Étude du rôle des protéines GASP dans le développement musculaire par des approches in vivo et de prédiction in silico

Abstract : Muscle mass is largely regulated by signaling pathways controlling the balance between synthesis and degradation of myofibrillar proteins. Thus, myostatin, a member of the TGFβ superfamily, targets a number of signaling networks involved in the regulation of muscle mass, in particular the Akt / mTOR signaling pathway. Myostatin is one of the major inhibitors of myogenesis by exerting a negativecontrol on the proliferation and differentiation of myoblasts. Today, myostatin is involved in many therapeutic strategies which aim to improve muscle function in cases of atrophy or myopathies.GASP-1 and GASP-2 are two secreted proteins containing several domains associated with protease inhibitors, and described as myostatin antagonists. The Animal Molecular Genetics laboratory has developed in vitro and in vivo strategies to determine the functions of GASPs proteins in a myogenic context. First, we generated a transgenic mouse line TgGasp-1 over-expressing the Gasp-1 gene. This line shows an overall increase in skeletal muscle weight and hypertrophy, a consequence of myostatin inhibition. However, unlike myostatin knockout mice (Mstn -/-), this line shows neither hyperplasia, nor change in the proportion of different types of muscle fibers. Moreover, the global metabolism is not affected. In order to better understand the role of GASPs proteins in musculoskeletal development, two complementary approaches were developed during this thesis :(i) the study of a murine TgGasp-2 line over-expressing Gasp-2 reveals a muscular phenotype similar to the TgGasp-1 mice. At 12 weeks, we observed an overall increase in body and some skeletal muscles weight due to a hypertrophy of the myofibers. As the TgGasp-1 mice, and unlike the Mstn -/- mice, the number of fibers and the metabolism of TgGasp-2 mice did not vary compared to the wildtype mice (ii) In silico analyses allow us to identify different biological processes and regulated pathways controlled by GASP-1.
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Victor Gondran Tellier. Étude du rôle des protéines GASP dans le développement musculaire par des approches in vivo et de prédiction in silico. Médecine humaine et pathologie. Université de Limoges, 2016. Français. ⟨NNT : 2016LIMO0099⟩. ⟨tel-01962945⟩

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