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Title: Myogenic and functional effects of deflazacort therapy on mdx dystrophic mice
Authors: Weber, Michael H.
Issue Date: 1-Aug-1999
Abstract: Duchenne muscular dystrophy (DMD) is caused by a lack of dystrophin. ' Mdx' dystrophic mice experience acute and extensive muscle fiber necrosis at 3wks-of-age, followed by regeneration with little disability. Early treatment with deflazacort, a glucocorticoid, slows dystrophy and improves repair. While the mechanism of action is unknown, effects on repair may be due to increased proliferation by myogenic precursor cells (mpc) or more recruitment to the cell cycle. Expression of myogenic regulatory factor gene transcripts in cells identified as mpc can be studied using 'in situ' hybridization (ISH). Along with labels for DNA synthesis, changes in mpc proliferation can be determined. Deflazacort may also increase laminin expression that could stabilize new fibers. We hypothesized that deflazacort treatment benefits function and promotes repair by increasing mpc proliferation and fiber differentiation. ' Mdx' mice (3.5wks) were treated with deflazacort (1.2mg/kg) for 4wks while muscle strength was measured regularly. A crush injury was given to one tibialis anterior muscle, and four days later, muscle was collected to study creatine kinase (CK) isoforms, mpc proliferation and laminin expression. ' Mdx' strength increased with deflazacort in correlation with a shift of CK isoforms to a more mature MM isoform. ISH/autoradiography experiments showed increased proliferation by myogenin+ but not MyoD+ mpc. Laminin mRNA and protein expression were increased (Northern and Western blots) by deflazacort treatment. Hence, deflazacort promoted functional gains and myogenic differentiation in regenerating dystrophic muscle, and these findings encourage future studies to optimize early treatment of DMD.
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