Insulin-like growth factor-I analogue protects muscles of dystrophic mdx mice from contraction-mediated damage.
Contraction-mediated injury is a major contributing factor to the pathophysiology of muscular dystrophy and therefore therapies that can attenuate this type of injury have clinical relevance. Systemic administration of insulin-like growth factor-I (IGF-I) has been shown to improve muscle function in dystrophic mdx mice, an effect associated with a shift towards a more oxidative muscle phenotype and a reduced susceptibility to contraction-mediated damage. The actions of IGF-I in vivo are modulated by IGF binding proteins (IGFBPs), which generally act to inhibit IGF-I signalling. We tested the hypothesis that an analogue of IGF-I (LR IGF-I), which has significantly reduced binding affinity for IGFBPs, would improve the dystrophic pathology by reducing the susceptibility to muscle injury. Dystrophic mdx and wild-type (C57BL/10) mice were administered LR IGF-I continuously ( approximately 1.5 mg kg(-1) day(-1)) via osmotic mini-pump for 4 weeks. Administration of LR IGF-I reduced the susceptibility of extensor digitorum longus, soleus and diaphragm muscles to contraction damage, as evident from lower force deficits after a protocol of lengthening contractions. In contrast to the mechanism of protection conferred by administration of IGF-I, the protection conferred by LR IGF-I was independent of changes in muscle fatigue and oxidative metabolism. This study further indicates that modulation of IGF-I signalling has therapeutic potential for muscular diseases.
Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria 3010, Australia.
Stefan M
SM
Gehrig
James G
JG
Ryall
Jonathan D
JD
Schertzer
Gordon S
GS
Lynch
D000818:Animals; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003964:Diaphragm / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D015918:Infusion Pumps, Implantable; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D009119:Muscle Contraction; D018763:Muscle Fatigue / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020127:Recovery of Function; D013997:Time Factors
C084339:LR(3)IGF-I; D020011:Protective Agents; D007334:Insulin-Like Growth Factor I; D002950:Citrate (si)-Synthase