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

摘要: Duchenne muscular dystrophy is characterized by progressive muscle weakness and early death resulting from dystrophin deficiency. Loss of results in disruption a large glycoprotein complex, leading to pathological calcium (Ca2+)-dependent signals that damage cells. We have identified structural functional defect the ryanodine receptor (RyR1), sarcoplasmic reticulum Ca2+ release channel, mdx mouse model contributes altered homeostasis dystrophic muscles. RyR1 isolated skeletal showed an age-dependent increase S-nitrosylation coincident with changes muscle. depleted channel complex FKBP12 (also known as calstabin-1, for stabilizing binding protein), 'leaky' channels. Preventing calstabin-1 depletion S107, compound binds enhances affinity nitrosylated inhibited leak, reduced biochemical histological evidence damage, improved function increased exercise performance mice. On basis these findings, we propose leak via due dystrophy, preventing RyR1-mediated may provide new therapeutic approach.