Cell Metabolism
Volume 14, Issue 2, 3 August 2011, Pages 196-207
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Article
Ryanodine Receptor Oxidation Causes Intracellular Calcium Leak and Muscle Weakness in Aging

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Summary

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 Ca2+ release, muscle-specific force, and exercise capacity. Taken together, these data indicate that leaky RyR1 contributes to age-related loss of muscle function.

Highlights

► RyR1 in skeletal muscle is oxidized, nitrosylated, and depleted of calstabin1 with age ► Maladaptation of the RyR1 channel leads to SR Ca2+ leak and muscle weakness ► Vicious cycle: Ca2+ leak raises mitochondrial ROS, which oxidizes RyR1-enhancing leak ► The RyR1-stabilizing drug S107 fixes Ca2+ leak and improves exercise capacity in aging

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