title: Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging.
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.
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Andersson
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Betzenhauser
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.forename: Albano C
authors.initials: AC
authors.lastname: Meli
authors.forename: Alisa
authors.initials: A
authors.lastname: Umanskaya
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xie
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shiomi
authors.forename: Ran
authors.initials: R
authors.lastname: Zalk
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000375:Aging; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D018908:Muscle Weakness / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000097:blood; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D055948:Sarcopenia / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000172:deficiency / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; C540746:S-107 compound; D013841:Thiazepines; D022021:Tacrolimus Binding Proteins; D002118:Calcium