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1 Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, California, USA; Research Centers in Minority Institutions, Charlse R Drew University of Medicine and Science, Los Angeles, California, USA
2 Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, California, USA
* To whom correspondence should be addressed. E-mail: kuma{at}cdrewu.edu.
The mechanism 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, 1200 µg/kg-bodyweight) of dexamethasone for five days resulted in rapid, dose-dependent loss of bodyweight (-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 bodyweight and muscle loss and upregulation of intramuscular myostatin expression was time-dependent. When the dexamethasone treatment (600 µg/kg/day) was the G/FDS muscle complex the G/FDS muscle complex extended from 5 to 10 days, the rate of bodyweight loss was markedly reduced to approximately 2% within this extended period. The concentrations of intramuscular myosin heavy chain type II (MHC II) in dexamethasone-treated rats were significantly lower (-43% after 5-day treatment, and -14% after 10-day treatment) than their corresponding controls respectively. The intramuscular myostatin concentration in rats treated with dexamethasone for ten days returned to basal level. Concurrent treatment with RU486 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.
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