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EBioMedicine. 2017 Feb;15:193-202. doi: 10.1016/j.ebiom.2016.12.011. Epub 2016 Dec 23.

Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy.

Author information

1
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.
2
Department of Neuromuscular Research, National Institute of Neuroscience, Kodaira, Tokyo, Japan.
3
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.
4
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.

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/GT mice develop non-progressive weakness from younger age, accompanied by stunted muscle growth due to reduced IGF-1 signaling activity. In addition, the Col6a1GT/GT mice 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.

KEYWORDS:

Collagen; Fibrosis; IGF-1; Mesenchymal; Mouse; Muscular dystrophy; Skeletal muscles; Weakness

PMID:
28043812
PMCID:
PMC5233815
DOI:
10.1016/j.ebiom.2016.12.011
[Indexed for MEDLINE]
Free PMC Article

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