AuPS Logo
Previous Next PDF

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).