Musclin, a novel skeletal muscle-derived secretory factor.
Skeletal muscle is involved in the homeostasis of glucose and lipid metabolism. We hypothesized that the skeletal muscle produces and secretes bioactive factor(s), similar to adipocytokines secreted by fat tissue. Here, we report the identification of a novel secretory factor, musclin, by signal sequence trap of mouse skeletal muscle cDNAs. Musclin cDNA encoded 130 amino acids, including NH(2)-terminal 30-amino acid signal sequence. Musclin protein contained a region homologous to natriuretic peptide family, and KKKR, a putative serine protease cleavage site, similar to the natriuretic peptide family. Full-length musclin protein and KKKR-dependent cleaved form were secreted in media of musclin cDNA-transfected mammalian cell cultures. Musclin mRNA was expressed almost exclusively in the skeletal muscle of mice. Musclin mRNA levels in skeletal muscle were markedly low in fasted, increased upon re-feeding, and were low in streptozotocin-treated insulin-deficient mice. Musclin mRNA expression was induced at late stage in the differentiation of C2C12 myocytes. In myocytes, insulin increased, while epinephrine, isoproterenol, and forskolin reduced musclin mRNA, all of which are known to increase the cellular content of cyclic AMP, a counter-regulator to insulin. Pathologically, overexpression of musclin mRNA was noted in the muscles of obese insulin-resistant KKAy mice. Functionally, recombinant musclin significantly attenuated insulin-stimulated glucose uptake and glycogen synthesis in myocytes. In conclusion, we identified musclin, a novel skeletal muscle-derived secretory factor. Musclin expression level is tightly regulated by nutritional changes and its physiological role could be linked to glucose metabolism.
Nishizawa
Hitoshi
H
Department of Medicine and Pathophysiology, Graduate School of Frontier Bioscience, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871.
Matsuda
Morihiro
M
Yamada
Yukio
Y
Kawai
Kenichiro
K
Suzuki
Emi
E
Makishima
Makoto
M
Kitamura
Toshio
T
Shimomura
Iichiro
I
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002460:Cell Line; D002478:Cells, Cultured; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D006003:Glycogen / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000378:metabolism* / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism* / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
D018076:DNA, Complementary; D007328:Insulin; D008164:Luminescent Proteins; D009124:Muscle Proteins; C480236:OSTN protein, human; C498449:Ostn protein, mouse; C498450:Ostn protein, rat; D010455:Peptides; D011506:Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D006003:Glycogen; D005947:Glucose