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

Cell Metab. 2011 Aug 3;14(2):196-207. doi: 10.1016/j.cmet.2011.05.014.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Calcium / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / pathology
  • Mitochondria / physiology
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Muscle Contraction / physiology
  • Muscle Weakness / metabolism*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Oxidation-Reduction
  • Oxidative Stress
  • Reactive Oxygen Species / blood
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Sarcopenia / metabolism*
  • Tacrolimus Binding Proteins / deficiency
  • Tacrolimus Binding Proteins / metabolism
  • Thiazepines / pharmacology


  • Reactive Oxygen Species
  • Ryanodine Receptor Calcium Release Channel
  • S-107 compound
  • Thiazepines
  • Tacrolimus Binding Proteins
  • Calcium