p38 plays a crucial role in myoblast fusion by induction of fusion factors

[Speaker] Kimitaka Yamaguchi:1
[Co-author] Taichiro Tomida:1, Masanori Ito:1, Shingo Murakami:1, Yoshinori Mikami:1, Satomi Adachi-Akahane:1
1:Department of Physiology, School of Medicine, Faculty of Medicine, Toho University, Japan

[Background] Myoblast fusion is an essential step for skeletal muscle development as well as in regeneration after injury. Differentiated myoblasts fuse with each other and form multinucleated myotube. It has been demonstrated that myoblast differentiation requires MAPK activity. However, how MAPK contributes to the fusion process remains unclear. Recently, the fusion factors that are essential for myoblast fusion have been identified by several independent groups. The KO mice lacking the factors demonstrated loss of skeletal muscle in embryo presumably due to the inability of the myoblast fusion. Those factors localized in the plasma membrane and supposed to tether between membranes of fusing cells. However, the expression, as well as its mechanistic role in cell-cell fusion, has been under investigation. It is possible that the expression, the post transcriptional modification, or the membrane localization of the factors are regulated. Understanding of fundamental fusion process would be important for overcoming myopathies such as diabetic amyotrophy, muscle atrophy or sarcopenia. We therefore investigated how fusion factors were regulated in cells.
[Purpose] The purpose is to reveal the relationship between MAPK and fusion factors.
[Methods] We used C2C12 cell as a model of myoblast. The expression levels of fusion factors were analyzed by qPCR and western blotting.
[Results] When C2C12 cells were differentiated for 2 days, mRNA level of MyoD did not change, while myogenin and fusion factors increased as compared with those of undifferentiated cells. Since MAPK activation is known to occur during myoblast differentiation, we examined effects of inhibitors of MAPK including ERK1/2, ERK5, JNK and p38 on the differentiation of C2C12 cells. The expression levels of fusion factors were not affected by inhibitors for ERK1/2, ERK5 nor JNK inhibitor, but were decreased in the presence of p38 inhibitor. In the normal differentiation medium, the shape of C2C12 cells became projecting and lengthened then formed multinucleated myotube. The application of p38 inhibitor abrogated cell-cell fusion, while the morphological change of cell shape occurred similarly as that in the normal differentiation medium.
[Conclusion] Our data demonstrated that p38 controls the expression of fusion factors and thus promote the subsequent fusion process.

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