Hypernitrosylated ryanodine receptor/calcium release channels are leaky in dystrophic muscle

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and early death resulting from dystrophin deficiency. Loss of dystrophin results in disruption of a large dystrophin glycoprotein complex (DGC) leading to pathologic calcium (Ca(2+))-dependent signals that damage muscle cells 1–5. We have identified a structural and functional defect in the sarcoplasmic reticulum (SR) Ca(2+) release channel/ryanodine receptor (RyR1) in the mdx mouse model of muscular dystrophy that may contribute to altered Ca(2+) homeostasis in dystrophic muscles. RyR1 isolated from mdx skeletal muscle exhibited an age-dependent increase in S-nitrosylation coincident with dystrophic changes in the muscle. RyR1 S-nitrosylation depleted the channel complex of FKBP12 (or “calstabin1” for calcium channel stabilizing binding protein) resulting in “leaky” channels. Preventing calstabin1 depletion from RyR1 using S107, a compound that binds to the RyR1 channel and enhances the binding affinity of calstabin1 to the nitrosylated channel, inhibited SR Ca(2+) leak, reduced biochemical and histologic evidence of muscle damage, improved muscle function and increased exercise performance in mdx mice. Thus, SR Ca(2+) leak via RyR1 due to S-nitrosylation of the channel and calstabin1 depletion likely contributes to muscle weakness in muscular dystrophy and preventing the RyR1-mediated SR Ca(2+) leak may provide a novel therapeutic approach.