Functions And Mechanisms Of Stk40 In Adipocyte And Skeletal Muscle Differentiation

Stk40 contains a conserved serine/threonine kinase domain. Our previous study indicates that it can induce mouse embryonic stem cells(mESCs) differentiation into extraembryonic endoderm(ExEn) through activating the MAPK signaling pathway. Stk40 knock out(KO, Stk40-/-) mice show neonatal lethality and have defects in lung development, which means Stk40 is also involved in lung development. In this study, to better understand the function of Stk40, we investigate the roles of Stk40 in the process of the adipogenesis and myogenesis.Multiple extracelluar signals and transcriptinal factors control the process of adipogenesis. C/EBP family members are important transcriptional regulators of adipogenesis. Our study reveals that Stk40 is a new repressor of adipogenesis through translational control of C/EBP? and ?. Mouse embryonic fibroblasts(MEFs) from Stk40 knock out mice and Stk40 deficient mesenchymal stem cells(MSCs) have enhanced adipogenesis and increased protein levels of C/EBP? and ?. However, the mRNA levels of C/EBP? and ? decrease in Stk40 depleted MEFs, which means Stk40 regulates the expression of C/EBP? and ? in the post-transcriptional level. Our further investigation uncovers Stk40 does not alter the degradation rate of C/EBP? and ?? instead participates in the translational control of C/EBP? and ?. Specifically, Stk40 depleted MEFs and deficient MSCs have higher levels of phosphorylated 4E-BP1, which leads to the release of eIF4 E to promote the translation of C/EBP? and ?.In addition, our study reveals Stk40 is a novel regulator of skeletal myogenesis. Stk40 expression levels increase during C2C12 myoblast differentiation, fetal muscle development and adult muscle regeneration, which indicates Stk40 may participate in skeletal myogenesis. Indeed,studies of loss-of-function and gain-of-function reveal that Stk40 functions as a positive regulator of the myogenic differentiation of C2C12 myoblasts. MRF(myogenic regulatory factors) and MEF2(myocyte enhancer factor 2) families work together to mediate the skeletal myogenesis. Mechanistically, we find that Stk40 enhances the transcriptional activity of MEF2 through negatively regulating the protein level of histone deacetylase 5(HDAC5), which works as a corepressor of the MEF2 transcriptional activity. We further investigate the physiological role of Stk40 in skeletal muscle development. In Stk40-/- mice, the fetal skeletal muscle formation is impaired, as shown by decreased expression of myogenic markers and the fewer number of myofibers.Taken together, our study reveals the novel function of Stk40 in adipocyte differentiation and skeletal muscle differentiation. These findings will facilitate further investigation of the physiological function of Stk40, the mechanism of obesity and obesity-related diseases, the mechanism of related diseases and regeneration of skeletal muscle.