Myostatin regulates cardiomyocyte growth through modulation of Akt signaling.
Myostatin is a highly conserved, potent negative regulator of skeletal muscle hypertrophy in many species, from rodents to humans, although its mechanisms of action are incompletely understood. Transcript profiling of hearts from a genetic model of cardiac hypertrophy revealed dramatic upregulation of myostatin, not previously recognized to play a role in the heart. Here we show that myostatin abrogates the cardiomyocyte growth response to phenylephrine in vitro through inhibition of p38 and the serine-threonine kinase Akt, a critical determinant of cell size in many species from drosophila to mammals. Evaluation of male myostatin-null mice revealed that their cardiomyocytes and hearts overall were slightly smaller at baseline than littermate controls but exhibited more exuberant growth in response to chronic phenylephrine infusion. The increased cardiac growth in myostatin-null mice corresponded with increased p38 phosphorylation and Akt activation in vivo after phenylephrine treatment. Together, these data demonstrate that myostatin is dynamically regulated in the heart and acts more broadly than previously appreciated to regulate growth of multiple types of striated muscle.
Morissette
Michael R
MR
Cardiology Division, Beth Israel Deaconess Medical Center, Boston, Mass 02215, USA.
Cook
Stuart A
SA
Foo
ShiYin
S
McKoy
Godfrina
G
Ashida
Noboru
N
Novikov
Mikhail
M
Scherrer-Crosbie
Marielle
M
Li
Ling
L
Matsui
Takashi
T
Brooks
Gavin
G
Rosenzweig
Anthony
A
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D055435:Myostatin; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000316:Adrenergic alpha-Agonists; C525911:MSTN protein, human; C525912:Mstn protein, mouse; C525913:Mstn protein, rat; D055435:Myostatin; D016212:Transforming Growth Factor beta; D010656:Phenylephrine; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases