Insulin‐like growth factor‐I analogue protects muscles of dystrophic mdx mice from contraction‐mediated damage
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abstract
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 (∼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.
