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.
| Patrinostro, Xiaobai; Roy, Pallabi; Lindsay, Angus et al. (2018) Essential nucleotide- and protein-dependent functions of Actb/?-actin. Proc Natl Acad Sci U S A 115:7973-7978 |
| 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 |
| Patrinostro, Xiaobai; O'Rourke, Allison R; Chamberlain, Christopher M et al. (2017) Relative importance of ?cyto- and ?cyto-actin in primary mouse embryonic fibroblasts. Mol Biol Cell 28:771-782 |
| Wu, Xin-Sheng; Lee, Sung Hoon; Sheng, Jiansong et al. (2016) Actin Is Crucial for All Kinetically Distinguishable Forms of Endocytosis at Synapses. Neuron 92:1020-1035 |
| Dandapat, Abhijit; Perrin, Benjamin J; Cabelka, Christine et al. (2016) High Frequency Hearing Loss and Hyperactivity in DUX4 Transgenic Mice. PLoS One 11:e0151467 |
| Simionescu-Bankston, Adriana; Pichavant, Christophe; Canner, James P et al. (2015) Creatine kinase B is necessary to limit myoblast fusion during myogenesis. Am J Physiol Cell Physiol 308:C919-31 |
| Narayanan, Praveena; Chatterton, Paul; Ikeda, Akihiro et al. (2015) Length regulation of mechanosensitive stereocilia depends on very slow actin dynamics and filament-severing proteins. Nat Commun 6:6855 |
| 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 |
| Cheever, Thomas R; Ervasti, James M (2013) Actin isoforms in neuronal development and function. Int Rev Cell Mol Biol 301:157-213 |
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