Costameres are subsarcolemmal protein assemblies in striated muscle cells that circumferentially align in register with the Z disk of peripheral myofibrils and physically couple force-generating sarcomeres with the sarcolemma. Costameres are clearly important for normal muscle function because several constituent proteins are the primary sites of defect in human muscular dystrophies and dilated cardiomyopathies. We previously demonstrated that dystrophin, the product of the gene defective in Duchenne and Becker muscular dystrophies, forms an important mechanical link between costameric y-actin filaments and the sarcolemma. Our preliminary data indicates that y-actin protein levels are dramatically increased in dystrophin-deficient muscle. While an increase in the y-actin monomer pool likely stabilizes costameric filaments by mass action, excess myoplasmic y-actin may have adverse consequences for muscle cell function. The major objective of this project is to elucidate the pathogenic mechanisms linking dystrophin gene defects to muscular dystrophy phenotypes. In this proposal, we will test the novel hypotheses that increased y-actin may directly alter the activity of other muscle cell constituents involved in signaling, gene expression, or contractility. We will characterize new transgenic mouse lines to determine which dystrophy phenotypes may be caused by increased myoplasmic y-actin concentration in the absence of sarcolemmal damage. Finally, we will assess the role of y-actin in costamere assembly and mechanical function by characterizing new lines of mice where it is specifically ablated in striated muscle. The proposed research will directly address the role of increased y-actin expression and costamere instability in causing the skeletal muscle pathologies associated with dystrophinopathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049899-05
Application #
7348384
Study Section
Special Emphasis Panel (ZRG1-MOSS-F (04))
Program Officer
Nuckolls, Glen H
Project Start
2005-02-01
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
5
Fiscal Year
2008
Total Cost
$336,457
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Lindsay, Angus; Schmiechen, Alexandra; Chamberlain, Christopher M et al. (2018) Neopterin/7,8-dihydroneopterin is elevated in Duchenne muscular dystrophy patients and protects mdx skeletal muscle function. Exp Physiol 103:995-1009
O'Rourke, Allison R; Lindsay, Angus; Tarpey, Michael D et al. (2018) Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms. FEBS J 285:481-500
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Dandapat, Abhijit; Perrin, Benjamin J; Cabelka, Christine et al. (2016) High Frequency Hearing Loss and Hyperactivity in DUX4 Transgenic Mice. PLoS One 11:e0151467
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Perrin, Benjamin J; Strandjord, Dana M; Narayanan, Praveena et al. (2013) ýý-Actin and fascin-2 cooperate to maintain stereocilia length. J Neurosci 33:8114-21

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