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PMID: 21803290 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cell metabolism ·Vol. 14 ·No. 2 ·2011-08-03 ·Pages 196-207

Andersson DC, Betzenhauser MJ, Reiken S, Meli AC, Umanskaya A, Xie W, Shiomi T, Zalk R, Lacampagne A, Marks AR

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.

MeSH Terms
Aging Animals Calcium/metabolism Mice Mice, Inbred C57BL Mice, Transgenic Mitochondria/pathology,physiology Motor Activity/drug effects,physiology Muscle Contraction/physiology Muscle Weakness/metabolism Muscle, Skeletal/drug effects,metabolism Oxidation-Reduction Oxidative Stress Reactive Oxygen Species/blood Ryanodine Receptor Calcium Release Channel/metabolism Sarcopenia/metabolism Tacrolimus Binding Proteins/deficiency,metabolism Thiazepines/pharmacology
Chemicals
Reactive Oxygen Species Ryanodine Receptor Calcium Release Channel S-107 compound Thiazepines Tacrolimus Binding Proteins Calcium
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Andersson Daniel C
Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Betzenhauser Matthew J
Reiken Steven
Meli Albano C
Umanskaya Alisa
Xie Wenjun
Shiomi Takayuki
Zalk Ran
Lacampagne Alain
Marks Andrew R
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Article Info
Journal
Cell metabolism
Abbr.
Cell Metab
ISSN
1932-7420
DOI
10.1016/j.cmet.2011.05.014
Published
2011-08-03
Pages
196-207
Language
English
Region
United States
NLM ID
101233170
PMCID
PMC3690519
Subset
IM
Grants
NIAMS NIH HHS · R01 AR060037 · United States
NHLBI NIH HHS · R01 HL056180 · United States
NHLBI NIH HHS · R01 HL061503 · United States
External Links
PubMed source DOI: 10.1016/j.cmet.2011.05.014 PMC Full Text View journal details
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