Peroxisome proliferator-activated receptor β/δ induces myogenesis by modulating myostatin activity

J Biol Chem. 2012 Apr 13;287(16):12935-51. doi: 10.1074/jbc.M111.319145. Epub 2012 Feb 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Differentiation / physiology
  • Cell Division / physiology
  • Cells, Cultured
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Muscle Development / physiology*
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism
  • Myoblasts / cytology
  • Myoblasts / metabolism*
  • Myostatin / genetics
  • Myostatin / metabolism*
  • PPAR delta / agonists
  • PPAR delta / metabolism*
  • PPAR-beta / agonists
  • PPAR-beta / metabolism*
  • Phenoxyacetates / pharmacology
  • Signal Transduction / physiology


  • 4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid
  • Carrier Proteins
  • Gprasp1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Mstn protein, mouse
  • Myostatin
  • PPAR delta
  • PPAR-beta
  • Phenoxyacetates