Cited by 424Muscle Physiology and DisordersIon channel regulation and functionMitochondrial Function and Pathology

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

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Andersson, Daniel C., Betzenhauser, Matthew J., Reiken, Steven, Meli, Albano C., Umanskaya, Alisa, Xie, Wenjun, Shiomi, Takayuki, Zalk, Ran +2 more·2011·Cell Metabolism

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.

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Crossref · 10.1016/j.cmet.2011.05.014

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  • An increase in Ca2+ concentration induces mPTP opening, which further exacerbates the imbalance of intracellular Ca2+ homeostasis, possibly caused by leaky ryanodine receptors in aged skeletal muscle.

    “An increase in Ca2+ concentration induces mPTP opening, which further exacerbates the imbalance of intracellular Ca2+ homeostasis, possibly caused by leaky ryanodine receptors in aged skeletal muscle (49).”

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Authors
Andersson, D. C., Betzenhauser, M. J., Reiken, S., Meli, A. C., Umanskaya, A., Xie, W., Shiomi, T., Zalk, R., Lacampagne, A., & Marks, A. R.
Affiliations
  • Columbia University Irving Medical Center (US)
  • Inserm (FR)
Corresponding author
Marks, Andrew R.
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2011-08
Volume
14
Issue
2
Pages
196-207
ISSN
1550-4131 (ISSN-L)
OpenAlex
W2078833625
Cited by
424
References
73
Citations by year
2026: 24 · 2025: 31 · 2024: 28 · 2023: 33 · 2022: 36 · 2021: 29 · 2020: 36 · 2019: 22 · 2018: 26 · 2017: 25 · 2016: 33 · 2015: 24 · 2014: 25 · 2013: 34 · 2012: 16
FWCI
9.86
Type
journal article
Language
en
Open access
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Vetenskapsrådet
  • National Heart, Lung, and Blood Institute (R01HL056180, R01HL061503)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR060037)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
RyR1, sarcopenia, aging, skeletal muscle, reactive oxygen species, muscle weakness, calcium release channel, exercise capacity, muscle force
MeSH terms
Aging, Animals, Calcium, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Motor Activity, Muscle Contraction, Oxidation-Reduction, Thiazepines, Reactive Oxygen Species, Oxidative Stress, Muscle, Skeletal, Muscle Weakness, Ryanodine Receptor Calcium Release Channel, Tacrolimus Binding Proteins, Mice, Sarcopenia

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