Blockade of Glucocorticoid Receptor Binding and Inhibition of Dexamethasone-Induced Muscle Atrophy in the Rat by RU38486, a Potent Glucocorticoid Antagonist*

Abstract

Glucocorticoid hormones cause marked muscular atrophy, the mechanism of which is unknown. We employed a potent glucocorticoid antagonist, RU38486 [11 beta-(4-dimethylaminophenyl)17 beta-hydroxy-17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one], to determine whether intracellular glucocorticoid receptors are involved. RU38486 was shown to be an effective blocker of glucocorticoid receptor binding in vivo and in vitro. Furthermore, this compound significantly blocked the loss of body and muscle weight caused by injection of dexamethasone. These data indicate that intracellular glucocorticoid receptors are important in the etiology of steroid myopathy. Studies with glucocorticoid antagonists may lead to the design of specific therapeutic modalities for the treatment of both endogenously and exogenously produced steroid myopathies.

Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids.

“…A higher dose of RU 38486 was used in this series of experiments than in the first series of experiments because in pilot experiments the dose of 10 mg/kg (as used in the first series of experiments) did not affect the dexamethasoneinduced metabolic changes. The higher dose of RU 38486 is consistent with the dosage used to block dexamethasone-induced metabolic changes reported in a previous study (23).…”

“…To further test the role of glucocorticoids in the regulation of energy-ubiquitin-dependent muscle proteolysis, normal rats were treated with dexamethasone. In initial experiments, rats were treated with 2.5 or 10 mg/kg of dexamethasone, doses which have been shown in previous studies to stimulate muscle proteolysis (19,23). Because the higher dose resulted in both increased total and myofibrillar protein breakdown (Fig.…”

“…RU 38486 is a potent glucocorticoid receptor antagonist with no agonist activity even at high concentrations (22). The drug has been used in previous studies to block sepsis-or dexamethasone-induced metabolic changes in skeletal muscle (21,23).…”

“…The rats were fasted but had free access to water after the treatment, and metabolic studies were performed after 16 h to make conditions similar to those in the septic rats. The doses of dexamethasone used here were chosen from previous studies in which they resulted in increased breakdown of muscle proteins (19,23).…”

A novel in vitro model of sarcopenia using BubR1 hypomorphic C2C12 myoblasts

“…The synthetic glucocorticoid dexamethasone binds to the glucocorticoid receptor, activating the ubiquitin-proteasome dependent proteolytic pathway (Konagaya et al 1986). Sarcopenia is classified as either primary or secondary.…”