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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/δ promotes the slow oxidative phenotype in skeletal muscle, we initiated studies to determine whether pharmacological activation of PPARβ/δ provides functional benefits to the  mdx  mouse. GW501516, a PPARβ/δ agonist, was found to stimulate utrophin A mRNA levels in C2C12 muscle cells through an element in the utrophin A promoter. Expression of PPARβ/δ 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 α1-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/δ might provide functional benefits to DMD patients through enhancement of utrophin A expression.

human molecular genetics

Pharmacological activation of PPARβ/δ stimulates utrophin A expression in skeletal muscle fibers and restores sarcolemmal integrity in mature  mdx  mice