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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR061545-02
Application #
8507145
Study Section
Special Emphasis Panel (ZAR1-EHB (M1))
Program Officer
Nuckolls, Glen H
Project Start
2012-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$71,725
Indirect Cost
$24,225
Name
University of Minnesota Twin Cities
Department
Neurology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
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
Motohashi, Norio; Asakura, Yoko; Asakura, Atsushi (2014) Isolation, culture, and transplantation of muscle satellite cells. J Vis Exp :
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