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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/1124    most recent ajpcell.00043.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Morissette, M. R. Articles by Rosenzweig, A. PubMed PubMed Citation Articles by Morissette, M. R. Articles by Rosenzweig, A.

Muscle Cell Biology and Cell Motility

Myostatin inhibits IGF-I-induced myotube hypertrophy through Akt

Cardiovascular Institute, ¹Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; Imperial College Faculty of Medicine, ²Hammersmith Hospital, London, United Kingdom; and ³Harvard Stem Cell Institute, Cambridge, Massachusetts

Submitted 22 January 2009 ; accepted in final form 4 September 2009

Myostatin is a highly conserved negative regulator of skeletal muscle growth. Loss of functional myostatin in cattle, mice, sheep, dogs, and humans results in increased muscle mass. The molecular mechanisms responsible for this increase in muscle growth are not fully understood. Previously, we have reported that phenylephrine-induced cardiac muscle growth and Akt activation are enhanced in myostatin knockout mice compared with controls. Here we report that skeletal muscle from myostatin knockout mice show increased Akt protein expression and overall activity at baseline secondary to an increase in Akt mRNA. We examined the functional role of myostatin modulation of Akt in C2C12 myotubes, a well-established in vitro model of skeletal muscle hypertrophy. Adenoviral overexpression of myostatin attenuated the insulin-like growth factor-I (IGF-I)-mediated increase in myotube diameter, as well as IGF-I-stimulated Akt phosphorylation. Inhibition of myostatin by overexpression of the NH₂-terminal portion of myostatin was sufficient to increase myotube diameter and Akt phosphorylation. Coexpression of myostatin and constitutively active Akt (myr-Akt) restored the increase in myotube diameter. Conversely, expression of dominant negative Akt (dn-Akt) with the inhibitory myostatin propeptide blocked the increase in myotube diameter. Of note, ribosomal protein S6 phosphorylation and atrogin-1/muscle atrophy F box mRNA were increased in skeletal muscle from myostain knockout mice. Together, these data suggest myostatin regulates muscle growth at least in part through regulation of Akt.

growth differentiation factor-8; muscle growth; C2C12