title: Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle.
abstract: Duchenne muscular dystrophy 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, leading to pathological calcium (Ca2+)-dependent signals that damage muscle cells. We have identified a structural and functional defect in the ryanodine receptor (RyR1), a sarcoplasmic reticulum Ca2+ release channel, in the mdx mouse model of muscular dystrophy that contributes to altered Ca2+ homeostasis in dystrophic muscles. RyR1 isolated from mdx skeletal muscle showed an age-dependent increase in S-nitrosylation coincident with dystrophic changes in the muscle. RyR1 S-nitrosylation depleted the channel complex of FKBP12 (also known as calstabin-1, for calcium channel stabilizing binding protein), resulting in 'leaky' channels. Preventing calstabin-1 depletion from RyR1 with S107, a compound that binds the RyR1 channel and enhances the binding affinity of calstabin-1 to the nitrosylated channel, inhibited sarcoplasmic reticulum Ca2+ leak, reduced biochemical and histological evidence of muscle damage, improved muscle function and increased exercise performance in mdx mice. On the basis of these findings, we propose that sarcoplasmic reticulum Ca2+ leak via RyR1 due to S-nitrosylation of the channel and calstabin-1 depletion contributes to muscle weakness in muscular dystrophy, and that preventing the RyR1-mediated sarcoplasmic reticulum Ca2+ leak may provide a new therapeutic approach.
authors.affiliation: Clyde and Helen Wu Center for Molecular Cardiology, Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Bellinger
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.forename: Christian
authors.initials: C
authors.lastname: Carlson
authors.forename: Marco
authors.initials: M
authors.lastname: Mongillo
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liu
authors.forename: Lisa
authors.initials: L
authors.lastname: Rothman
authors.forename: Stefan
authors.initials: S
authors.lastname: Matecki
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D004195:Disease Models, Animal; D006706:Homeostasis; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism*; D009603:Nitroso Compounds / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D009603:Nitroso Compounds; D019837:Ryanodine Receptor Calcium Release Channel; D022061:Tacrolimus Binding Protein 1A; D002118:Calcium