Skeletal muscle derived Musclin protects the heart during pathological overload

Malgorzata Szaroszyk, Badder Kattih (), Abel Martin-Garrido, Felix A. Trogisch, Gesine M. Dittrich, Andrea Grund, Aya Abouissa, Katja Derlin, Martin Meier, Tim Holler, Mortimer Korf-Klingebiel, Katharina Völker, Tania Garfias Macedo, Cristina Pablo Tortola, Michael Boschmann, Nora Huang, Natali Froese, Carolin Zwadlo, Mona Malek Mohammadi, Xiaojing Luo, Michael Wagner, Julio Cordero, Robert Geffers, Sandor Batkai, Thomas Thum, Nadja Bork, Viacheslav O. Nikolaev, Oliver J. Müller, Hugo A. Katus, Ali El-Armouche, Theresia Kraft, Jochen Springer, Gergana Dobreva, Kai C. Wollert, Jens Fielitz, Stephan Haehling, Michaela Kuhn, Johann Bauersachs and Joerg Heineke ()
Additional contact information
Malgorzata Szaroszyk: Hannover Medical School
Badder Kattih: Hannover Medical School
Abel Martin-Garrido: Heidelberg University
Felix A. Trogisch: Heidelberg University
Gesine M. Dittrich: Hannover Medical School
Andrea Grund: Hannover Medical School
Aya Abouissa: Heidelberg University
Katja Derlin: Hannover Medical School
Martin Meier: Hannover Medical School
Tim Holler: Hannover Medical School
Mortimer Korf-Klingebiel: Hannover Medical School
Katharina Völker: University of Würzburg
Tania Garfias Macedo: University of Göttingen Medical Center, DZHK (German Center for Cardiovascular Research), partner site Göttingen
Cristina Pablo Tortola: Charité-University Medical Center Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association
Michael Boschmann: Charité-University Medical Center Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association
Nora Huang: Charité-University Medical Center Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association
Natali Froese: Hannover Medical School
Carolin Zwadlo: Hannover Medical School
Mona Malek Mohammadi: Heidelberg University
Xiaojing Luo: Dresden University of Technology
Michael Wagner: Dresden University of Technology
Julio Cordero: Heidelberg University
Robert Geffers: Helmholtz Center for Infection Research
Sandor Batkai: Hannover Medical School
Thomas Thum: Hannover Medical School
Nadja Bork: University Medical Center Hamburg-Eppendorf
Viacheslav O. Nikolaev: University Medical Center Hamburg-Eppendorf
Oliver J. Müller: University Hospital Schleswig-Holstein
Hugo A. Katus: University Hospital Heidelberg
Ali El-Armouche: Dresden University of Technology
Theresia Kraft: Hannover Medical School
Jochen Springer: Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT)
Gergana Dobreva: Heidelberg University
Kai C. Wollert: Hannover Medical School
Jens Fielitz: Charité-University Medical Center Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association
Stephan Haehling: University of Göttingen Medical Center, DZHK (German Center for Cardiovascular Research), partner site Göttingen
Michaela Kuhn: University of Würzburg
Johann Bauersachs: Hannover Medical School
Joerg Heineke: Hannover Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27634-5

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