Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging

Daniel C. Andersson, Matthew J. Betzenhauser, Steven Reiken, Albano C. Meli, Alisa Umanskaya, Wenjun Xie, Takayuki Shiomi, Ran Zalk, Alain Lacampagne, Andrew R. Marks

Research output: Contribution to journalArticlepeer-review

305 Scopus citations

Abstract

Age-related loss of muscle mass and force (sarcopenia) contributes to disability and increased mortality. Ryanodine receptor 1 (RyR1) is the skeletal muscle sarcoplasmic reticulum calcium release channel required for muscle contraction. RyR1 from aged (24 months) rodents was oxidized, cysteine-nitrosylated, and depleted of the channel-stabilizing subunit calstabin1, compared to RyR1 from younger (3-6 months) adults. This RyR1 channel complex remodeling resulted in "leaky" channels with increased open probability, leading to intracellular calcium leak in skeletal muscle. Similarly, 6-month-old mice harboring leaky RyR1-S2844D mutant channels exhibited skeletal muscle defects comparable to 24-month-old wild-type mice. Treating aged mice with S107 stabilized binding of calstabin1 to RyR1, reduced intracellular calcium leak, decreased reactive oxygen species (ROS), and enhanced tetanic Ca 2+ release, muscle-specific force, and exercise capacity. Taken together, these data indicate that leaky RyR1 contributes to age-related loss of muscle function.

Original languageEnglish
Pages (from-to)196-207
Number of pages12
JournalCell Metabolism
Volume14
Issue number2
DOIs
StatePublished - 3 Aug 2011
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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