Prednisolone-induced changes in dystrophic skeletal muscle.
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 alpha 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.
Fisher
Ivan
I
Muscle Cell Biology Group, MRC Clinical Sciences Centre, Imperial College, London, UK.
Abraham
David
D
Bouri
Khaled
K
Hoffmann
Eric P
EP
Hoffman
Eric P
EP
Muntoni
Francesco
F
Morgan
Jennifer
J
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D019703:Calcineurin / Q000032:analysis; D002352:Carrier Proteins / Q000235:genetics; D010450:Endopeptidases / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D000072233:Homer Scaffolding Proteins; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000032:analysis; D009336:Necrosis; D020411:Oligonucleotide Array Sequence Analysis; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D011239:Prednisolone / Q000494:pharmacology*; D018013:Receptors, Neuropeptide / Q000235:genetics; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D049411:Utrophin / Q000235:genetics; D000099159:Tacrolimus Binding Protein 5
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D019703:Calcineurin; D002352:Carrier Proteins; D010450:Endopeptidases; D000072233:Homer Scaffolding Proteins; D050778:NFATC Transcription Factors; D024661:Potassium Channels, Inwardly Rectifying; D011239:Prednisolone; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D022021:Tacrolimus Binding Proteins; D049411:Utrophin; D000099159:Tacrolimus Binding Protein 5; C494005:Nfatc1 protein, mouse; C089327:inward rectifier potassium channel 2; C509282:Bace1 protein, mouse; C048250:somatotropin releasing hormone receptor