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Fibroblast Growth Factor Inhibits Insulin-Like Growth Factor-II (IGF-II) Gene Expression and Increases IGF-I Receptor Abundance in BC3H-1 Muscle Cells

Department of Pediatrics, University of California San Francisco, California 94143
Department of Medicine and Physiology, University of California San Francisco, California 94143
Division of Diabetes and Endocrine Research, Mount Zion Medical Center, University of California San Francisco, California 94120

Address requests for reprints to: Stephen M. Rosenthai, M.D., Box 0434, University of California, San Francisco, California 94143.

Abstract

Muscle is an important target tissue for insulin-like growth factor (IGF) action. We have previously reported that muscle cell differentiation is associated with down-regulation of the IGF-I receptor at the level of gene expression that is concomitant with an increase in the expression and secretion of IGF-II. Furthermore, treatment of myoblasts with IGF-II resulted in a similar decrease in IGF-I receptor mRNA abundance, suggesting an autocrine role of IGF-II in IGF-I receptor regulation. To explore further the role of IGF-II in IGF-I receptor regulation, BC3H-1 mouse muscle cells were exposed to differentiation medium in the presence of basic fibroblast growth factor (FGF), a known inhibitor of myogenic differentiation. FGF treatment of cells resulted in a 50% inhibition of IGF-II gene expression compared to that in control myoblasts and markedly inhibited IGF-II secretion. Concomitantly, FGF resulted in a 60–70% increase in IGF-I binding compared to that in control myoblasts. Scatchard analyses and studies of gene expression demonstrated that the increased IGF-I binding induced by FGF reflected parallel increases in IGF-I receptor content and mRNA abundance. These studies indicate that FGF may up-regulate IGF-I receptor expression in muscle cells through inhibition of IGF-II peptide expression and further support the concept of an autocrine role of IGF-II in IGF-I receptor regulation. In addition, these studies suggest that one mechanism by which FGF inhibits muscle cell differentiation is through inhibition of IGF-II expression.

FOOTNOTES

This work was presented in part at the Annual Meeting of the Society for Pediatric Research, May 1990, in Anaheim, CA. This work was supported by grants from the NIH (NICHHD KO8-HD-00836 and NIDDK DK-26667), the John A. Kerner Fund, and Basil O'Connor Starter Research Award 5–754 through funds received from the Lifespring Foundation to the March of Dimes Birth Defects Foundation.

Received for publication January 21, 1991. Revision received March 4, 1991. Accepted for publication March 5, 1991.

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