Published online before print June 8, 2006, doi: 10.1161/01.RES.0000231290.45676.d4
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Submitted on February 21, 2005
Revised on May 17, 2006
Accepted on May 26, 2006
Myostatin Regulates Cardiomyocyte Growth Through Modulation of Akt Signaling
Michael R. Morissette ;
From the Cardiology Division (M.R.M., S.F., N.A., M.N., L.L., T.M., A.R.), Beth Israel Deaconess Medical Center; and Division of Cardiology (M.S.-C.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass; Medical Research Center Clinical Sciences Center (S.A.C.), Hammersmith Hospital, London, UK; and Cardiovascular Research Group (G.M., G.B.), School of Pharmacy, The University of Reading Whiteknights, Berkshire, UK.
* To whom correspondence should be addressed. E-mail: arosenzw{at}bidmc.harvard.edu.
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.
Key words: myostatin • Akt • p38 • hypertrophy
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