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1Division of Endocrinology, Metabolism, and Molecular Medicine and 2Research Centers in Minority Institutions, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059
Submitted 7 November 2002 ; accepted in final form 21 April 2003
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 µg/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
µg · kg-1 · day-1) was extended from 5
to 10 days, the rate of body weight loss was markedly reduced to 
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.
regulation; RU-486
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