Disruption of IGF‐I/IGFBP interactions decreases contraction‐induced injury in dystrophic skeletal muscle

Duchenne muscular dystrophy (DMD) is caused by a lack of dystrophin, a structural protein thought to confer stability to skeletal muscle fibers. A lack of dystrophin results in an increased susceptibility to contraction‐induced (CI) injury. Insulin‐like growth factor‐I (IGF‐I) therapy has beneficial effects on muscle function in mdx mice, a model of DMD. The actions of IGF‐I are strongly modified by IGF binding proteins (IGFBPs). The IGF‐I aptamer, NBI‐31772, displaces IGFBPs from their interaction with IGF‐I, releasing free biologically active IGF‐I. We tested the hypothesis that disruption of IGF‐I/IGFBP interactions using NBI‐31772 would reduce the dystrophic pathology in mdx mice. NBI‐31772 was administered to mdx mice (continuous infusion; ~6 mg/kg/day) for 4 weeks via mini osmotic pump. Muscle contractile properties were examined in vitro. NBI‐31772 treatment reduced the susceptibility of the EDL and diaphragm muscles to CI injury, concomitant with reduced fatigue resistance and lower citrate synthase activity. The findings indicate that displacing IGF‐I from its binding proteins can protect dystrophic muscles from CI injury. Supported by the Muscular Dystrophy Association (USA).