Myostatin induces interstitial fibrosis in the heart via TAK1 and p38

• Published in: Cell and tissue research Vol. 361; no. 3; pp. 779 - 787
• Main Authors: Biesemann, Nadine, Mendler, Luca, Kostin, Sawa, Wietelmann, Astrid, Borchardt, Thilo, Braun, Thomas
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2015; Springer; Springer Nature B.V
• Subjects: adults; Animals; Biomedical and Life Sciences; Biomedicine; Bone morphogenetic proteins; cardiac output; cardiomyocytes; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Cardiovascular disease; Cell growth; fibroblasts; Fibrosis; Fibrosis - genetics; Fibrosis - metabolism; Gene Expression - genetics; Heart; heart failure; Human Genetics; long term effects; MAP Kinase Kinase Kinases - metabolism; mice; Mice, Inbred C57BL; Molecular Medicine; mortality; Muscle Development - genetics; Muscle, Skeletal - metabolism; Myocytes, Cardiac - drug effects; myostatin; Myostatin - genetics; Myostatin - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Protein expression; Proteomics; Regular Article; Rodents; Signal transduction; Signal Transduction - genetics; Skeletal muscle; transforming growth factor beta; Transforming growth factors; Heart; Myostatin; p38; Mouse models; Fibrosis
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-015-2139-2

Myostatin, a member of the TGF-β superfamily of secreted growth factors, is a negative regulator of skeletal muscle growth. In the heart, it is expressed at lower levels compared to skeletal muscle but up-regulated under disease conditions. Cre recombinase-mediated inactivation of myostatin in adult cardiomyocytes leads to heart failure and increased mortality but cardiac function of surviving mice is restored after several weeks probably due to compensatory expression in non-cardiomyocytes. To study long-term effects of increased myostatin expression in the heart and to analyze the putative crosstalk between cardiomyocytes and fibroblasts, we overexpressed myostatin in cardiomyocytes. Increased expression of myostatin in heart muscle cells caused interstitial fibrosis via activation of the TAK-1-MKK3/6-p38 signaling pathway, compromising cardiac function in older mice. Our results uncover a novel role of myostatin in the heart and highlight the necessity for tight regulation of myostatin to maintain normal heart function.