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Department of Biochemistry (M.L.A., X.M.), The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900; The Jackson Laboratory (C.L.A.-B., L.R.D., W.G.B., C.J.R.), Bar Harbor, Maine 04609-1500; and The Maine Center for Osteoporosis Research and Education (C.J.R.), Bangor, Maine 04401
Address all correspondence and requests for reprints to: Martin L. Adamo, Ph.D., Department of Biochemistry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MSC 7760, San Antonio, Texas 78229-3900. E-mail: adamo{at}biochem.uthscsa.edu.
C3H/HeJ (C3H) mice exhibit 30–40% higher serum IGF-I than do C57BL/6J (B6) mice, in association with increased bone mineral density and strength. These differences are inherited and thus provide a model for determining molecular mechanisms for genetic variation of serum IGF-I and downstream actions. We now report that increased serum IGF-I in C3H mice is associated with increased transcription from the minor exon 2 promoter in liver from female and male mice. The increase in hepatic IGF-I gene expression caused by increased abundance of IGF-I mRNA transcribed from the exon 2 promoter can quantitatively account for the increased serum IGF-I in C3H mice. Also, levels of both Ea and Eb IGF-I mRNAs are increased in livers of male C3H mice. Fasting lowered serum IGF-I and liver IGF-I mRNA levels in female mice of both strains. However, serum IGF-I and liver IGF-I mRNA levels remained higher in fasted C3H mice compared with fasted B6 mice. Levels of IGF-I transcripts initiated from exon 2 are also significantly increased in skeletal muscle, fat, ovaries, and kidneys of C3H mice. IGF binding protein (IGFBP)-5 mRNA levels are significantly higher in muscle and fat of C3H mice than in B6 mice. Levels of exon 1-containing transcripts are increased in whole femurs of male and female C3H mice. We conclude that increased transcription of the IGF-I gene occurs in a promoter- and tissue-specific manner in C3H mice. The increased IGF binding protein-5 mRNA levels in fat and muscle suggest that IGF-I signaling is increased in these tissues in C3H mice.
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