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 von Haehling; Michaela Kuhn; Johann Bauersachs; Joerg Heineke

doi:10.1038/s41467-021-27634-5

Skeletal muscle derived Musclin protects the heart during pathological overload

Nat Commun. 2022 Jan 10;13(1):149. doi: 10.1038/s41467-021-27634-5.

Authors

Malgorzata Szaroszyk^#¹, Badder Kattih^#^{2

3

4}, Abel Martin-Garrido⁵, Felix A Trogisch⁵, Gesine M Dittrich^{1

5}, Andrea Grund^{1

5}, Aya Abouissa⁵, Katja Derlin⁶, Martin Meier⁷, Tim Holler⁸, Mortimer Korf-Klingebiel¹, Katharina Völker⁹, Tania Garfias Macedo¹⁰, Cristina Pablo Tortola¹¹, Michael Boschmann¹¹, Nora Huang^{11

12}, Natali Froese¹, Carolin Zwadlo¹, Mona Malek Mohammadi⁵, Xiaojing Luo¹³, Michael Wagner^{13

14}, Julio Cordero¹⁵, Robert Geffers¹⁶, Sandor Batkai¹⁷, Thomas Thum^{17

18

19}, Nadja Bork²⁰, Viacheslav O Nikolaev²⁰, Oliver J Müller^{21

22}, Hugo A Katus^{23

24}, Ali El-Armouche¹³, Theresia Kraft⁸, Jochen Springer²⁵, Gergana Dobreva^{15

24}, Kai C Wollert^{1

19}, Jens Fielitz^{11

26

27}, Stephan von Haehling¹⁰, Michaela Kuhn⁹, Johann Bauersachs^{1

19}, Joerg Heineke^{28

29

30

31}

Affiliations

¹ Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
² Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany. [email protected].
³ Department for Cardiovascular Physiology, European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. [email protected].
⁴ Department of Medicine, Cardiology, Goethe University Hospital, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. [email protected].
⁵ Department for Cardiovascular Physiology, European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
⁶ Institute for Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany.
⁷ Central Animal Facility, Hannover Medical School, Hannover, Germany.
⁸ Institute of Molecular and Cell Physiology, Hannover Medical School, Hannover, Germany.
⁹ Institute of Physiology and Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany.
¹⁰ Department of Cardiology and Pneumology, University of Göttingen Medical Center, DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany.
¹¹ Experimental and Clinical Research Center (ECRC), Charité-University Medical Center Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
¹² Department of Cardiology, Heart Center Brandenburg and Medical University Brandenburg (MHB), Bernau, Germany.
¹³ Institute of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany.
¹⁴ Department of Electrophysiology, Heart Center, Dresden University of Technology, Dresden, Germany.
¹⁵ Anatomy and Developmental Biology, ECAS, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁶ RG Genome Analytics, Helmholtz Center for Infection Research, Braunschweig, Germany.
¹⁷ Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.
¹⁸ National Heart and Lung Institute, Imperial College London, London, UK.
¹⁹ Excellence Cluster REBIRTH, Hannover Medical School, Hannover, Germany.
²⁰ Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²¹ Department of Internal Medicine III, University Hospital Schleswig-Holstein, Kiel, Germany.
²² DZHK, partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
²³ Department of Cardiology, Angiology, and Pneumology, Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
²⁴ DZHK, partner site Heidelberg/Mannheim, Heidelberg, Germany.
²⁵ Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany.
²⁶ Department of Internal Medicine B, Cardiology, University Medicine Greifswald, Greifswald, Germany.
²⁷ DZHK, partner site Greifswald, Greifswald, Germany.
²⁸ Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany. [email protected].
²⁹ Department for Cardiovascular Physiology, European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. [email protected].
³⁰ Excellence Cluster REBIRTH, Hannover Medical School, Hannover, Germany. [email protected].
³¹ DZHK, partner site Heidelberg/Mannheim, Heidelberg, Germany. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / genetics
2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / metabolism
Aged
Aged, 80 and over
Animals
Cachexia / genetics*
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 / genetics*
Endomyocardial Fibrosis / metabolism
Endomyocardial Fibrosis / physiopathology
Endomyocardial Fibrosis / prevention & control
Female
Gene Expression Regulation
Heart Failure / genetics*
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
Muscle Proteins / genetics*
Muscle, Skeletal / metabolism*
Muscular Atrophy / genetics*
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
Transcription Factors / genetics*

Substances

Muscle Proteins
OSTN protein, human
Ostn protein, mouse
RNA, Small Interfering
Transcription Factors
Cyclic AMP-Dependent Protein Kinases
Cyclic GMP-Dependent Protein Kinases
2',3'-Cyclic Nucleotide 3'-Phosphodiesterase
Cnp protein, mouse