Duchenne Muscular Dystrophy (DMD) is a progressive disorder in which the absence of the dystrophin protein results in loss of the dystrophin bridge at the muscle membrane. Recent work demonstrates the involvement of dystrophin in blood flow regulation, which is disturbed in DMD and causes increased muscle damage. However, the importance of angiogenesis in DMD treatment has not yet been well addressed. We propose that administration of pro-angiogenic factors can restore muscle fibers and blood vessels. To reveal the relationship between neuromuscular disease and angiogenesis, we recently created Flt-1 heterozygous mdx mice (mdx:Flt- 1+/-). mdx mice serve as a model for DMD, and vascular endothelial growth factor (VEGF) binds with Flt-1 receptors to negatively regulate angiogenesis. Recently, our work revealed that the mdx:Flt-1+/- mice display an increased number of blood vessels in addition to improved muscle pathology and function (Verma et al., 2010). Utrophin deficient mdx mice (mdx:utrn-/-) display a more severe phenotype than mdx mice, and the mdx:utrn-/- mice more closely resemble a human DMD phenotype. Importantly, mdx:utrn-/-:Flt-1+/- triple mutant mice display improved muscle histology and significantly higher survival rates compared to mdx:utrn-/-:Flt-1+/+ mice. Our project will build on these preliminary data to more closely reveal how increased angiogenesis ultimately affects the DMD phenotype in mdx mice. In addition, we will examine whether increased vasculature provided by the administration of an anti-Flt-1 peptide or shRNA for Flt-1 that block Flt-1 function can improve the muscular dystrophic phenotype in mdx and mdx:utrn-/- mice.
Project Narrative Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene, which normally functions to maintain muscle membrane integrity and prevent contraction-induced damage. It may be possible to reduce muscle fiber damage by using pro-angiogenic factors to increase the number of blood vessels and observe the resultant effects on the muscular dystrophy phenotype. We predict that these pro-angiogenic factors will assist development of new therapies for DMD via increased vascular density in blood starved dystrophic muscles.
|Shimizu-Motohashi, Yuko; Asakura, Yoko; Motohashi, Norio et al. (2015) Pregnancy-induced amelioration of muscular dystrophy phenotype in mdx mice via muscle membrane stabilization effect of glucocorticoid. PLoS One 10:e0120325|
|Motohashi, Norio; Asakura, Yoko; Asakura, Atsushi (2014) Isolation, culture, and transplantation of muscle satellite cells. J Vis Exp :|
|Shimizu-Motohashi, Yuko; Asakura, Atsushi (2014) Angiogenesis as a novel therapeutic strategy for Duchenne muscular dystrophy through decreased ischemia and increased satellite cells. Front Physiol 5:50|
|Ennen, James P; Verma, Mayank; Asakura, Atsushi (2013) Vascular-targeted therapies for Duchenne muscular dystrophy. Skelet Muscle 3:9|
|Mull, Jesse L; Asakura, Atsushi (2012) A New Look at an Immortal DNA Hypothesis for Stem Cell Self-Renewal. J Stem Cell Res Ther 2:|
|Motohashi, Norio; Asakura, Atsushi (2012) Molecular Regulation of Muscle Satellite Cell Self-Renewal. J Stem Cell Res Ther Suppl 11:|
|Biressi, Stefano; Asakura, Atsushi (2012) Satellite Cells and the Universe of Adult Muscle Stem Cells. J Stem Cell Res Ther Suppl 11:|
|Asakura, Atsushi (2012) Skeletal Muscle-derived Hematopoietic Stem Cells: Muscular Dystrophy Therapy by Bone Marrow Transplantation. J Stem Cell Res Ther Suppl 11:|
|Watanabe, Shuichi; Hirai, Hiroyuki; Asakura, Yoko et al. (2011) MyoD gene suppression by Oct4 is required for reprogramming in myoblasts to produce induced pluripotent stem cells. Stem Cells 29:505-16|