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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR017662-09
Application #
8360553
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2011-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
9
Fiscal Year
2011
Total Cost
$246,603
Indirect Cost
Name
Sanford Research/Usd
Department
Type
DUNS #
050113252
City
Sioux Falls
State
SD
Country
United States
Zip Code
57104
Eclov, Julie A; Qian, Qingwen; Redetzke, Rebecca et al. (2015) EPA, not DHA, prevents fibrosis in pressure overload-induced heart failure: potential role of free fatty acid receptor 4. J Lipid Res 56:2297-308
Savinova, Olga V; Fillaus, Kristi; Harris, William S et al. (2015) Effects of niacin and omega-3 fatty acids on the apolipoproteins in overweight patients with elevated triglycerides and reduced HDL cholesterol. Atherosclerosis 240:520-5
McKenzie, Casey W; Craige, Branch; Kroeger, Tiffany V et al. (2015) CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice. Mol Biol Cell 26:3140-9
Kobayashi, Satoru; Liang, Qiangrong (2015) Autophagy and mitophagy in diabetic cardiomyopathy. Biochim Biophys Acta 1852:252-61
O'Connell, Timothy D; Jensen, Brian C; Baker, Anthony J et al. (2014) Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev 66:308-33
Savinova, Olga V; Fillaus, Kristi; Jing, Linhong et al. (2014) Reduced apolipoprotein glycosylation in patients with the metabolic syndrome. PLoS One 9:e104833
Jensen, Brian C; O?Connell, Timothy D; Simpson, Paul C (2014) Alpha-1-adrenergic receptors in heart failure: the adaptive arm of the cardiac response to chronic catecholamine stimulation. J Cardiovasc Pharmacol 63:291-301
Wu, Steven C; Dahl, Erika F; Wright, Casey D et al. (2014) Nuclear localization of a1A-adrenergic receptors is required for signaling in cardiac myocytes: an “inside-out” a1-AR signaling pathway. J Am Heart Assoc 3:e000145
Xu, Xianmin; Kobayashi, Satoru; Chen, Kai et al. (2013) Diminished autophagy limits cardiac injury in mouse models of type 1 diabetes. J Biol Chem 288:18077-92
Chen, Kai; Kobayashi, Satoru; Xu, Xianmin et al. (2013) AMP activated protein kinase is indispensable for myocardial adaptation to caloric restriction in mice. PLoS One 8:e59682

Showing the most recent 10 out of 63 publications