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

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

Author information

1
Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.

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.

PMID:
21803290
PMCID:
PMC3690519
DOI:
10.1016/j.cmet.2011.05.014
[Indexed for MEDLINE]
Free PMC Article

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