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Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90509
We cloned and
characterized a 3.3-kb fragment containing the 5'-regulatory region of
the human myostatin gene. The promoter sequence contains putative
muscle growth response elements for glucocorticoid, androgen, thyroid
hormone, myogenic differentiation factor 1, myocyte enhancer factor 2, peroxisome proliferator-activated receptor, and nuclear
factor-
B. To identify sites important for myostatin's gene
transcription and regulation, eight deletion constructs were placed in
C2C12 and L6 skeletal muscle cells. Transcriptional activity of the constructs was found to be
significantly higher in myotubes compared with that of myoblasts. To
investigate whether glucocorticoids regulate myostatin gene expression,
we incubated both cell lines with dexamethasone. On both occasions, dexamethasone dose dependently increased both the promoter's
transcriptional activity and the endogenous myostatin expression. The
effects of dexamethasone were blocked when the cells were coincubated with the glucocorticoid receptor antagonist RU-486. These findings suggest that glucocorticoids upregulate myostatin expression by inducing gene transcription, possibly through a glucocorticoid receptor-mediated pathway. We speculate that glucocorticoid-associated muscle atrophy might be due in part to the upregulation of myostatin expression.
glucocorticoid; RU-486; skeletal muscle; C2C12 cells
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