title: Therapeutic potential of PEGylated insulin-like growth factor I for skeletal muscle disease evaluated in two murine models of muscular dystrophy.
abstract: OBJECTIVE
  Duchenne muscular dystrophy (DMD) is a fatal monogenetic disease with affected males displaying severe and progressive muscle wasting and weakness eventually leading to premature death. Possible therapeutic benefits of insulin-like growth factor I (IGF-I) have been studied extensively in various models of muscle disease and DMD with IGF-I as a mediator of improved skeletal muscle regeneration by enhancing myoblast proliferation and differentiation.
  
  
  METHODS
  We tested the efficacy of a novel IGF-I analogue, a polyethylene glycol modified IGF-I (PEG-IGF-I), to ameliorate the pathophysiology of muscular dystrophy in two mouse models of DMD. We used mdx mice which lack dystrophin (as in DMD) but exhibit only a relatively mild phenotype, and the dko mouse which is a transgenic model lacking utrophin in addition to dystrophin, and which exhibits a more severe, lethal phenotype like that in DMD.
  
  
  RESULTS
  In young mdx mice, twice-weekly PEG-IGF-I s.c. injections for 6 weeks protected the diaphragm muscle against fatigue and the tibialis anterior (TA) muscle against contraction-induced injury. However, this beneficial effect of PEG-IGF-I was less pronounced in mdx mice when treatment was initiated later in adulthood. In severely affected dko mice PEG-IGF-I treatment did not affect pathophysiological parameters including animal survival.
  
  
  CONCLUSIONS
  These data suggest a therapeutic benefit with PEG-IGF-I treatment only in mild muscle pathologies, since its potential to ameliorate the pathophysiology in models of severe muscular dystrophies was limited. Treatment should be initiated only for mild muscle pathologies if functional benefits are to be realised and therefore may be relevant as a short-term therapy to hasten the functional repair of otherwise healthy muscles after injury.
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Gehrig
authors.forename: Chris
authors.initials: C
authors.lastname: van der Poel
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeflich
authors.forename: Timur
authors.initials: T
authors.lastname: Naim
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Lynch
authors.forename: Friedrich
authors.initials: F
authors.lastname: Metzger
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D016189:Dystrophin / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000737:chemistry* / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000473:pathology; D010641:Phenotype; D011092:Polyethylene Glycols / Q000737:chemistry*; D013997:Time Factors
chemical_list: D016189:Dystrophin; D011092:Polyethylene Glycols; D007334:Insulin-Like Growth Factor I