Prednisolone‐induced changes in dystrophic skeletal muscle

I Fisher, D Abraham, K Bouri, EP Hoffman… - The FASEB …, 2005 - Wiley Online Library
I Fisher, D Abraham, K Bouri, EP Hoffman, F Muntoni, J Morgan
The FASEB journal, 2005Wiley Online Library
Although glucocorticoids delay the progression of Duchenne muscular dystrophy (DMD)
their mechanism of action is unknown. Skeletal muscle gene expression profiles of mdx
mice, an animal model of DMD, treated with prednisolone were compared with control mice
at 1 and 6 wk. Of the 89 early differentially regulated genes and ESTs, delta‐sarcoglycan,
myosin Va, FK506‐binding protein 51 (FKBP51), the potassium channel regulator potassium
inwardly‐rectifying channel Isk‐like (IRK2) and ADAM 10 were overexpressed, whereas …
Abstract
Although glucocorticoids delay the progression of Duchenne muscular dystrophy (DMD) their mechanism of action is unknown. Skeletal muscle gene expression profiles of mdx mice, an animal model of DMD, treated with prednisolone were compared with control mice at 1 and 6 wk. Of the 89 early differentially regulated genes and ESTs, delta‐sarcoglycan, myosin Va, FK506‐binding protein 51 (FKBP51), the potassium channel regulator potassium inwardly‐rectifying channel Isk‐like (IRK2) and ADAM 10 were overexpressed, whereas growth hormone‐releasing hormone receptor (GHRHR) and Homer‐2 were underexpressed. The 58 late differentially overexpressed genes included kallikreins (13, 16, and 26), FKBP51, PI3K a regulatory subunit, and IGFBP6, while underexpressed genes included NeuroD and nicotinic cholinergic receptor gamma. At both time points, overexpression of a cohort of genes relating to metabolism and proteolysis was apparent, alongside the differential expression of genes relating to calcium metabolism. Treatment did not increase muscle regeneration, reduce the number of infiltrating macrophages, or alter utrophin expression or localization. However, in the treated mdx soleus muscle, the percentage of slow fibers was significantly lower compared with untreated controls after 6 wk of treatment. These results show that glucocorticoids confer their benefit to dystrophic muscle in a complex fashion, culminating in a switch to a more normal muscle fiber type.
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