The JAK1-STAT1 pathway was previously shown by us to regulate myogenic differentiation in cultured myoblasts. Dual specificity phosphatase 27 (Dusp27), a poorly characterized gene, was identified in a screen for downstream targets of the JAK1-STAT1 pathway in myoblast differentiation. Dusp27, a catalytically inactive pseudophosphatase, is preferentially expressed in the mouse heart and skeletal muscles. When Dusp27 was conditionally deleted in mouse embryos using a non-inducible Pax7-Cre driver, the sarcomere structure of skeletal muscle was severely disrupted during embryonic muscle development, which led to death of mutant pups at birth. To assess the functions of Dusp27 in adult muscles, we generated two additional mouse models. In one model, we used an inducible HSA-CreER to delete...[ Read more ]

The JAK1-STAT1 pathway was previously shown by us to regulate myogenic differentiation in cultured myoblasts. Dual specificity phosphatase 27 (Dusp27), a poorly characterized gene, was identified in a screen for downstream targets of the JAK1-STAT1 pathway in myoblast differentiation. Dusp27, a catalytically inactive pseudophosphatase, is preferentially expressed in the mouse heart and skeletal muscles. When Dusp27 was conditionally deleted in mouse embryos using a non-inducible Pax7-Cre driver, the sarcomere structure of skeletal muscle was severely disrupted during embryonic muscle development, which led to death of mutant pups at birth. To assess the functions of Dusp27 in adult muscles, we generated two additional mouse models. In one model, we used an inducible HSA-CreER to delete Dusp27 in mature myofibers. We found that the function of skeletal muscle was not affected indicating that Dusp27 is not required for the maintenance of existing sarcomeres in adult muscles. In the other model, we used an inducible Pax7-CreER to delete Dusp27 in adult muscle satellite cells (MuSCs) followed by a round of muscle injury and regeneration before assessment. In this model, sarcomeres in regenerating muscles would undergo de novo assembly in the absence of Dusp27. We found that loss of Dusp27 in regenerating muscles led to partial defects in twitch force generation, indicative of defective sarcomere structures. Mechanistically, non-muscle myosin IIs (i.e., Myh9 and Myh10) were identified as interaction partners of Dusp27. Non-muscle myosin IIs are known to be involved in the early phase of sarcomere assembly and are subsequently degraded upon myofibril maturation. Without Dusp27, the degradation of non-muscle myosin IIs was delayed. Dusp27 was found to promote the degradation of non-muscle myosin IIs via the autophagy-lysosome pathway. Therefore, Dusp27 facilitates de novo sarcomere assembly by promoting degradation of non-muscle myosin II.

In addition, I also started to investigate the role of Pax7 in adult MuSCs. Pax7 is known to be essential for the maintenance of the quiescent muscle stem cell pool. However, its exact roles in adult MuSCs remain obscure. I found that Pax7-null myoblasts were able to proliferate and differentiate in culture and in vivo. Importantly, Pax7-null MuSCs were also capable of injury-induced muscle regeneration in vivo even though the regeneration process was slower than that in the control mice. There were increased apoptotic cells in Pax7-null myoblasts, consistent with its role in cell survival. More detailed analysis is underway to further elucidate the roles of Pax7 in adult MuSCs.