TUESDAY, Aug. 9 (HealthDay News) -- The ryanodine receptor 1 (RyR1) channel complex is oxidized, nitrosylated, and depleted of calstabin1 with age, resulting in "leaky" calcium channels, which appear to contribute to the age-related loss of muscle function, according to an experimental study published in the Aug. 3 issue of Cell Metabolism.
Daniel C. Andersson, M.D., Ph.D., from the College of Physicians and Surgeons of Columbia University in New York City, and colleagues investigated the role that RyR1 plays in age-related loss of muscle function by comparing RyR1 in 24-month-old (aged) wild-type mice with RyR1 from younger wild-type mice between the ages of 3 and 6 months. A murine model with leaky RyR1 was generated (RyR1-S2844D) and was compared with muscle-specific calstabin1 deficient mice and aged mice.
The investigators found that, compared to RyR1 from young mice, RyR1 from aged mice was oxidized, cysteine-nitrosylated, and depleted of calstabin1. This modification led to intracellular calcium leak in skeletal muscle resulting from "leaky" channels with increased open probability. Similar skeletal muscle defects comparable to those in 24-month-old wild-type mice were seen in RyR1-S2844D mutant mice. In aged mice, treatment with S107 was found to stabilize the binding of calstabin1 to RyR1, reduce intracellular calcium leak, and decrease reactive oxygen species. The treatment also enhanced titanic Ca2+ release, muscle-specific force, and exercise capacity.
"We show that oxidized RyR1 in muscle from aged mice is depleted of calstabin1, resulting in leaky channels, reduced tetanic Ca2+, decreased muscle-specific force, and impaired exercise capacity," the authors write.
One of the study authors disclosed a financial tie to ARMGO Pharma.
Abstract
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