Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and early death resulting from dystrophin deficiency. Loss of dystrophin results in disruption of a large dystrophin glycoprotein complex (DGC) leading to pathologic calcium (Ca2+)-dependent signals that damage muscle cells 1–5. We have identified a structural and functional defect in the sarcoplasmic reticulum (SR) Ca2+ release channel/ryanodine receptor (RyR1) in the mdx mouse model of muscular dystrophy that may contribute to altered Ca2+ homeostasis in dystrophic muscles. RyR1 isolated from mdx skeletal muscle exhibited an age-dependent increase in S-nitrosylation coincident with dystrophic changes in the muscle. RyR1 S-nitrosylation depleted the channel complex of FKBP12 (or “calstabin1” for calcium channel stabilizing binding protein) resulting in “leaky” channels. Preventing calstabin1 depletion from RyR1 using S107, a compound that binds to the RyR1 channel and enhances the binding affinity of calstabin1 to the nitrosylated channel, inhibited SR Ca2+ leak, reduced biochemical and histologic evidence of muscle damage, improved muscle function and increased exercise performance in mdx mice. Thus, SR Ca2+ leak via RyR1 due to S-nitrosylation of the channel and calstabin1 depletion likely contributes to muscle weakness in muscular dystrophy and preventing the RyR1-mediated SR Ca2+ leak may provide a novel therapeutic approach.

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.

Summary Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time those of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15 month-old mice the exercise capacity of 3 month-old mice. This study uncovers a bone to muscle feed-forward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity.