title: Bmi1 enhances skeletal muscle regeneration through MT1-mediated oxidative stress protection in a mouse model of dystrophinopathy.
abstract: The Polycomb group (PcG) protein Bmi1 is an essential epigenetic regulator of stem cell function during normal development and in adult organ systems. We show that mild up-regulation of Bmi1 expression in the adult stem cells of the skeletal muscle leads to a remarkable improvement of muscle function in a mouse model of Duchenne muscular dystrophy. The molecular mechanism underlying enhanced physiological function of Bmi1 depends on the injury context and it is mediated by metallothionein 1 (MT1)-driven modulation of resistance to oxidative stress in the satellite cell population. These results lay the basis for developing Bmi1 pharmacological activators, which either alone or in combination with MT1 agonists could be a powerful novel therapeutic approach to improve regeneration in muscle wasting conditions.
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, England, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Di Foggia
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, England, UK.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: CBM S.c.r.l., 34012 Trieste, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Licastro
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6DE, England, UK.
authors.forename: Mattia F M
authors.initials: MF
authors.lastname: Gerli
authors.affiliation: The Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital for Children, London WC1N 3JH, England, UK.
authors.forename: Rahul
authors.initials: R
authors.lastname: Phadke
authors.affiliation: The Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital for Children, London WC1N 3JH, England, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Stem Cells and Development, Department of Developmental and Stem Cell Biology, Institut Pasteur, CNRS, URA 2578 Paris, France.
authors.forename: Philippos
authors.initials: P
authors.lastname: Mourikis
authors.affiliation: Stem Cells and Development, Department of Developmental and Stem Cell Biology, Institut Pasteur, CNRS, URA 2578 Paris, France.
authors.forename: Shahragim
authors.initials: S
authors.lastname: Tajbakhsh
authors.affiliation: Division of Neuropathology, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, England, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ellis
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE4 2HH, England, UK.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Greaves
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE4 2HH, England, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Institute for Inflammation and Repair, University of Manchester, Manchester M13 9PL, England, UK.
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, England, UK.
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Robson
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, England, UK s.marino@qmul.ac.uk.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marino
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002908:Chronic Disease; D004249:DNA Damage; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D008668:Metallothionein / Q000378:metabolism*; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D024510:Muscle Development; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000293:injuries / Q000473:pathology / Q000503:physiopathology*; D018384:Oxidative Stress; D051763:PAX7 Transcription Factor / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration; D015203:Reproducibility of Results; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology; D049490:Systems Biology
chemical_list: C489421:Bmi1 protein, mouse; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; C525355:metallothionein-1, mouse; D008668:Metallothionein; D063150:Polycomb Repressive Complex 1