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

Classically, peroxisome proliferator-activated receptor ß/δ (PPARß/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 PPARß/δ during skeletal muscle growth and regeneration. Although PPARß/δ has been implicated in regulating myogenesis, little is presently known about the role and, for that matter, the mechanism(s) of action of PPARß/δ in regulating postnatal myogenesis. Here we report for the first time, using a PPARß/δ-specific ligand (L165041) and the PPARß/δ-null mouse model, that PPARß/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 PPARß/δ in skeletal muscle. In agreement, reduced Gasp-1 expression was detected in PPARß/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 PPARß/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 PPARß/δ. Moreover, we analyzed the ability of hGASP-1 to regulate myogenesis independently of PPARß/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 PPARß/δ is a positive regulator of skeletal muscle myogenesis, which functions through negatively modulating myostatin activity via a mechanism involving Gasp-1.