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

Department of Cellular & Molecular Medicine and Center for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5.
Human Molecular Genetics (Impact Factor: 6.68). 10/2009; 18(23):4640-9. DOI: 10.1093/hmg/ddp431
Source: PubMed

ABSTRACT 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) beta/delta promotes the slow oxidative phenotype in skeletal muscle, we initiated studies to determine whether pharmacological activation of PPARbeta/delta provides functional benefits to the mdx mouse. GW501516, a PPARbeta/delta agonist, was found to stimulate utrophin A mRNA levels in C2C12 muscle cells through an element in the utrophin A promoter. Expression of PPARbeta/delta 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 alpha1-syntrophin and beta-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 PPARbeta/delta might provide functional benefits to DMD patients through enhancement of utrophin A expression.

    • "Slow oxidative phenotype in skeletal muscle can be promoted by the activation of peroxisome proliferator-activated receptor (PPAR) β/δ. Pharmacological activation of (PPAR)β/δ with GW501516, a drug has been found to increase more oxidative muscle phenotype with concomitant increased utrophin expression in murine muscle cell line C2C12 as well as in mdx mice model [59]. Engineered " Jazz " the artificial zinc finger transcription factors (ZF ATFs) restores sarcolemmal integrity by increasing utrophin expression in mdx mice [60]. "
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    ABSTRACT: Duchenne Muscular Dystrophy (DMD) is one the most frequent genetic disorder that affects 1 in every 3500 males worldwide. This fatal neuromuscular disorder arises from the defects in the protein, called dystrophin. The dystrophin coding gene is the largest known gene and present in X chromosome. Several strategies, ranging from cell based therapy to small RNA mediated exon skipping have been proposed as an effective therapy for this disease. Experiments in mice model have shown that upregulation of utrophin, the autosomal homologue of dystrophin can compensate dystrophin deficiency and ameliorate the dystrophic phenotype. Therefore utrophin has also been considered as a potent target for development of strategies against DMD. In the current review we describe different therapeutic approaches for DMD along with challenges they have to overcome.
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