SDC3 acts as a timekeeper of myogenic differentiation by regulating the insulin/AKT/mTOR axis in muscle stem cell progeny

Abstract

Muscle stem cells (MuSCs) are indispensable for muscle regeneration. A multitude of extracellular stimuli affect MuSCs from quiescent progenitors to differentiated myocytes, the activity of which is modulated by coreceptors such as syndecan-3 (SDC3). Here we investigated the global landscape of SDC3-mediated regulation of myogenesis using a phosphoproteomics approach which revealed, with the precision level of individual phosphosites, the large-scale extent of SDC3-mediated regulation of MuSC signal transduction. We then focused on INSR/AKT/mTOR as a key pathway regulated by SDC3 during myogenesis and mechanistically dissected SDC3-mediated inhibition of insulin signalling in MuSCs. SDC3 interacts with INSR limiting insulin signal transduction via INSR/AKT/mTOR. Both knockdown of INSR and inhibition of AKT rescue Sdc3-/- MuSC differentiation to wild type levels. Since SDC3 is rapidly downregulated at the onset of differentiation, our study suggests that SDC3 acts a timekeeper to maintain proliferating MuSC response to insulin to low levels and prevent premature differentiation.

mTOR signalling pathway in stem cell bioactivities and angiogenesis potential

“…50 Upon myogenic differentiation, syndecan-3 reduces the activity of insulin receptor after interaction with AKT/mTOR pathway. 51 It was suggested that modulation of miR-143-3p and miR-100-5p via the mTOR pathway is involved in driving human MSC fate for tissue regeneration. 52 Both miRNAs act as mechanosensitive factors and their expression can be changed in response to matrix stiffness and RhoA activity.…”

“…Upon myogenic differentiation, syndecan‐3 reduces the activity of insulin receptor after interaction with AKT/mTOR pathway. 51 It was suggested that modulation of miR‐143‐3p and miR‐100‐5p via the mTOR pathway is involved in driving human MSC fate for tissue regeneration. 52 Both miRNAs act as mechanosensitive factors and their expression can be changed in response to matrix stiffness and RhoA activity.…”