Abstract
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 the 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 SCDMs differentiated earlier concomitant with 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 SCDMs, 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.
Highlights
Skeletal muscles are composed of post-mitotic multinucleated myofibres and satellite cells, which are mononucleated cells located at the periphery of myofibres between the plasma membrane and basal lamina [1]
Similar results were found with 12 and 24 week old mice. These results showed that higher muscle weight/body weight (M/B) ratios in Pofut1cax/cax mice seem to be unrelated to the type of muscle metabolism and could be due to myofibre hypertrophy, hyperplasia or both
Our present data show for the first time that the downregulated expression of Pofut1 affects postnatal muscle growth in mice leading to a moderate muscular hypertrophy of skeletal muscles with myonuclear accretion and a significant decrease in the satellite cell pool
Summary
Skeletal muscles are composed of post-mitotic multinucleated myofibres and satellite cells, which are mononucleated cells located at the periphery of myofibres between the plasma membrane and basal lamina [1]. Satellite cells are precursor stem cells, which are involved in after-birth muscle growth and muscle regeneration after injuries, either by exercise or by disease [2]. Postnatal muscle growth mainly occurs by myofibre hypertrophy and not hyperplasia, with a steady increase in the number of myonuclei per myofibre from birth to three weeks after birth (P21) [7,8]. This myonuclear accretion in myofibres has been shown to be the result of cell fusion between satellite cell-derived myoblasts (SCDMs) and pre-existing myofibres, increasing their width and length [9,10]. From P21 to adulthood and thereafter, muscle growth by hypertrophy does not occur by a satellite celldependent myogenic fusion [11], but mainly by increased protein synthesis,
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