title: Overexpression of Latent TGFβ Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFβ.
abstract: Latent TGFβ binding proteins (LTBPs) regulate the extracellular availability of latent TGFβ. LTBP4 was identified as a genetic modifier of muscular dystrophy in mice and humans. An in-frame insertion polymorphism in the murine Ltbp4 gene associates with partial protection against muscular dystrophy. In humans, nonsynonymous single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation in Duchenne muscular dystrophy. To better understand LTBP4 and its role in modifying muscular dystrophy, we created transgenic mice overexpressing the protective murine allele of LTBP4 specifically in mature myofibers using the human skeletal actin promoter. Overexpression of LTBP4 protein was associated with increased muscle mass and proportionally increased strength compared to age-matched controls. In order to assess the effects of LTBP4 in muscular dystrophy, LTBP4 overexpressing mice were bred to mdx mice, a model of Duchenne muscular dystrophy. In this model, increased LTBP4 led to greater muscle mass with proportionally increased strength, and decreased fibrosis. The increase in muscle mass and reduction in fibrosis were similar to what occurs when myostatin, a related TGFβ family member and negative regulator of muscle mass, was deleted in mdx mice. Supporting this, we found that myostatin forms a complex with LTBP4 and that overexpression of LTBP4 led to a decrease in myostatin levels. LTBP4 also interacted with TGFβ and GDF11, a protein highly related to myostatin. These data identify LTBP4 as a multi-TGFβ family ligand binding protein with the capacity to modify muscle disease through overexpression.
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.|Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, United States of America.
authors.forename: Kay-Marie
authors.identifier: 0000-0001-9572-8384
authors.initials: KM
authors.lastname: Lamar
authors.affiliation: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, United States of America.
authors.forename: Sasha
authors.identifier: 0000-0003-4514-7893
authors.initials: S
authors.lastname: Bogdanovich
authors.affiliation: Molecular Pathogenesis and Molecular Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Brandon B
authors.initials: BB
authors.lastname: Gardner
authors.affiliation: Committee on Development, Regeneration, and Stem Cell Biology, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Quan Q
authors.initials: QQ
authors.lastname: Gao
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Tamari
authors.identifier: 0000-0001-8629-7973
authors.initials: T
authors.lastname: Miller
authors.affiliation: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, United States of America.
authors.forename: Judy U
authors.identifier: 0000-0002-6872-6516
authors.initials: JU
authors.lastname: Earley
authors.affiliation: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, United States of America.
authors.forename: Michele
authors.initials: M
authors.lastname: Hadhazy
authors.affiliation: Committee on Development, Regeneration, and Stem Cell Biology, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Andy H
authors.initials: AH
authors.lastname: Vo
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wren
authors.affiliation: Cincinnati Children's Hospital, Howard Hughes Medicine Institutes, Cincinnati, Ohio, United States of America.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago Illinois, United States of America.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D055412:Growth Differentiation Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055435:Myostatin / Q000235:genetics* / Q000378:metabolism; D009284:Naphthols; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014227:Triazines
chemical_list: C409762:2-(3-aminophenol)-6-(4-amino-1-naphthol)-4-chloro-triazine; D019485:Bone Morphogenetic Proteins; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors; C509040:LTBP4 protein, human; D053779:Latent TGF-beta Binding Proteins; D055435:Myostatin; D009284:Naphthols; D016212:Transforming Growth Factor beta; D014227:Triazines