Preventing Ryanodine Receptor 1 calcium Leak Improves Age-Dependent Muscle Dysfunction

Abstract

A hallmark of mammalian aging is the progressive decline in muscle function, referred to as sarcopenia. It is commonly found that the force-generating capacity of aged muscle is reduced when normalized to the muscle cross-sectional area (specific force). This indicates defective excitation-contraction coupling. In this process, sarcoplasmic reticulum (SR) Ca2+ release via the ryanodine receptor 1 (RyR1) is a pivotal step that grades muscle contractile force. It has previously been shown that impaired contractility and SR Ca2+ release in muscular dystrophy can be caused by excessive RyR1-cysteine nitrosylation and reduced binding of the stabilizing protein FK506 binding protein 12 (FKBP12 or calstabin1) to RyR1. We hypothesized that maladaptations in the RyR1-SR Ca2+ release system could underlie impaired muscle function also in aging. Using immunoprecipitation and immuonblotting, we found that RyR1 from aged (24-26 month) mouse muscle were oxidized, cysteine-nitrosylated, and depleted of FKBP12, compared to RyR1 from younger (3-6 months) adult mice. This remodeling of the RyR1 resulted in “leaky” channels, which displayed an increased open probability and Ca2+ spark frequency.Moreover, tetanic Ca2+ transients and muscle specific forcewere reduced in 24-month-old mice. Treating aged mice with the RyR-stabilizing compound, S107, restored RyR1-FKBP12 interaction, and improved tetanic Ca2+ release, muscle specific force and exercise capacity.Together, these findings highlight the role of impaired SR Ca2+ release in age-dependent muscle weakness and introduce a novel therapeutic target for sarcopenia.