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bioRxiv · 10.1101/2020.08.10.244152

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

Jones, F. K.·Phillips, A.·Jones, A. R.·Pisconti, A.
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Abstract

Muscle stem cells (MuSCs) are indispensable for muscle regeneration. A multitude of extracellular stimuli direct MuSC fate decisions from quiescent progenitors to differentiated myocytes. The activity of these signals is modulated by coreceptors such as syndecan-3 (SDC3). 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 signal transduction in MuSCs. We then focused on INSR/AKT/mTOR as a key pathway regulated by SDC3 during myogenesis and mechanistically dissected SDC3-mediated inhibition of insulin signaling in MuSCs. SDC3 interacts with INSR limiting insulin signal transduction via 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 restrain proliferating MuSC response to insulin and prevent premature differentiation.

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Jones, F. K., Phillips, A., Jones, A. R., Pisconti, A.. 2020-08-10. SDC3 acts as a timekeeper of myogenic differentiation by regulating the insulin/AKT/mTOR axis in muscle stem cell progeny. https://doi.org/10.1101/2020.08.10.244152

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