Unknown

Dataset Information

0

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.

SUBMITTER: Bellinger AM 

PROVIDER: S-EPMC2910579 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Bellinger Andrew M AM   Reiken Steven S   Carlson Christian C   Mongillo Marco M   Liu Xiaoping X   Rothman Lisa L   Matecki Stefan S   Lacampagne Alain A   Marks Andrew R AR  

Nature medicine 20090208 3


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 al  ...[more]

Similar Datasets

| S-EPMC6259491 | biostudies-literature
| S-EPMC5337111 | biostudies-literature
| S-EPMC3990285 | biostudies-literature
| S-EPMC5657546 | biostudies-literature
| S-EPMC2527938 | biostudies-literature
| S-EPMC2381750 | biostudies-literature
| S-EPMC9950431 | biostudies-literature
| S-EPMC4342579 | biostudies-literature
| S-EPMC8821920 | biostudies-literature
| S-EPMC5680226 | biostudies-literature