Absence of hyperplasia in Gasp-1 overexpressing mice is dependent on myostatin up-regulation

Caroline Brun (1) , Luce Périé (1) , Fabienne F. Baraige (1) , Barbara Vernus (2) , Anne Bonnieu (2) , Véronique V. Blanquet (1)

1 UMR GMA - Unité de Génétique Moléculaire Animale
2 DMEM - Dynamique Musculaire et Métabolisme

Background/Aims: Overexpression of Gasp-1, an inhibitor of myostatin, leads to a hypermuscular phenotype due to hypertrophy rather than hyperplasia in mice. However to date, the cellular and molecular mechanisms underlying this phenotype are not investigated. Methods: Skeletal muscles of overexpressing Gasp-1 mice, called Tg(Gasp-1) mice, were analyzed by histological methods. Satellite cell-derived myoblasts from these mice were used to investigate the molecular mechanisms. Results: We demonstrated that hypertrophy in Tg(Gasp-1) mice was related to a myonuclear accretion during the first 3 postnatal weeks and an activation of the pro-hypertrophic Akt/mTORC/p70S6K signaling. In accordance with these results, we showed that overexpressing Gasp-1 primary myoblasts proliferated faster and myonuclei average per myotube was increased during differentiation. Molecular analysis revealed that Gasp-1 overexpression resulted in increased myostatin expression related to its auto-regulation. Despite its inhibition, myostatin led to Pax7 deregulation through its non-canonical Erk1/2 signaling pathway. Consistent with this, inhibition of Erk1/2 signaling pathway as well as neutralization of secreted myostatin rescue the Pax7 expression in overexpressing Gasp-1 myoblasts. Conclusion: Our study shows that myostatin is able to act independently of its canonical pathway to regulate the Pax7 expression. Altogether, our results indicate that myostatin could regulate muscle development despite its protein inhibition.

Mots clés: GASP-1; Myostatin; Muscle development; Hypertrophy; Hyperplasia; Satellite cells; Pax7; Smad2/3; Akt; Erk1/2

Domaines: Sciences agricoles

Caroline Brun, Luce Périé, Fabienne F. Baraige, Barbara Vernus, Anne Bonnieu, et al.. Absence of hyperplasia in Gasp-1 overexpressing mice is dependent on myostatin up-regulation. Cellular Physiology and Biochemistry, 2014, 34 (4), pp.1241-1259. ⟨10.1159/000366335⟩. ⟨hal-01123375⟩