Myostatin induces interstitial fibrosis in the heart via TAK1 and p38.
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.
Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Ludwigstrasse 43, D-61231, Bad Nauheim, Germany.
Nadine
N
Biesemann
Luca
L
Mendler
Sawa
S
Kostin
Astrid
A
Wietelmann
Thilo
T
Borchardt
Thomas
T
Braun
D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects*; D055435:Myostatin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D055435:Myostatin; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C525912:Mstn protein, mouse