title: Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice.
abstract: Fibrillins are large extracellular macromolecules that polymerize to form the backbone structure of connective tissue microfibrils. Mutations in the gene for fibrillin-1 cause the Marfan syndrome, while mutations in the gene for fibrillin-2 cause Congenital Contractural Arachnodactyly. Both are autosomal dominant disorders, and both disorders affect musculoskeletal tissues. Here we show that Fbn2 null mice (on a 129/Sv background) are born with reduced muscle mass, abnormal muscle histology, and signs of activated BMP signaling in skeletal muscle. A delay in Myosin Heavy Chain 8, a perinatal myosin, was found in Fbn2 null forelimb muscle tissue, consistent with the notion that muscle defects underlie forelimb contractures in these mice. In addition, white fat accumulated in the forelimbs during the early postnatal period. Adult Fbn2 null mice are already known to demonstrate persistent muscle weakness. Here we measured elevated creatine kinase levels in adult Fbn2 null mice, indicating ongoing cycles of muscle injury. On a C57Bl/6 background, Fbn2 null mice showed severe defects in musculature, leading to neonatal death from respiratory failure. These new findings demonstrate that loss of fibrillin-2 results in phenotypes similar to those found in congenital muscular dystrophies and that FBN2 should be considered as a candidate gene for recessive congenital muscular dystrophy. Both in vivo and in vitro evidence associated muscle abnormalities and accumulation of white fat in Fbn2 null mice with abnormally activated BMP signaling. Genetic rescue of reduced muscle mass and accumulation of white fat in Fbn2 null mice was accomplished by deleting a single allele of Bmp7. In contrast to other reports that activated BMP signaling leads to muscle hypertrophy, our findings demonstrate the exquisite sensitivity of BMP signaling to the fibrillin-2 extracellular environment during early postnatal muscle development. New evidence presented here suggests that fibrillin-2 can sequester BMP complexes in a latent state.
authors.affiliation: Department of Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, Oregon, United States of America; Shriners Hospital for Children, Portland, Oregon, United States of America.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Sengle
authors.affiliation: Department of Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, Oregon, United States of America; Shriners Hospital for Children, Portland, Oregon, United States of America.
authors.forename: Valerie
authors.initials: V
authors.lastname: Carlberg
authors.affiliation: Shriners Hospital for Children, Portland, Oregon, United States of America.
authors.forename: Sara F
authors.initials: SF
authors.lastname: Tufa
authors.affiliation: Shriners Hospital for Children, Portland, Oregon, United States of America.
authors.forename: Noe L
authors.initials: NL
authors.lastname: Charbonneau
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Silvia
authors.initials: S
authors.lastname: Smaldone
authors.affiliation: Shriners Hospital for Children, Portland, Oregon, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Carlson
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ramirez
authors.affiliation: Shriners Hospital for Children, Portland, Oregon, United States of America.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.affiliation: Department of Biochemistry & Molecular Biology, Oregon Health & Science University, Portland, Oregon, United States of America; Shriners Hospital for Children, Portland, Oregon, United States of America.
authors.forename: Lynn Y
authors.initials: LY
authors.lastname: Sakai
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D003402:Creatine Kinase / Q000097:blood; D005260:Female; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D005786:Gene Expression Regulation; D017880:Limb Deformities, Congenital / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000002:abnormalities / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000235:genetics; D009924:Organ Culture Techniques; D015398:Signal Transduction / Q000235:genetics; D054392:Adipokines
chemical_list: D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D003402:Creatine Kinase; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C000605728:Fbn2 protein, mouse; C525820:bmp7 protein, mouse