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Dualités fonctionnelles de GASP-1 et GASP-2, deux protéines multi-domaines antagonistes de la myostatine

Alexis Parente 1, 2
2 GAMAA - Génomique AniMale, Amélioration, Adaptation
INRA - Institut National de la Recherche Agronomique : USC1061, PEIRENE - PEIRENE
Abstract : GASP-1 and GASP-2 are two closely related proteins structurally characterized by several protease inhibitor modules and identified as inhibitors of several members of the TGF-ß family such as myostatin or GDF-11, negative regulators of myogenesis and osteogenesis, respectively. Despite the common structural organization of GASPs proteins, their different expression profiles suggest distinct physiological roles. We generated Tg(Gasp-1) and Tg(Gasp-2) mouse models overexpressing Gasp-1 or Gasp-2 in order to better understand the functions of these proteins. Functional analyses, carried out in vitro and in vivo in muscular, skeletal and anti-proteasic context, allowed us to highlight a functional duality between GASP-1 and GASP-2 in the different contexts. Both lines Tg(Gasp-1) and Tg(Gasp-2) exhibit an increase in muscle mass due to myofiber hypertrophy without hyperplasia. However, Tg(Gasp-1) mice have an overall deregulation of glucose homeostasis and metabolic defects with age, a phenotype not found in Tg(Gasp-2) mice. These results allowed us to propose the GASP-2 protein as a better therapeutic candidate for muscle diseases. In the skeletal context, only the Gasp-2 overexpression leads to a bone phenotype. Altogether, our findings highlighted a gene expression regulatory network of TGF-ß members and their inhibitors in muscle.
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Alexis Parente. Dualités fonctionnelles de GASP-1 et GASP-2, deux protéines multi-domaines antagonistes de la myostatine. Biologie cellulaire. Université de Limoges, 2019. Français. ⟨NNT : 2019LIMO0028⟩. ⟨tel-02790534v2⟩

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