Modulation of insulin-like growth factor (IGF)-I and IGF-binding protein interactions enhances skeletal muscle regeneration and ameliorates the dystrophic pathology in mdx mice.
Administration of recombinant human insulin-like growth factor-I (rhIGF-I) has beneficial effects in animal models of muscle injury and muscular dystrophy. However, the results of these studies may have been confounded by interactions of rhIGF-I with endogenous IGF-binding proteins (IGFBPs). To date, no study has examined whether inhibiting IGFBP interactions with endogenous IGF-I can improve muscle fiber regeneration or muscular pathologies. We tested the hypothesis that reducing IGFBP interactions with endogenous IGF-I would enhance muscle regeneration after myotoxic injury and improve the dystrophic pathology in mdx mice. We administered an IGF-I aptamer (NBI-31772; 6 mg/kg per day, continuous infusion) to C57BL/10 mice undergoing regeneration after myotoxic injury or to mdx dystrophic mice. NBI-31772 binds all six IGFBPs with high affinity and releases "free" endogenous IGF-I. NBI-31772 treatment increased the rate of functional repair in fast-twitch tibialis anterior muscles after notexin-induced injury as evidenced by an increase in maximum force producing capacity (P(o)) at 10 days after injury. In contrast, NBI-31772 administration for 28 days did not alter P(o) of extensor digitorum longus (EDL) and soleus muscles or normalized force of diaphragm muscle strips from mdx mice. Although IGFBP inhibition reduced the susceptibility of the fast-twitch EDL and the diaphragm muscle to contraction-mediated damage, it increased muscle fatigability during repeated maximal contractions. Although the results in the myotoxic injury model suggest IGF-I signaling is important in this model, the results in the mdx model are mixed.
Schertzer
Jonathan D
JD
Department of Physiology, The University of Melbourne, Melbourne, VIC, 3010, Australia. gsl@unimelb.edu.au.
Gehrig
Stefan M
SM
Ryall
James G
JG
Lynch
Gordon S
GS
D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D002396:Catechols / Q000494:pharmacology; D018969:Insulin-Like Growth Factor Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D018101:Mice, Inbred mdx; D018763:Muscle Fatigue / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000473:pathology*; D009929:Organ Size; D012038:Regeneration / Q000187:drug effects