IGF‐I improves excitation‐contraction coupling in skeletal muscle fibers of dystrophic mdx mice

The absence of dystrophin in Duchenne muscular dystrophy (DMD) causes progressive muscle wasting and possibly aberrant intracellular signaling including abnormal excitation‐contraction coupling (ECC) in skeletal muscle. Insulin‐like growth factor‐I (IGF‐I) is a potential therapy for DMD, and can alter ECC. We tested the hypothesis that muscle specific over‐expression of IGF‐I could ameliorate disruptions in ECC in muscle fibers from transgenic mdx (IGF‐mdx) mice. Mechanically‐skinned single fibers were prepared from the EDL muscles of mdx, IGF‐mdx, and wild type mice. The number of depolarization‐induced contractions (DICR) before a 50% reduction in amplitude was lower in mdx fibres (7 ± 1, n=15 fibers) than control (16 ± 2, n=12, P<0.05). There was no difference in SR Ca2+ properties. Rundown of DICR was improved significantly in IGF‐mdx (14 ± 2, n=14) compared with mdx mice (7 ± 1, n=15, P<0.05). SR Ca2+ release was 300% higher in IGF‐I‐mdx mice, possibly due to a decrease in SR Ca2+ leak rate [mdx, 19.0 ± 3.5% of loaded SR (n=13) vs. IGF‐mdx, 7.2 ± 3.0% (n=14)]. These results demonstrate that muscle specific over‐expression of IGF‐I in mdx mice can attenuate abnormal E‐C coupling. Supported by the Muscular Dystrophy Association (USA).