Characterization of 5 '-regulatory region of human myostatin gene: regulation by dexamethasone in vitro

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 horm one, myogenic differentiation factor 1, myocyte enhancer factor 2, peroxiso me proliferator-activated receptor, and nuclear factor-kappaB. To identify sites important for myostatin's gene transcription and regulation, eight de letion constructs were placed in C2C12 and L6 skeletal muscle cells. Transc riptional activity of the constructs was found to be significantly higher i n myotubes compared with that of myoblasts. To investigate whether glucocor ticoids regulate myostatin gene expression, we incubated both cell lines wi th dexamethasone. On both occasions, dexamethasone dose dependently increas ed both the promoter's transcriptional activity and the endogenous myostati n expression. The effects of dexamethasone were blocked when the cells were coincubated with the glucocorticoid receptor antagonist RU-486. These find ings suggest that glucocorticoids upregulate myostatin expression by induci ng gene transcription, possibly through a glucocorticoid receptor-mediated pathway. We speculate that glucocorticoid-associated muscle atrophy might b e due in part to the upregulation of myostatin expression.