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

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.

Peroxisome Proliferator-activated Receptor β/δ Induces Myogenesis by Modulating Myostatin Activity

“…Pharmacological activation of the muscle-specific PPAR␤/␦ isoform promotes muscle development, myonuclear accretion, and satellite cell proliferation and restores sarcolemmal integrity in dystrophic mice models (17,19,23,50,51), strongly supporting a role for PPAR␤/␦ in regulating postnatal muscle growth and development. However, no study has yet clearly revealed the molecular mechanism(s) through which PPAR␤/␦ regulates skeletal muscle growth.…”

“…Microarray and subsequent expression analysis collectively confirm that PPAR␤/␦ positively regulates Gasp-1 gene expression; as such, we suggest that Gasp-1 represents a novel muscle-specific downstream target of PPAR␤/␦. Previously published work has revealed that PPAR␤/␦ expression is greater in atrophying muscle tissue isolated from mdx mice, a mouse model of Duchenne muscular dystrophy (23). Based on this observation, we next wanted to ascertain whether increased endogenous PPAR␤/␦ expression, as seen in mdx mice, would induce Gasp-1 expression in vivo.…”

“…In addition, pharmacological activation of PPAR␤/␦ by GW0742 increases angiogenesis, enhances oxidative myofiber number, and improves myonuclear accretion in vivo (19), all features observed in response to exercise (20 -22). Furthermore, pharmacological activation of PPAR␤/␦ may act as a potential therapeutic in preventing the dramatic muscle wasting observed during muscular dystrophy (23). Specifically, activation of PPAR␤/␦ results in increased utrophin A transcript levels in mdx mice (a model of Duchene muscular dystrophy), which is a protein that can functionally compensate for the loss of dystrophin in mdx mice and as such helps to maintain the sarcolemmal integrity of degenerating muscle fibers.…”

Effects of prednisolone on the dystrophin-associated proteins in the blood–brain barrier and skeletal muscle of dystrophic mdx mice

“…The ability of PDN to upregulate utrophin is well known; the underlying mechanism involves both enhanced NF-AT transcription and translation. 27,84 Utrophin might act as a surrogate for dystrophin and associate with b-DG to rescue the complex. 84 A critical tyrosine residue of b-DG is exposed in the absence of dystrophin, and the consequent phosphorylation contributes to internalization and ubiquitin -related degradation of b-DG.…”

“…27,84 Utrophin might act as a surrogate for dystrophin and associate with b-DG to rescue the complex. 84 A critical tyrosine residue of b-DG is exposed in the absence of dystrophin, and the consequent phosphorylation contributes to internalization and ubiquitin -related degradation of b-DG. Nonetheless, bortezomib, a proteasome inhibitor, has been found to increase the expression of dystrophin-glycoprotein complex in muscles of mdx mice and in DMD biopsies.…”