title: Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice.
abstract: Duchenne muscular dystrophy (DMD) is caused by mutations in dystrophin and the subsequent disruption of the dystrophin-associated protein complex (DAPC). Utrophin is a dystrophin homolog expressed at high levels in developing muscle that is an attractive target for DMD therapy. Here we show that the extracellular matrix protein biglycan regulates utrophin expression in immature muscle and that recombinant human biglycan (rhBGN) increases utrophin expression in cultured myotubes. Systemically delivered rhBGN up-regulates utrophin at the sarcolemma and reduces muscle pathology in the mdx mouse model of DMD. RhBGN treatment also improves muscle function as judged by reduced susceptibility to eccentric contraction-induced injury. Utrophin is required for the rhBGN therapeutic effect. Several lines of evidence indicate that biglycan acts by recruiting utrophin protein to the muscle membrane. RhBGN is well tolerated in animals dosed for as long as 3 months. We propose that rhBGN could be a therapy for DMD.
authors.affiliation: Department of Neuroscience, Brown University, Providence, RI 02912, USA.
authors.forename: Alison R
authors.initials: AR
authors.lastname: Amenta
authors.forename: Atilgan
authors.initials: A
authors.lastname: Yilmaz
authors.forename: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.forename: Beth A
authors.initials: BA
authors.lastname: McKechnie
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Abedi
authors.forename: Tejvir S
authors.initials: TS
authors.lastname: Khurana
authors.forename: Justin R
authors.initials: JR
authors.lastname: Fallon
mesh_terms: D000818:Animals; D058578:Biglycan / Q000737:chemistry* / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D009132:Muscles / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000628:therapy*; D011994:Recombinant Proteins / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012508:Sarcolemma / Q000378:metabolism*; D015854:Up-Regulation; D049411:Utrophin / Q000737:chemistry*
chemical_list: D058578:Biglycan; D011994:Recombinant Proteins; D049411:Utrophin