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: 6.39).
10/2009; 18(23):4640-9. DOI: 10.1093/hmg/ddp431
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.
Available from: nuclearreceptorsignaling.com
- "Over a 4- week trial period, the agonist treatment augmented the percentage of muscle fibers expressing slower myosin heavy chain isoforms and stimulated transcription of utrophin A and its expression in the sarcolemma. The mdx sarcolemma integrity was improved, together with a limitation of the eccentric contraction-induced damage of mdx skeletal muscles [Miura et al., 2009]. More generally, a better knowledge of the metabolic role of PPARβ/δ in skeletal muscle, where it contributes to enhanced muscle endurance, might be useful in designing therapeutic strategies for muscular degenerative diseases such as muscular dystrophy. "
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ABSTRACT: The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of genes involved in cellular differentiation, development, metabolism and also tumorigenesis. Three PPAR isotypes (α, β/δ and γ) have been identified, among which PPARβ/δ is the most difficult to functionally examine due to its tissue-specific diversity in cell fate determination, energy metabolism and housekeeping activities. PPARβ/δ acts both in a ligand-dependent and -independent manner. The specific type of regulation, activation or repression, is determined by many factors, among which the type of ligand, the presence/absence of PPARβ/δ-interacting corepressor or coactivator complexes and PPARβ/δ protein post-translational modifications play major roles. Recently, new global approaches to the study of nuclear receptors have made it possible to evaluate their molecular activity in a more systemic fashion, rather than deeply digging into a single pathway/function. This systemic approach is ideally suited for studying PPARβ/δ, due to its ubiquitous expression in various organs and its overlapping and tissue-specific transcriptomic signatures. The aim of the present review is to present in detail the diversity of PPARβ/δ function, focusing on the different information gained at the systemic level, and describing the global and unbiased approaches that combine a systems view with molecular understanding.
Nuclear Receptor Signaling 04/2015; 13. DOI:10.1621/nrs.13001
Available from: Trinath Ghosh
- "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 . Engineered " Jazz " the artificial zinc finger transcription factors (ZF ATFs) restores sarcolemmal integrity by increasing utrophin expression in mdx mice . "
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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.
Current Chemical Biology 04/2015; 8(3):117-131. DOI:10.2174/221279680803150420094222
Available from: PubMed Central
- "Another approach could use pharmaceutical activation of the PGC-1α pathway. Recent reports have reported benefits in mdx mice with administration of activators of AMPK, SIRT1, or PPARδ, all of which also activate PGC-1α
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ABSTRACT: Duchenne muscle dystrophy (DMD) afflicts 1 million boys in the US and has few effective treatments. Constitutive transgenic expression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha improves skeletal muscle function in the murine "mdx" model of DMD, but how this occurs, or whether it can occur post-natally, is not known. The leading mechanistic hypotheses for the benefits conferred by PGC-1alpha include the induction of utrophin, a dystrophin homolog, and/or induction and stabilization of the neuromuscular junction.
The effects of transgenic overexpression of PGC-1beta, a homolog of PGC-1alpha in mdx mice was examined using different assays of skeletal muscle structure and function. To formally test the hypothesis that PGC-1alpha confers benefit in mdx mice by induction of utrophin and stabilization of neuromuscular junction, PGC-1alpha transgenic animals were crossed with the dystrophin utrophin double knock out (mdx/utrn-/-) mice, a more severe dystrophic model. Finally, we also examined the effect of post-natal induction of skeletal muscle-specific PGC-1alpha overexpression on muscle structure and function in mdx mice.
We show here that PGC-1beta does not induce utrophin or other neuromuscular genes when transgenically expressed in mouse skeletal muscle. Surprisingly, however, PGC-1beta transgenesis protects as efficaciously as PGC-1alpha against muscle degeneration in dystrophin-deficient (mdx) mice, suggesting that alternate mechanisms of protection exist. When PGC-1alpha is overexpressed in mdx/utrn-/- mice, we find that PGC-1alpha dramatically ameliorates muscle damage even in the absence of utrophin. Finally, we also used inducible skeletal muscle-specific PGC-1alpha overexpression to show that PGC-1alpha can protect against dystrophy even if activated post-natally, a more plausible therapeutic option.
These data demonstrate that PGC-1alpha can improve muscle dystrophy post-natally, highlighting its therapeutic potential. The data also show that PGC-1alpha is equally protective in the more severely affected mdx/utrn-/- mice, which more closely recapitulates the aggressive progression of muscle damage seen in DMD patients. The data also identify PGC-1beta as a novel potential target, equally efficacious in protecting against muscle dystrophy. Finally, the data also show that PGC-1alpha and PGC-1beta protect against dystrophy independently of utrophin or of induction of the neuromuscular junction, indicating the existence of other mechanisms.
Skeletal Muscle 01/2014; 4(1):2. DOI:10.1186/2044-5040-4-2
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