Human Molecular Genetics Advance Access originally published online on September 10, 2009
Human Molecular Genetics 2009 18(23):4640-4649; doi:10.1093/hmg/ddp431
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Pharmacological activation of PPARβ/
stimulates utrophin A expression in skeletal muscle fibers and restores sarcolemmal integrity in mature mdx mice
1 Department of Cellular & Molecular Medicine and Center for Neuromuscular Disease and 2 Kidney Research Centre, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5 and 3 Ottawa Hospital Research Institute, Ottawa Hospital, Ottawa, ON, Canada K1H 8L6
* To whom correspondence should be addressed at: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada K1H 8M5. Tel: +1 6135625800 ext: 8383; Fax: +1 6135625636; Email: jasmin{at}uottawa.ca
Received July 6, 2009; Accepted September 7, 2009
A therapeutic strategy to treat Duchenne muscular dystrophy (DMD) involves identifying compounds that can elevate utrophin A expression in muscle fibers of affected patients. The dystrophin homologue utrophin A can functionally substitute for dystrophin when its levels are enhanced in the mdx mouse model of DMD. Utrophin A expression in skeletal muscle is regulated by mechanisms that promote the slow myofiber program. Since activation of peroxisome proliferator-activated receptor (PPAR) β/
promotes the slow oxidative phenotype in skeletal muscle, we initiated studies to determine whether pharmacological activation of PPARβ/ provides functional benefits to the mdx mouse. GW501516, a PPARβ/ agonist, was found to stimulate utrophin A mRNA levels in C2C12 muscle cells through an element in the utrophin A promoter. Expression of PPARβ/ was greater in skeletal muscles of mdx versus wild-type mice. We treated 5–7-week-old mdx mice with GW501516 for 4 weeks. This treatment increased the percentage of muscle fibers expressing slower myosin heavy chain isoforms and stimulated utrophin A mRNA levels leading to its increased expression at the sarcolemma. Expression of 
1-syntrophin and β-dystroglycan was restored to the sarcolemma. Improvement of mdx sarcolemmal integrity was evidenced by decreased intracellular IgM staining and decreased in vivo Evans blue dye (EBD) uptake. GW501516 treatment also conferred protection against eccentric contraction (ECC)-induced damage of mdx skeletal muscles, as shown by a decreased contraction-induced force drop and reduction of dye uptake during ECC. These results demonstrate that pharmacological activation of PPARβ/ might provide functional benefits to DMD patients through enhancement of utrophin A expression.