J Biol Chem.; co-auth. W Wahli

J Biol Chem. 2012 Feb 23. [Epub ahead of print]

Peroxisome Proliferator Activated Receptor β/δ induces myogenesis by modulating Myostatin activity.


Nanyang Technological University, Singapore;


Classically, 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 highly conserved PPAR responsive element (PPRE) within the 1.5kb 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 find enhanced secretion of Gasp-1, increased Gasp-1 Myostatin interaction and significantly reduced Myostatin activity upon L165041-mediated activation of PPARβ/δ. Moreover, we have analyzed the ability of hGASP-1 to regulate myogenesis, independent of PPARβ/δ activation. Results reveal that hGASP-1 protein treatment enhances myoblast proliferation and differentiation, whereas silencing of hGASP-1 results in defective myogenesis. Taken together these data reveal that PPARβ/δ is a positive regulator of skeletal muscle myogenesis, which functions through negatively modulating Myostatin activity via a mechanism involving Gasp-1.

PMID: 22362769 [PubMed – as supplied by publisher]