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Characteristics of skeletal muscles from 5, 12 and 24 week old Pofut1+/+ and Pofut1cax/cax mice from Reduced Notch signalling leads to postnatal skeletal muscle hypertrophy in Pofut1cax/cax mice

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posted on 2016-09-08, 06:44 authored by Bilal Al Jaam, Katy Heu, Florian Pennarubia, Alexandre Segelle, Laetitia Magnol, Agnès Germot, Sébastien Legardinier, Véronique Blanquet, Abderrahman Maftahy
Postnatal skeletal muscle growth results from the activation of satellite cells and/or an increase in protein synthesis. The Notch signalling pathway maintains satellite cells in a quiescent state, and once activated, sustains their proliferation and commitment towards differentiation. In mammals, POFUT1-mediated O-fucosylation regulates the interactions between NOTCH receptors and ligands of the DELTA/JAGGED family, thus initiating the activation of canonical Notch signalling. Here, we analysed the consequences of downregulated expression of Pofut1 gene on postnatal muscle growth in mutant Pofut1cax/cax (cax, compact axial skeleton) mice and differentiation of their satellite cell-derived myoblasts (SCDMs). Pofut1cax/cax mice exhibited muscle hypertrophy, no hyperplasia and a decrease in satellite cell numbers compared with wild-type C3H mice. In agreement with these observations, Pofut1cax/cax SCDM differentiated earlier concomitant to reduced Pax7 expression and decrease in PAX7+/MYOD progenitor cells. In vitro binding assays showed a reduced interaction of DELTA-LIKE 1 ligand (DLL1) with NOTCH receptors expressed at the cell surface of SCDM, leading to a decreased Notch signalling as seen by the quantification of cleaved NICD and Notch target genes. These results demonstrated that POFUT1-mediated O-fucosylation of NOTCH receptors regulates myogenic cell differentiation and affects postnatal muscle growth in mice.

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