Foxo1 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 Foxo1 (Foxo1-3A), suggesting the involvement of Foxo1 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 Foxo1. Chromatin immunoprecipitation assay showed that Foxo1 bound to musclin promoter. Musclin mRNA level was markedly downregulated in gastrocnemius muscle of Foxo1 transgenic mice. Our results demonstrated that Foxo1 downregulates musclin mRNA expression both in vitro and in vivo, which should explain insulin-mediated upregulation of this gene in muscle cells.
Yasui
Atsutaka
A
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Nishizawa
Hitoshi
H
Okuno
Yosuke
Y
Morita
Kentaro
K
Kobayashi
Hironori
H
Kawai
Kenichiro
K
Matsuda
Morihiro
M
Kishida
Ken
K
Kihara
Shinji
S
Kamei
Yasutomi
Y
Ogawa
Yoshihiro
Y
Funahashi
Tohru
T
Shimomura
Iichiro
I
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D032342:Muscle Cells / Q000378:metabolism*; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D002867:Chromones; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D009025:Morpholines; D009124:Muscle Proteins; C480236:OSTN protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one