title: Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy.
abstract: Congenital muscular dystrophies with collagen VI deficiency are inherited muscle disorders with a broad spectrum of clinical presentation and are caused by mutations in one of COL6A1-3 genes. Muscle pathology is characterized by fiber size variation and increased interstitial fibrosis and adipogenesis. In this study, we define critical events that contribute to muscle weakness and fibrosis in a mouse model with collagen VI deficiency. The Col6a1GT/GTmice develop non-progressive weakness from younger age, accompanied by stunted muscle growth due to reduced IGF-1 signaling activity. In addition, the Col6a1GT/GTmice have high numbers of interstitial skeletal muscle mesenchymal progenitor cells, which dramatically increase with repeated myofiber necrosis/regeneration. Our results suggest that impaired neonatal muscle growth and the activation of the mesenchymal cells in skeletal muscles contribute to the pathology of collagen VI deficient muscular dystrophy, and more importantly, provide the insights on the therapeutic strategies for collagen VI deficiency.
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, Kodaira, Tokyo, Japan; Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan. Electronic address: noguchi@ncnp.go.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Noguchi
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, Kodaira, Tokyo, Japan.
authors.forename: Megumu
authors.initials: M
authors.lastname: Ogawa
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, 20892, MD, USA.
authors.forename: May Christine
authors.initials: MC
authors.lastname: Malicdan
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, Kodaira, Tokyo, Japan.
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, Kodaira, Tokyo, Japan; Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
mesh_terms: D000483:Alleles; D000818:Animals; D024142:Collagen Type VI / Q000172:deficiency*; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D005838:Genotype; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000235:genetics; D018908:Muscle Weakness / Q000235:genetics* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal; D009154:Mutation; D010641:Phenotype; D015398:Signal Transduction
chemical_list: D024142:Collagen Type VI; D007334:Insulin-Like Growth Factor I
keywords: Collagen; Fibrosis; IGF-1; Mesenchymal; Mouse; Muscular dystrophy; Skeletal muscles; Weakness