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

Abstract

Background: PPAR␤/␦ has been implicated in muscle regeneration; however the signaling mechanism(s) is unclear. Results: Activation of PPAR␤/␦-promoted Gasp-1 expression blocked myostatin activity and enhanced myogenesis. Conclusion: Activation of PPAR␤/␦ led to inhibition of myostatin activity and thus increased myogenesis. Significance: PPAR␤/␦ agonists are novel myostatin antagonists that have potential benefits toward improving postnatal muscle growth and repair.Classically, peroxisome proliferator-activated receptor ␤/␦ (PPAR␤/␦) 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 PPAR␤/␦ during skeletal muscle growth and regeneration. Although PPAR␤/␦ has been implicated in regulating myogenesis, little is presently known about the role and, for that matter, the mechanism(s) of action of PPAR␤/␦ in regulating postnatal myogenesis. Here we report for the first time, using a PPAR␤/␦-specific ligand (L165041) and the PPAR␤/␦-null mouse model, that PPAR␤/␦ 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 PPAR␤/␦ in skeletal muscle. In agreement, reduced Gasp-1 expression was detected in PPAR␤/␦-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 PPAR␤/␦ 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 PPAR␤/␦. Moreover, we analyzed the ability of hGASP-1 to regulate myogenesis independently of PPAR␤/␦ 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 PPAR␤/␦ is a positive regulator of skeletal muscle myogenesis, which functions through negatively modulating myostatin activity via a mechanism involving Gasp-1.In the late 1960s, work performed by De Duve et al.(1) led to the identification of a series of compounds that promote peroxisome proliferation. These compounds were subsequently grouped into a family known as peroxisome proliferators. Peroxisome proliferators were shown to elicit biological function through binding to ligand-inducible nuclear hormone receptors, of which the first receptor, cloned from mouse liver, was termed peroxisome proliferator-activated receptor (PPAR) 2 (2). Upon ligand binding, PPARs become activated and bind to their target genes by forming heterodimeric complexes with retinoid-X receptors (RXR) (3, 4). The activated PPAR-RXR complex then binds to consensus peroxisome pr...

High-fat diet reduces local myostatin-1 paralog expression and alters skeletal muscle lipid content in rainbow trout, Oncorhynchus mykiss

“…Interestingly, the promoter of myostatin-2a does not appear to contain any PPARREs, and experimental data failed to reveal any changes in the transcription of this paralog. At the protein level, PPARβδ has been shown to upregulate Gasp-1 expression, a protein that attenuates the actions of myostatin (Bonala et al 2012). Further, crosstalk between PPARγ and myostatin signaling has been demonstrated in human mesenchymal stem cells (hMSCs) (Guo et al 2008).…”

Absence of Hyperplasia inGasp-1Overexpressing Mice is Dependent on Myostatin Up-Regulation

“…In this paper, we investigated the cellular and molecular mechanisms deregulated by Gasp-1 overexpression to provide a detailed muscle phenotype characterization. Previous studies have shown that GASP-1 is capable of binding both myostatin and GDF-11 to inhibit their canonical pathway in vitro [29,38]. Mice lacking Gasp-1 exhibit only a slight muscle atrophy without an axial skeletal phenotype.…”

WFIKKN1 and WFIKKN2: “Companion” proteins regulating TGFB activity

“…Further, inhibition of the canonical MSTN-Smad pathway by WFIKKN2 was demonstrated in an in vitro myoblast cell line and led to an increase in myoblast differentiation and proliferation [8,37]. The WFIKKN function in muscle is also consistent with ovine polymorphisms present in intron 1 and 3 0 UTR region of the WFIKKN2 gene in 8 sheep breeds.…”

“…Regarding the regulation of the expression of the WFIKKN genes, a functional PPARB/G (peroxisome proliferator-activated receptor beta/gamma) site in the promoter of murine Wfikkn2 was found to be involved in the regulation of Wfikkn2 expression [8]. Further, increased expression of Pparg in mice overexpressing Wfikkn2 [7] provided some evidence of auto-regulation of Wfikkn2 gene expression by PPARB/G.…”

“…In 2003, a major advance in the understanding of the function of this gene family was made when WFIKKN2 was described as an MSTN associated protein found in human and mouse sera that could specifically inhibit MSTN, but not activin activity [3]. Since 2003, many studies confirmed that the WFIKKN proteins act as myostatin and GDF11 inhibitors [4][5][6][7][8][9] and are implicated in muscle growth [10][11][12][13][14]. However, only weak effects on muscle tissue were observed after overexpression or inactivation of Wfikkn1/Wfikkn2 in mice [7,9].…”