TY - JOUR
T1 - Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging
AU - Andersson, Daniel C.
AU - Betzenhauser, Matthew J.
AU - Reiken, Steven
AU - Meli, Albano C.
AU - Umanskaya, Alisa
AU - Xie, Wenjun
AU - Shiomi, Takayuki
AU - Zalk, Ran
AU - Lacampagne, Alain
AU - Marks, Andrew R.
N1 - Funding Information:
This project was supported by grants from the National Heart, Lung, and Blood Institute to A.R.M. and the Swedish Research Council and the Swedish Heart-Lung Foundation to D.C.A. The authors thank Susan Hamilton (Baylor College of Medicine) for providing the muscle-specific FKBP12 (calstabin1)-deficient mice. We thank Peter S. Rabinovitch (University of Washington) and Gerald Shulman (Yale University) for generously providing us with muscles from MCAT mice. A.R.M. is a consultant for a start-up company, ARMGO Pharma, that is targeting RyR1 to improve exercise capacity in muscle diseases.
PY - 2011/8/3
Y1 - 2011/8/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79960940824&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2011.05.014
DO - 10.1016/j.cmet.2011.05.014
M3 - Article
C2 - 21803290
AN - SCOPUS:79960940824
SN - 1550-4131
VL - 14
SP - 196
EP - 207
JO - Cell Metabolism
JF - Cell Metabolism
IS - 2
ER -