A Calpain Inhibitor Fails To Rescue Dystrophic Skeletal Muscle

Duchenne muscular dystrophy (DMD) is a fatal muscle disease caused by the absence of a functional dystrophin protein and is modeled by the mdx mouse. Numerous studies have reported an elevated calcium influx potentially leading to increased calpain activity and fiber necrosis. Efforts to target calpain with leupeptin (Leu), a calpain inhibitor, and Leu-based agents have been met with mixed results in the mdx mouse. In an effort to help clarify the ability or inability of calpain to alter disease progression, 12 mdx and 12 C57 mice were divided into four groups, including: mdx Leu, mdx PBS, C57 Leu, and C57 PBS. Animals were injected daily with Leu (36 mg/kg) or PBS i.p. for 6 mo beginning at 2 mo of age and ending at 8 mo of age. Leupeptin administration failed to improve serum creatine kinase activity or diaphragmatic specific tension. Further, muscle mass was unchanged in hind limb skeletal muscles. Lastly, histology revealed either no or minor improvements in fibrosis between PBS and leu treated animals. In summary, this evidence suggests that 36 mg/kg of Leu administration does not change muscle mass, histology, function or serum CK calling into question the validity of calpain as a long-term therapeutic target for the treatment of Duchenne muscular dystrophy. We are analyzing adaptive changes in the muscle to elucidate possible reasons for lack of a therapeutic effect. Supported by NIAMS (AR052646).