Foxol represses expression of musclin, a skeletal muscle-derived secretory factor

Musclin is a novel skeletal muscle-derived secretory factor, whose mRNA level is markedly regulated by nutritional status. In the present study, we investigated the mechanism of musclin mRNA regulation by insulin. In C2C12 myocytes, insulin-induced upregulation of musclin mRNA was significantly decreased by treatment of phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and was abolished in C2C12 myocytes stably expressing a constitutively active Foxo 1 (Foxo 1-3A), suggesting the involvement of Foxo I in the regulation of musclin mRNA. Promoter deletion analysis of musclin promoter revealed that the region of -303/-123 is important for the repression of promoter activity by Foxol. Chromatin immunoprecipitation assay showed that Foxol bound to musclin promoter. Musclin mRNA level was markedly downregulated in gastrocnemius muscle of Foxol transgenic mice. Our results demonstrated that Foxol downregulates musclin mRNA expression both in vitro and in vivo, which should explain insulin-mediated upregulation of this gene in muscle cells. (C) 2007 Elsevier Inc. All rights reserved.