title: Pregnancy-induced amelioration of muscular dystrophy phenotype in mdx mice via muscle membrane stabilization effect of glucocorticoid.
abstract: Duchenne muscular dystrophy (DMD), the most common and severe type of dystrophinopathy, is an X-linked recessive genetic disease caused by the absence of dystrophin, which leads to fragility and vulnerability of the sarcolemma to mechanical stretching with increased membrane permeability. Currently, glucocorticoids such as prednisolone are the only medication available for DMD. However, molecular pathways responsible for this effect are still unclear. In addition, it remains unclear whether sex-related factors, including pregnancy and the postpartum period, affect the phenotype of dystrophinopathy. Here, we report the amelioration of muscle membrane permeability in the diaphragm muscle of pregnant and postpartum, but not in nulliparous, mdx mice, an animal model for DMD, during the physiological surge of corticosterone, the most abundant glucocorticoid in rodents. Cultures of single muscle fibers and myotubes isolated from mdx mouse diaphragm demonstrate resistance to hypo-osmotic shock when treated with corticosterone but not with estradiol or progesterone. This corticosterone-mediated resistance was diminished by an antagonist of corticosterone, indicating that the glucocorticoid-glucocorticoid receptor axis plays a role in this membrane stabilization effect on muscle. Moreover, subcutaneous injection of corticosterone into mdx mice showed decreased membrane permeability. This is the first report to demonstrate that pregnancy-related resistance to muscle fiber damage in mdx mice due to the membrane stabilization effect of corticosterone. We also propose that this membrane stabilization effect is exerted through annexin A1 up-regulation as the molecular mechanisms of glucocorticoid effects on DMD muscle. Furthermore, single muscle fiber culture studies provide a sensitive chemical screening platform for muscular dystrophies.
authors.affiliation: Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, United States of America.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shimizu-Motohashi
authors.affiliation: Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, United States of America.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Asakura
authors.affiliation: Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, United States of America.
authors.forename: Norio
authors.initials: N
authors.lastname: Motohashi
authors.affiliation: Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, United States of America.
authors.forename: Nandkishore R
authors.initials: NR
authors.lastname: Belur
authors.affiliation: Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Baumrucker
authors.affiliation: Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, United States of America.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Asakura
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability; D003345:Corticosterone / Q000097:blood* / Q000494:pharmacology; D005260:Female; D051379:Mice; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism* / Q000473:pathology; D009997:Osmotic Pressure; D010641:Phenotype; D011247:Pregnancy; D015854:Up-Regulation
chemical_list: D017305:Annexin A1; D003345:Corticosterone