Zac1/GPR39 phosphorylating CaMK-II contributes to the distinct roles of Pax3 and Pax7 in myogenic progression

Both Pax3 and Pax7 can activate a large panel of genes involved in muscle stem cell function. Despite a significant overlap in their transcriptional network, functional difference between them is observed. After overexpressing Pax3 or Pax7 in C2C12, we find both Zac1 and GPR39 are upregulated by Pax7 but not Pax3. Further studies suggest Zac1 interacts directly with Pax7, which can regulate GPR39 expression by activating Zac1. In addition, the effect of Zac1/GPR39 system on myogenic progression has been illuminated: Zac1/GPR39 can promote myogenic differentiation and produce type-II muscle fibers. Gait analysis verifies that transplanting GFP-labeled Pax7 RV/siZac1 transfected cells into mdx mice with muscle injury would delay muscle function repair. Molecular mechanism studies reveal the Zac1/GPR39 system is associated with different myogenic functions of Pax3 and Pax7: Pax7 activates Zac1/GPR39, which mediates the phosphorylation of CaMK-II, resulting in p-ERK1/2 dephosphorylation and β-catenin inhibition, that promotes the formation of type-II muscle fibers; cells lacking Zac1/GPR39 system tend to remain stemness and form type-I muscle fibers after induced differentiation. This study will help the better understanding of the molecular mechanism of Pax3 and Pax7 in the regulation of myogenic progression and muscle fiber types, laying the providing suitable targets for the treatment of muscle diseases.