The long-term objective of this project is to determine the function(s) of dystrophin in striated muscle in order to understand how its absence or abnormality leads to the pathologies observed in Duchenne (DMD) and Becker (BMD) muscular dystrophies. During the most recent project period, we uniquely employed the baculovirus expression system and an array of biochemical/biophysical assays to define the actin binding properties of dystrophin and its homologue utrophin. We also demonstrated that dystrophin functions to organize the microtubule lattice of skeletal muscle through a direct binding interaction. Finally, we demonstrated that a baculovirus-expressed TAT-micro-utrophin construct shows promise as a novel protein replacement therapy for DMD. Based on these published results and exciting new preliminary data, we propose three new specific aims to: 1) test the hypothesis that disease-causing missense mutations in dystrophin cause a loss of function through protein aggregation, 2) determine the functional importance of microtubule lattice organization in skeletal muscle, and 3) reinvestigate functional necessity for the dystrophin carboxyl-terminal domain in skeletal muscle. The project will employ biochemical/biophysical methods to characterize a variety of dystrophin and utrophin protein constructs in combination with complementary experiments in isolated cells and transgenic mice. The proposed studies will address several fundamental questions about the function of dystrophin in normal skeletal muscle and how its absence or abnormality causes human diseases of skeletal muscle.
Duchenne muscular dystrophy (DMD) afflicts 1 in 3,500 live-born males and is typically lethal by the third decade. No effective therapies are currently available for DMD. Dystrophin is the protein missing in patients with DMD, but its function in muscle is not fully understood. Through rigorous biochemical/biophysical characterization of full-length dystrophin and utrophin in combination with complementary experiments in isolated cells and transgenic mice, the proposed studies will elucidate the functions of dystrophin in normal muscle and how its absence causes muscular dystrophy. Thus, this project is highly relevant to understanding the pathological mechanism of Duchenne muscular dystrophy and for the development of effective therapies.
| Nelson, D'anna M; Lindsay, Angus; Judge, Luke M et al. (2018) Variable rescue of microtubule and physiological phenotypes in mdx muscle expressing different miniaturized dystrophins. Hum Mol Genet 27:2090-2100 |
| 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 |
| Lindsay, Angus; McCourt, Preston M; Karachunski, Peter et al. (2018) Xanthine oxidase is hyper-active in Duchenne muscular dystrophy. Free Radic Biol Med 129:364-371 |
| Strakova, Jana; Kamdar, Forum; Kulhanek, Debra et al. (2018) Integrative effects of dystrophin loss on metabolic function of the mdx mouse. Sci Rep 8:13624 |
| Le, Shimin; Yu, Miao; Hovan, Ladislav et al. (2018) Dystrophin As a Molecular Shock Absorber. ACS Nano : |
| McCourt, Jackie L; Talsness, Dana M; Lindsay, Angus et al. (2018) Mouse models of two missense mutations in actin-binding domain 1 of dystrophin associated with Duchenne or Becker muscular dystrophy. Hum Mol Genet 27:451-462 |
| Belanto, Joseph J; Olthoff, John T; Mader, Tara L et al. (2016) Independent variability of microtubule perturbations associated with dystrophinopathy. Hum Mol Genet 25:4951-4961 |
| Filareto, Antonio; Rinaldi, Fabrizio; Arpke, Robert W et al. (2015) Pax3-induced expansion enables the genetic correction of dystrophic satellite cells. Skelet Muscle 5:36 |
| McCourt, Jackie L; Rhett, Katrina K; Jaeger, Michele A et al. (2015) In vitro stability of therapeutically relevant, internally truncated dystrophins. Skelet Muscle 5:13 |
| Talsness, Dana M; Belanto, Joseph J; Ervasti, James M (2015) Disease-proportional proteasomal degradation of missense dystrophins. Proc Natl Acad Sci U S A 112:12414-9 |
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