Dyrk1b is a key Regulatory Kinase Integrating Fgf, Shh and mTORC1 signaling in Skeletal Muscle Development and Homeostasis

ABSTRACTThe advent of human genetics has provided unprecedented opportunities for discovery of novel disease pathways. Mutations in DYRK1B have been associated with metabolic syndrome and sarcopenic obesity in humans, underscoring the critical role of the encoded protein in skeletal muscle development and homeostasis. By the novel creation of Dyrk1b knockout zebrafish models we demonstrate that Dyrk1b kinase activity is critical for specification of the paraxial myoD. Mechanistically, Dyrk1b mediates and amplifies Fgf signaling in the paraxial domain by the transcriptional suppression of its negative feedback inhibitor sprouty1. In the adaxial myoD domain, Dyrk1b amplifies Shh signaling and partially rescues defects caused by its disruption. The investigations of C2C12 terminal differentiation revealed that Dyrk1b also plays a critical role in myofiber fusion. Combined biochemical and proteomic analysis of C2C12 myoblasts undergoing differentiation showed that Dyrk1b kinase activation is induced by shh inhibition, and triggers differentiation by inhibiting mTOR, subsequent upregulation of 4e-bp1 and induction of autophagy. In conclusion, we demonstrate that Dyrk1b plays a critical role in sustaining myocyte specification and differentiation by integrating Fgf, Shh and mTORC1 signaling pathways.