Glucocorticoid-mediated regulation of utrophin levels in human muscle fibers.

Previous studies on transgenic mice indicate that upregulation of utrophin protein may offer a potential treatment strategy for Duchenne muscular dystrophy. We have analyzed the effect of the glucocorticoid 6alpha-methylprednisolone-21 sodium succinate on utrophin protein levels, using a cell-based assay with differentiated human myotubes, derived from biopsies of healthy individuals or Duchenne muscular dystrophy patients. We found that within 5-7 days 6alpha-methylprednisolone-21 sodium succinate increases utrophin protein up to approximately 40% in both normal and dystrophin-deficient myotubes compared to untreated control cultures. When analyzed in promoter-reporter assays 6alpha-methylprednisolone-21 sodium succinate activated a utrophin promoter A-fragment but did not activate a utrophin promoter B-fragment. Surprisingly, endogenous levels of utrophin mRNA in 6alpha-methylprednisolone-21 sodium succinate-treated muscle cells were unaltered indicating that the utrophin-inducing effect of glucocorticoids may be a result of post-transcriptional mechanisms. We have also analyzed 66 glucocorticoids for their effect on utrophin protein levels and found that glucocorticoids in general are able to induce utrophin protein in human myotubes.