The mechanisms by which excessive
glucocorticoids cause
muscular atrophy remain unclear. We previously demonstrated that
dexamethasone increases the expression of
myostatin, a negative regulator of skeletal muscle mass, in vitro. In the present study, we tested the hypothesis that
dexamethasone-induced muscle loss is associated with increased
myostatin expression in vivo. Daily administration (60, 600, 1,200 micro g/kg body wt) of
dexamethasone for 5 days resulted in rapid, dose-dependent loss of
body weight (-4.0, -13.4, -17.2%, respectively, P < 0.05 for each comparison), and
muscle atrophy (6.3, 15.0, 16.6% below controls, respectively). These changes were associated with dose-dependent, marked induction of intramuscular
myostatin mRNA (66.3, 450, 527.6% increase above controls, P < 0.05 for each comparison) and
protein expression (0.0, 260.5, 318.4% increase above controls, P < 0.05). We found that the effect of
dexamethasone on
body weight and muscle loss and upregulation of intramuscular
myostatin expression was time dependent. When
dexamethasone treatment (600 micro g. kg-1. day-1) was extended from 5 to 10 days, the rate of
body weight loss was markedly reduced to approximately 2% within this extended period. The concentrations of intramuscular
myosin heavy chain type II in
dexamethasone-treated rats were significantly lower (-43% after 5-day treatment, -14% after 10-day treatment) than their respective corresponding controls. The intramuscular
myostatin concentration in rats treated with
dexamethasone for 10 days returned to basal level. Concurrent treatment with
RU-486 blocked
dexamethasone-induced
myostatin expression and significantly attenuated body loss and
muscle atrophy. We propose that
dexamethasone-induced muscle loss is mediated, at least in part, by the upregulation of
myostatin expression through a
glucocorticoid receptor-mediated pathway.