title: Skeletal muscle-specific overexpression of IGFBP-2 promotes a slower muscle phenotype in healthy but not dystrophic mdx mice and does not affect the dystrophic pathology.
abstract: The insulin-like growth factor binding proteins (IGFBPs) are thought to modulate cell size and homeostasis via IGF-I-dependent and -independent pathways. There is a considerable dearth of information regarding the function of IGFBPs in skeletal muscle, particularly their role in the pathophysiology of Duchenne muscular dystrophy (DMD). In this study we tested the hypothesis that intramuscular IGFBP-2 overexpression would ameliorate the pathology in mdx dystrophic mice.
  
  
  
  4week old male C57Bl/10 and mdx mice received a single intramuscular injection of AAV6-empty or AAV6-IGFBP-2 vector into the tibialis anterior muscle. At 8weeks post-injection the effect of IGFBP-2 overexpression on the structure and function of the injected muscle was assessed.
  
  
  
  AAV6-mediated IGFBP-2 overexpression in the tibialis anterior (TA) muscles of 4-week-old C57BL/10 and mdx mice reduced the mass of injected muscle after 8weeks, inducing a slower muscle phenotype in C57BL/10 but not mdx mice. Analysis of inflammatory and fibrotic gene expression revealed no changes between control and IGFBP-2 injected muscles in dystrophic (mdx) mice.
  
  
  
  Together these results indicate that the IGFBP-2-induced promotion of a slower muscle phenotype is impaired in muscles of dystrophin-deficient mdx mice, which contributes to the inability of IGFBP-2 to ameliorate the dystrophic pathology. The findings implicate the dystrophin-glycoprotein complex (DGC) in the signaling required for this adaptation.
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, VIC 3010, Australia.
authors.forename: Kristy
authors.initials: K
authors.lastname: Swiderski
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, VIC 3010, Australia.
authors.forename: Karen Janet Bernice
authors.initials: KJ
authors.lastname: Martins
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, VIC 3010, Australia.
authors.forename: Annabel
authors.initials: A
authors.lastname: Chee
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, VIC 3010, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Trieu
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, VIC 3010, Australia.
authors.forename: Timur
authors.initials: T
authors.lastname: Naim
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, VIC 3010, Australia.
authors.forename: Stefan Martin
authors.initials: SM
authors.lastname: Gehrig
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, VIC 3010, Australia.
authors.forename: Dale Michael
authors.initials: DM
authors.lastname: Baum
authors.affiliation: Institute for Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), 18196, Dummerstorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Brenmoehl
authors.affiliation: Institute for Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), 18196, Dummerstorf, Germany.
authors.forename: Luong
authors.initials: L
authors.lastname: Chau
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, VIC 3010, Australia.
authors.forename: René
authors.initials: R
authors.lastname: Koopman
authors.affiliation: Muscle Biology and Therapeutics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC 3004, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.affiliation: F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, DTA Neuroscience, 4070, Basel, Switzerland.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Metzger
authors.affiliation: Institute for Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), 18196, Dummerstorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeflich
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, VIC 3010, Australia. Electronic address: gsl@unimelb.edu.au.
authors.forename: Gordon Stuart
authors.initials: GS
authors.lastname: Lynch
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis / Q000235:genetics; D007249:Inflammation / Q000235:genetics; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne; D010641:Phenotype; D059467:Transcriptome
chemical_list: D018971:Insulin-Like Growth Factor Binding Protein 2
keywords: Dystrophy; Fiber type; IGFBP-2; Muscle; Muscle function