Myostatin Regulates Cardiomyocyte Growth Through Modulation of Akt Signaling

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Circ Res. 2006 Jun 8

Myostatin Regulates Cardiomyocyte Growth Through Modulation of Akt

Signaling.

Morissette MR, Cook SA, Foo S, McKoy G, Ashida N, Novikov M, Scherrer-

Crosbie M, Li L, Matsui T, G, Rosenzweig A.

Cardiology Division, Beth Israel Deaconess Medical Center; and

Division of Cardiology, Massachusetts General Hospital, Harvard

Medical School, Boston, Mass; Medical Research Center Clinical

Sciences Center, Hammersmith Hospital, London, UK; and Cardiovascular

Research Group, School of Pharmacy, The University of Reading

Whiteknights, Berkshire, UK.

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.