Ryanodine Receptor Oxidation Causes Intracellular Calcium Leak and Muscle Weakness in Aging

Abstract

Summary 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 were 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, six-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 Ca2+ release, muscle specific force and exercise capacity. Taken together these data indicate that leaky RyR1 contribute to age-related loss of muscle function.

Ryanodine receptor fragmentation and sarcoplasmic reticulum Ca 2+ leak after one session of high-intensity interval exercise

“…Moreover, the ROS dependency of RyR1 modifications offers a tentative explanation as to why an effective antioxidant treatment hampers beneficial adaptations induced by endurance training (17)(18)(19). Finally, destabilized RyR1 has predominantly been linked to muscle weakness in several pathological conditions as well as in normal aging (8)(9)(10)(11)(12)(13), but here we show that RyR1 modifications can also have an integral role in physiological muscle adaptations.…”

“…Defective RyR1 function is also implied in several pathological states, including generalized inflammatory disorders (10), heart failure (11), and inherited conditions such as malignant hyperthermia (12) and Duchenne muscular dystrophy (13). In many of the above conditions, there is a link between the impaired RyR1 function and modifications induced by reactive oxygen/nitrogen species (ROS) (6,8,10,12,13). Conversely, altered RyR1 function may also be beneficial by increasing the cytosolic free [Ca 2+ ] ([Ca 2+ ] i ) at rest, which can stimulate mitochondrial biogenesis and thereby increase fatigue resistance (14)(15)(16).…”

“…Recent studies imply a key role of the sarcoplasmic reticulum (SR) Ca 2+ release channel, the ryanodine receptor 1 (RyR1), in the reduced muscle strength observed in numerous physiological conditions, such as after strenuous endurance training (6), in situations with prolonged stress (7), and in normal aging (8,9). Defective RyR1 function is also implied in several pathological states, including generalized inflammatory disorders (10), heart failure (11), and inherited conditions such as malignant hyperthermia (12) and Duchenne muscular dystrophy (13).…”

A change of heart: oxidative stress in governing muscle function?

“…The Ca 2+ concentration within the SR is determined by the delicate balance between Ca 2+ release through the RyRs and Ca 2+ uptake via SERCA (Periasamy and Janssen 2008). Ca 2+ is central to a number of cellular functions and impairment of membrane Ca 2+ transport has serious deleterious effects, including muscle injury (Zalk et al 2007;Murphy et al 2008;Durham et al 2008;Bellinger et al 2009;González et al 2010b;Andersson et al 2011). Muscle force generation initiates with the rise in cytoplasmic free Ca 2+ concentration, whereas the removal of Ca 2+ imparts a state of relaxation.…”

“…All mechanisms that regulate Ca 2+ in skeletal and cardiac muscles are known to be susceptible to oxidative stress produced by organic free radicals and ROS (Comporti 1989). Increased intracellular Ca 2+ is associated with oxidative damage to muscle (Zalk et al 2007;Durham et al 2008;Bellinger et al 2009;Andersson et al 2011) while the sodium-calcium exchanger is known to contribute to increased intracellular Ca 2+ loading during Na + accumulation (Louch et al 2010). In addition, oxidative posttranslational modifications and Ca 2+ mishandling have been shown to be associated with diastolic dysfunction .…”