin, K., Meier, M., Holler, T., Korf-Klingebiel, M., Völker, K., Macedo, T.G., Tortola, C.P., 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, V.O., Müller, O.J., Katus, H.A., El-Armouche, A., Kraft, T., Springer, J., Dobreva, G., Wollert, K.C., Fielitz, J., von Haehling, S., Kuhn, M., Bauersachs, J. and Heineke, J.
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.
Keywords:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase, 80 and over Aged, Cachexia, Case-Control Studies, Cyclic AMP-Dependent Protein Kinases, Animal Disease Models, Endomyocardial Fibrosis, Gene Expression Regulation, Heart Failure, Heart Function Tests, Muscle Proteins, Skeletal Muscle, Muscular Atrophy, Myocardium, Cardiac Myocytes, Small Interfering RNA, Signal Transduction, Transcription Factors, Transcription Factors / genetics, Inbred C57BL Mice, Knockout Mice, Animals, Mice
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group
Volume:13
Number:1
Page Range:149
Date:10 January 2022
Official Publication:https://doi.org/10.1038/s41467-021-27634-5
PubMed:View item in PubMed

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