MYOTONIC DYSTROPHY KINASE IN MYOCYTE DEVELOPMENT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal of the proposed study is to identify the function of human myotonic dystrophy protein kinase (DMPK) in myocyte development. DMPK was originally identified by the detection of a CTG triplet repeat sequence located in the 3' untranslated region of the DMPK gene that is expanded in patients with myotonic dystrophy (DM1). A role for the reduced DMPK expression in the pathophysiology of DM1 cannot be determined until the function of the kinase has been clearly defined. Our preliminary data suggests DMPK may regulate myocyte development. DMPK is expressed in developing myocytes when proliferating cells transition into postmitotic cells. Overexpression studies in HeLa cells demonstrate that DMPK is sufficient to disrupt the cell cycle. The depletion of DMPK in cultured mouse myoblasts (C2C12 cells) inhibits differentiation into myotubes and alters cell morphology. We will test the novel hypothesis that DMPK has a key role in myogenesis. DMPK is required for myogenic gene expression and is sufficient to prematurely induce myogenic gene expression in myoblasts. Aim 1 will test the hypothesis that DMPK is necessary for myocyte differentiation and is sufficient to induce premature myocyte differentiation. Aim 2 will test the hypothesis that DMPK initiates exit from the cell cycle. Aim 3 will test the hypothesis that DMPK is required for the differentiation of immature myoblasts. Together, these experiments will lead to an understanding of DMPK function in muscle cell development and will lay the groundwork for treatments for DM1 based on a complete understanding of DM1 myocyte pathophysiology.