Am J Physiol Cell Physiol AJP: Heart and Circulatory Physiology
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Am J Physiol Cell Physiol (April 8, 2009). doi:10.1152/ajpcell.00105.2009
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00105.2009v1
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Submitted on March 6, 2009
Accepted on March 23, 2009

MYOSTATIN REDUCES AKT/TORC1/p70S6K SIGNALING, INHIBITING MYOBLAST DIFFERENTIATION AND MYOTUBE SIZE

Anne Ulrike Trendelenburg1, Angelika Meyer1, Daisy Rohner1, Joseph Boyle1, Shinji Hatakeyama1, and David J Glass1*

1 Novartis Institutes for Biomedical Research

* To whom correspondence should be addressed. E-mail: david.glass{at}novartis.com.

Myostatin is a negative regulator of skeletal muscle size, previously shown to inhibit muscle cell differentiation. Myostatin requires both Smad2 and Smad3 downstream of the ActRII/Alk receptor complex. Other TGF-{beta}-like molecules can also block differentiation, including TGF-{beta}1, GDF-11, activins, BMP-2 and BMP-7. Myostatin inhibits activation of the Akt/mTOR/p70S6 protein synthesis pathway, which mediates both differentiation in myoblasts and hypertrophy in myotubes. Blockade of the Akt/mTOR pathway, using siRNA to RAPTOR, a component of "TORC1" (TOR signaling Complex 1), increases myostatin-induced phosphorylation of Smad2, establishing a myostatin signaling-amplification role for blockade of Akt. Blockade of RAPTOR also facilitates myostatin's inhibition of muscle differentiation. Inhibition of TORC2, via RICTOR, is sufficient to inhibit differentiation on its own. Furthermore, myostatin decreases the diameter of post-differentiated myotubes. However, rather than causing upregulation of the E3 ubiquitin ligases MuRF1 and MAFbx, previously shown to mediate skeletal muscle atrophy, myostatin decreases expression of these atrophy markers in differentiated myotubes, as well as other genes normally up-regulated during differentiation. These findings demonstrate that myostatin signaling acts by blocking genes induced during differentiation, even in a myotube, as opposed to activating the distinct "atrophy program". In vivo, inhibition of myostatin increases muscle CK activity, coincident with an increase in muscle size, demonstrating that this in vitro differentiation measure is also upregulated in vivo.




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