Myostatin: Down-regulation of Akt/mTOR signaling pathway in response to myostati

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Endocrinology. 2008 Sep 18.

Down-regulation of Akt/mTOR signaling pathway in response to

myostatin overexpression in skeletal muscle.

Amirouche A, Durieux AC, Banzet S, Koulmann N, Bonnefoy R, Mouret C,

Bigard X, Peinnequin A, Freyssenet D.

PRES LYON, Université Monnet, Laboratoire de Physiologie de

l'Exercice, EA4338, Saint-Etienne, France; Institut d'Anatomie,

Université de Berne, Suisse; Department des Facteurs Humains, Centre

de Recherche du Service de Santé des Armées, La Tronche, France;

Département de Radiobiologie et Radiopathologie, Centre de Recherche

du Service de Santé des Armées, La Tronche, France.

Myostatin, a member of transforming growth factor beta family, has

been identified as a master regulator of embryonic myogenesis and

early post-natal skeletal muscle growth. However, cumulative

evidences also suggest that alterations in skeletal muscle mass are

associated with dysregulation in myostatin expression and that

myostatin may contribute to muscle mass loss in adulthood.

Two major branches of the Akt pathway are relevant for the regulation

of skeletal muscle mass, the Akt/mammalian target of rapamycin (mTOR)

pathway, which controls protein synthesis, and the Akt/FOXO pathway,

which controls protein degradation.

Here, we provide further insights into the mechanisms by which

myostatin regulates skeletal muscle mass by showing that myostatin

negatively regulate Akt/mTOR signaling pathway.

Electrotransfer of a myostatin expression vector into the Tibialis

anterior muscle of Sprague Dawley male rats increased myostatin

protein level and decreased skeletal muscle mass 7 d after gene

electrotransfer. Using RT-PCR and immunoblots analyses, we showed

that myostatin overexpression was ineffective to alter the ubiquitin-

proteasome pathway.

By contrast, myostatin acted as a negative regulator of Akt/mTOR

pathway. This was supported by data showing that the phosphorylation

of Akt on Thr308, tuberous sclerosis complex 2 on Thr1462, ribosomal

protein S6 on Ser235/236 and 4E-BP1 on Thr37/46 was attenuated 7 d

after myostatin gene electrotransfer.

The data support the conclusion that Akt/mTOR signaling is a key

target that accounts for myostatin function during muscle atrophy,

uncovering a novel role for myostatin in protein metabolism and more

specifically in the regulation of translation in skeletal muscle.