Abstract P113: Protein Tyrosine Phosphatase-Like A Is a Unique Regulator for Myogenesis

Abstract

Background: Protein tyrosine phosphatase-like A (PTPLa) is highly expressed in skeletal and cardiac muscle. Therefore, it has been implicated to play a role in skeletal myogenesis and cardiogenesis. Mutations in PTPLa correlated with arrhythmogenic right ventricular dysplasia in humans and congenital centronuclear myopathy with severe hypotonia in dogs. However, the molecular mechanisms of PTPLa in myogenesis are unknown. Method and results: Mouse myoblast C2C12 cells were used to generate PTPLa deficient and PTPLa overexpression cell lines and the cells were cultured in proliferating and differentiating media, respectively, to study regulatory role of PTPLa in cell proliferation and differentiation. We demonstrated that PTPLa was required for myoblast growth and differentiation. The cells lacking PTPLa remained immature and failed to differentiate into mature myotubes along with repressed MyoG expression. To define the role of MyoG in PTPLa-mediated myoblast differentiation, myoblast cell line lacking MyoG expression was generated. Two cell lines, the PTPLa-deficient and MyoG-deficient myoblasts were used to demonstrate that PTPLa-mediated myoblast differentiation was through MyoG regulation. Meanwhile, the impeded cell growth with an obvious S-phase arrest was observed in PTPLa-deficient myoblasts. Further study demonstrated that the upregulation of cyclin D1 and cyclin E2 complexes along with a compromised Cdk1 activity contributed to the mutant cell S-phase arrest and eventually led to the retarded cell growth. Finally, the transcriptional regulation of PTPLa gene was explored. We identified that PTPLa was a new target gene of serum response factor (SRF). Skeletal- and cardiac-specific SRF knockouts resulted in significant decreases in PTPLa expression, suggesting a conserved transcriptional regulation of PTPLa gene in mice. Conclusion: PTPLa is a unique pro-myogenic factor regulated by SRF. It regulates myoblast proliferation and differentiation through MyoG and cell cycling signaling pathway.