Fig. 9.

Schematic summary of the findings. We found that Hrs depletion strongly inhibits myogenesis. Mechanistically, Hrs silencing impairs MRFs in the early steps of differentiation through the upregulation of the MEK/ERK signaling pathway concomitant with impaired Akt2 signaling network and activation of the downstream FOXO1 repressor of myogenesis. Upstream, degradation of EGFR, a regulator of the MEK/ERK signaling, was impaired in absence of Hrs. The activity of the myogenic repressors GSK3β was also found to be upregulated when Hrs was absent. Inhibition of GSK3β by the azakenpaullone GSK3β-specific inhibitor compound significantly restores the impaired differentiation observed in Hrs-depleted cells. In addition, functional autophagy that is required for myogenesis was also found to be strongly inhibited. Left panel: under normal condition. Right panel: upon Hrs depletion