title: Peroxisome proliferator-activated receptor β/δ induces myogenesis by modulating myostatin activity.
abstract: Classically, peroxisome proliferator-activated receptor β/δ (PPARβ/δ) function was thought to be restricted to enhancing adipocyte differentiation and development of adipose-like cells from other lineages. However, recent studies have revealed a critical role for PPARβ/δ during skeletal muscle growth and regeneration. Although PPARβ/δ has been implicated in regulating myogenesis, little is presently known about the role and, for that matter, the mechanism(s) of action of PPARβ/δ in regulating postnatal myogenesis. Here we report for the first time, using a PPARβ/δ-specific ligand (L165041) and the PPARβ/δ-null mouse model, that PPARβ/δ enhances postnatal myogenesis through increasing both myoblast proliferation and differentiation. In addition, we have identified Gasp-1 (growth and differentiation factor-associated serum protein-1) as a novel downstream target of PPARβ/δ in skeletal muscle. In agreement, reduced Gasp-1 expression was detected in PPARβ/δ-null mice muscle tissue. We further report that a functional PPAR-responsive element within the 1.5-kb proximal Gasp-1 promoter region is critical for PPARβ/δ regulation of Gasp-1. Gasp-1 has been reported to bind to and inhibit the activity of myostatin; consistent with this, we found that enhanced secretion of Gasp-1, increased Gasp-1 myostatin interaction and significantly reduced myostatin activity upon L165041-mediated activation of PPARβ/δ. Moreover, we analyzed the ability of hGASP-1 to regulate myogenesis independently of PPARβ/δ activation. The results revealed that hGASP-1 protein treatment enhances myoblast proliferation and differentiation, whereas silencing of hGASP-1 results in defective myogenesis. Taken together these data revealed that PPARβ/δ is a positive regulator of skeletal muscle myogenesis, which functions through negatively modulating myostatin activity via a mechanism involving Gasp-1.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Sabeera
authors.initials: S
authors.lastname: Bonala
authors.forename: Sudarsanareddy
authors.initials: S
authors.lastname: Lokireddy
authors.forename: Harikumar
authors.initials: H
authors.lastname: Arigela
authors.forename: Serena
authors.initials: S
authors.lastname: Teng
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.forename: Mridula
authors.initials: M
authors.lastname: Sharma
authors.forename: Craig
authors.initials: C
authors.lastname: McFarlane
authors.forename: Ravi
authors.initials: R
authors.lastname: Kambadur
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D055435:Myostatin / Q000235:genetics / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism*; D010642:Phenoxyacetates / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
chemical_list: C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D002352:Carrier Proteins; C479636:Gprasp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C525912:Mstn protein, mouse; D055435:Myostatin; D047494:PPAR delta; D048068:PPAR-beta; D010642:Phenoxyacetates