The PPARγ Agonist Troglitazone Induces Musclin mRNA Expression in Human Myotubes

Introduction

Very recently, a novel skeletal muscle-derived secreted protein, or myokine, was identified in mice and named musclin [1]. Murine musclin was shown to be almost exclusively expressed in skeletal muscle [1]. More than 10-fold lower expression levels were detected in brown adipose tissue, testis, spleen, and bone, where it is known as osteocrin, a factor secreted by osteoblasts and young osteocytes [2]. Musclin consists of 100 amino acids, contains a C-terminal domain highly homologous to natriuretic peptides, and similar to those, is cleaved at an internal serine protease cleavage site [1] [2]. Its expression is repressed by fasting and catecholamines and induced by insulin [1]. Finally, treatment of murine C2C12 myocytes with recombinant musclin revealed inhibitory effects of this protein on insulin-stimulated glucose uptake as well as on basal and insulin-stimulated glycogen synthesis [1].

Thiazolidinediones (TZD) are high-affinity ligands of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) γ. Furthermore, in vitro and ex vivo studies have consistently shown that TZD improve insulin sensitivity in all major insulin-responsive tissues including skeletal muscle [3]. Fibrates, acting as highly specific PPARα activators, are therapeutically used as hypolipidemic agents [4], and new evidences suggest that they might also prove effective for treating obesity and insulin resistance [5]. In this study, we have examined whether in vitro differentiated human skeletal muscle cells (myotubes) express musclin mRNA. Furthermore, we wanted to find out whether agonists of PPARα and PPARγ modulate musclin mRNA expression. To this end, we treated myotubes with the TZD troglitazone and the fibrate Wy-14,643, representative compounds of the above mentioned drug classes that are frequently used in vitro.

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