Dystrophin is a large cytoplasmic protein predominantly expressed in striated muscle. Mutations in dystrophin that abolish or reduce its functionality lead to Duchenne (DMD) or Becker (BMD) muscular dystrophy. Approximately one in every 4000 boys is born with DMD, and all will inevitably become wheelchair-bound and succumb to fatal cardiac arrest or respiratory failure. Current treatment is limited to ventilator support, which prolongs life, and corticosteroids, which also provide benefit, but can cause serious side effects. The majority of DMD or BMD cases are caused by deletions or nonsense mutations, but patients with missense mutations represent a small, yet rapidly growing population who could potentially benefit from personalized therapy approaches. In the current project period, we showed that single amino acid changes associated with DMD-, or BMD-causing missense mutations dramatically impair the stability of dystrophin. We also engineered new transgenic C2C12 myoblasts and mdx mouse lines expressing dystrophins with missense mutations associated with DMD or BMD. We propose in aim 1 to make use of these new tools to investigate whether increasing mutant protein levels by small molecule proteasome inhibitors exacerbates dystrophy or instead provides a potential therapy for this orphaned subpopulation of dystrophinopathy patients. Dystrophin also organizes microtubules into a subsarcolemmal rectilinear lattice that becomes disorganized when the protein is absent, as in the mdx mouse. We and others have recently shown that microtubule disorganization contributes to eccentric contraction induced force drop, which is the most robust phenotype of the mdx mouse.
In aim 2, we propose new in vivo rescue experiments to delineate the mechanism by which dystrophin regulates microtubule lattice organization. Finally, in aim 3 we propose physiological and biochemical analyses designed to elucidate the long enigmatic function of the dystrophin carboxy-terminal domain.
We have developed new patient-based cell and animal models of Duchenne and Becker muscular dystrophies caused by missense mutations. These models enable new understanding of disease pathogenesis and therapy development for a rapidly growing sub-group of underserved dystrophinopathy patients. We have also developed new animal models and assays to elucidate the contribution of microtubule disorganization to the pathogenesis of Duchenne muscular dystrophy.
| 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 |
| 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 |
| 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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