Intramuscular administration of PEGylated IGF-I improves skeletal muscle regeneration after myotoxic injury

• Published in: Growth hormone & IGF research 2013-08, Vol.23 (4), p.128-133
• Main Authors: Martins, Karen J.B, Gehrig, Stefan M, Naim, Timur, Saenger, Stefanie, Baum, Dale, Metzger, Friedrich, Lynch, Gordon S
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Blotting, Western; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Endocrinology & Metabolism; Fluorescent Antibody Technique; Humans; IGF-I; Injections, Intramuscular; Insulin-Like Growth Factor I - administration & dosage; Male; Mice; Mice, Inbred C57BL; Muscle Development - drug effects; Muscle regeneration; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Muscle, Skeletal - injuries; Muscular Diseases - drug therapy; Muscular Diseases - metabolism; Muscular Diseases - pathology; Myotoxic injury; PEGylated IGF-I; Polyethylene Glycols - chemistry; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Real-Time Polymerase Chain Reaction; Recovery of Function - drug effects; Regeneration - drug effects; Regeneration - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics
• ISSN: 1096-6374; 1532-2238
• DOI: 10.1016/j.ghir.2013.03.002

Abstract Objective Musculoskeletal injuries represent a major public health problem and drugs that can improve muscle repair and restore function are needed for patients with these conditions and other related muscular pathologies. Increasing insulin-like growth factor-I (IGF-I) levels in skeletal muscle improves regeneration after myotoxic injury and while administration of IGF-I has a potential for accelerating healing after trauma, optimizing its method of delivery and obviating potential side-effects currently associated with recombinant human (rh) IGF-I, remain a hurdle. Design We compared the treatment efficacy of rhIGF-I with a polyethylene glycol modified IGF-I (PEG-IGF-I) analog to improve functional repair of mouse tibialis anterior muscles after myotoxic injury, testing the hypothesis that PEG-IGF-I would exert greater beneficial effects on regenerating skeletal muscles than rhIGF-I due to improved pharmacokinetic properties. We also examined the relative efficacy of systemic versus local delivery of these IGF-I variants for improving functional muscle regeneration. Results Local delivery of PEG-IGF-I, but not rhIGF-I, at 4 days post-injury significantly improved early functional recovery as evident by a 27% increase in normalized force compared with saline control ( P < 0.05), whereas systemic application of either IGF-I variant was not effective. The improved function with intramuscular PEG-IGF-I administration was attributed to a greater and prolonged residence within the regenerating muscles, resulting in increased Akt activation and a 13% larger fiber cross-sectional area compared with rhIGF-I ( P < 0.05). Conclusions These data support the hypothesis that PEG-IGF-I is more efficacious than rhIGF-I in hastening early fiber regeneration and improving muscle function after injury, highlighting its therapeutic potential for muscular pathologies.