IGF-I overexpression in muscles of mdx mice improves excitation-contraction coupling in isolated mechanically skinned muscle fibres

C. Van Der Poel,¹ J.D. Schertzer,¹ T. Shavlakadze,² M.D. Grounds² and G.S. Lynch,¹ ¹Basic and Clinical Myology Laboratory, Department of Physiology, University of Melbourne, Victoria 3010, Australia and ²School of Anatomy and Human Biology, The University of Western Australia, Crawley, Perth, Western Australia 6009, Australia.

Excitation-contraction coupling (ECC) is impaired in muscles of mdx mice, an animal model of Duchenne muscular dystrophy (DMD). Insulin-like growth factor-I (IGF-I) has therapeutic potential for DMD, and has been shown to enhance skeletal muscle dihydropyridine receptor function and gene expression. We tested the hypothesis that muscle specific overexpression of IGF-I in mdx mice (mIGF-I-mdx) improves ECC. Mechanically skinned fibres were prepared from EDL muscles excised from C57BL/10, mdx, and mIGF-I-mdx mice that were anaesthetised with pentobarbital sodium (60 mg/kg, i.p.). The mice were then killed by cardiac excision. The number of depolarization-induced contractions (DICR) before reaching a 50% reduction in DICR amplitude, was lower in fibres from mdx (7 ± 1, n = 15 fibres) than C57BL/10 mice (16 ± 2, n = 12 fibres), but there was no difference in SR Ca²⁺ loading or Ca²⁺ leak rates. In mIGF-I-mdx mice, rundown of DICR was improved significantly compared to mdx mice (14 ± 2 depolarizations, n = 14 fibres, P < 0.05). There was no change in SR Ca²⁺ loading, but the amount of releasable SR Ca²⁺ was increased, possibly due to the reduction in Ca²⁺ leak rate (mdx: 19 ± 3% reduction, n = 13 vs mIGF-I-mdx: 7 ± 3% reduction, n = 14). The results support the hypothesis that muscle specific overexpression of IGF-I improves ECC in mdx mice.

Supported by the Muscular Dystrophy Association (USA).