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Activation of PPARδ stimulates utrophin A expression in skeletal muscle cells
Author(s) -
Miura Pedro,
Chakkalakal Joe V.,
Lunde John,
Shaver Amanda,
Belanger Guy,
Jasmin Bernard J.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1301-d
Subject(s) - utrophin , c2c12 , downregulation and upregulation , transfection , reporter gene , chemistry , skeletal muscle , dystrophin , duchenne muscular dystrophy , microbiology and biotechnology , peroxisome proliferator activated receptor , myocyte , endocrinology , medicine , biology , gene expression , receptor , myogenesis , gene , biochemistry
A potential therapeutic strategy to treat Duchenne Muscular Dystrophy (DMD) involves upregulation of utrophin in muscle fibers of patients. Our recent studies demonstrated that utrophin A is regulated by mechanisms that also promote expression of the slow myofiber program (PNAS 100: –6, 2003; Hum Mol Genet. 13: –88, 2004). Since activation of PPARδ in muscle causes a fiber type shift towards the slower, more oxidative phenotype, we initiated studies to determine whether PPARδ activation also increases utrophin expression. Treatment of C2C12 muscle cells with GW501516 , a PPARδ agonist, caused a 50–100% increase in utrophin A mRNA levels. Examination of the human utrophin A promoter region revealed the presence of a conserved PPAR response element (PPRE). GW501516 treatment of C2C12 cells transfected with a utrophin A promoter‐reporter construct induced a 50–100% increase in reporter activity. This effect was abrogated by deletion of the PPRE. Treatment of utrophin A promoter reporter transgenic mice with GW501516 also stimulated utrophin A promoter activity. In mdx mice, PPARδ was found to be higher in edl and soleus muscles compared to wild type control mice. Based on these results, activation of PPARδ, which promotes utrophin A expression, appears as a promising therapeutic intervention to counteract the devastating effects of DMD. Funded by MDA.