Le rôle de myostatine dans les voies de signalisation régulant la balance atrophie/hypertrophie dans le muscle squelettique – MYOTROPHY

Signal transduction pathways that promote the synthesis or degradation of muscle proteins mediate the regulation of muscle mass homeostasis as well as muscle atrophy or hypertrophy. Myostatin is a highly conserved, potent negative regulator of skeletal muscle growth in many species, from rodents to humans. Recent important data have been established that myostatin functions by inducing muscle atrophy and that this effect involved the activation of catabolic pathways. While atrophy is not just the reverse of hypertrophy, an important question to address is whether myostatin can act on the intracellular pathways that regulate muscle hypertrophy. In support of this, the myostatin deficient mice lost more muscle mass than normal controls after hindlimb suspension, indicating that absence of myostatin does not protect against muscle atrophy and also suggesting that the action of myostatin might be to inhibit muscle hypertrophy rather than induce atrophy. Recently we showed that the activation of myostatin pathway counteracts the myotube hypertrophy caused by inhibition of Notch signalling. Collectively, these data support the notion that the action of myostatin could also involve inactivation of anabolic pathways. In addition, it has been shown recently that FoxO, a key factor in the cross-talk between hypertrophic and atrophic signalling, will regulate the expression of myostatin. Our program concerns the understanding of the molecular mechanisms by which myostatin controls the antagonism atrophy/hypertrophy in skeletal muscle. In this project we will analyse whether myostatin affects protein synthesis and whether this action is mediated by the intracellular pathway PI(3)K/Akt and its downstream anabolic targets (mTOR, S6K and E-IF3 ). The proteolysis and in particular the calcium-dependent proteolysis being largely supposed implied in the antagonism atrophy/hypertrophy, the regulation of this proteolytic system by myostatin will be carefully analyzed. We will investigate also new targets of myostatin revealed by genomic approach, particularly cell survival/apoptosis pathways. Finally, we will determine whether change of myostatin expression depends of change in FoxO activity during atrophy and hypertrophy of myotubes. For these experiments, we will use a combination of in vivo and in vitro model systems to study myostatin function in the muscle. The effect of the lack of myostatin will be analysed on in vivo models of knockout mice and their littermates and at the cellular level using primary myoblasts from these mice. Its under-expression will be studied also in muscles of double-muscled (DM) cattle and in vitro in myoblasts isolated from double-muscled cattle vs normal ones. In parallel the effect of over-expression of myostatin will be analysed in cell models of C2C12 lines and in primary cultures of trout cells. The results obtained on each model will be validated on the other complementary models.