title: Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy.
abstract: We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor β-centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are observed in bouts separated by 4 d, whereas a chronic profibrotic state was seen in bouts separated by 10 d. Treatment of asynchronously remodeling WT muscle with either prednisone or VBP15 mitigated the molecular phenotype. Our asynchronous regeneration model for pathological fibrosis and muscle wasting in the muscular dystrophies is likely generalizable to tissue failure in chronic inflammatory states in other regenerative tissues.
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
authors.forename: Sherry
authors.initials: S
authors.lastname: Dadgar
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
authors.forename: Helen
authors.initials: H
authors.lastname: Johnston
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
authors.forename: Akanchha
authors.initials: A
authors.lastname: Kesari
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
authors.forename: D Ashley
authors.initials: DA
authors.lastname: Hill
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
authors.forename: Terence A
authors.initials: TA
authors.lastname: Partridge
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
authors.forename: Mamta
authors.initials: M
authors.lastname: Giri
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Freishtat
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010.
authors.forename: Javad
authors.initials: J
authors.lastname: Nazarian
authors.affiliation: The Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 24061.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xuan
authors.affiliation: The Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 24061.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 Center for Genetic Medicine Research, Children's National Medical Center, and Department of Integrative Systems Biology, George Washington University, Washington, DC 20010 ehoffman@childrensnational.org.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D016189:Dystrophin / Q000235:genetics; D005355:Fibrosis / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000473:pathology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000473:pathology*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics / Q000473:pathology; D011241:Prednisone / Q000494:pharmacology; D011244:Pregnadienediols / Q000494:pharmacology; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics; D012038:Regeneration / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology; D016212:Transforming Growth Factor beta
chemical_list: D000893:Anti-Inflammatory Agents; D016189:Dystrophin; D011244:Pregnadienediols; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C584811:VBP15 compound; D011241:Prednisone