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Am J Physiol Endocrinol Metab 287: E591-E601, 2004. First published April 20, 2004; doi:10.1152/ajpendo.00073.2004
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IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1

Jennifer M. Sacheck,1,* Akira Ohtsuka,2,* S. Christine McLary,1 and Alfred L. Goldberg1

1Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115; and 2Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Kagoshima 890-0065, Japan

Submitted 16 February 2004 ; accepted in final form 16 April 2004

Muscle atrophy results primarily from accelerated protein degradation and is associated with increased expression of two muscle-specific ubiquitin ligases (E3s): atrogin-1 and muscle ring finger 1 (MuRF1). Glucocorticoids are essential for many types of muscle atrophy, and their effects are opposite to those of insulin-like growth factor I (IGF-I) and insulin, which promote growth. In myotubes, dexamethasone (Dex) inhibited growth and enhanced breakdown of long-lived cell proteins, especially myofibrillar proteins (as measured by 3-methylhistidine release), while also increasing atrogin-1 and MuRF1 mRNA. Conversely, IGF-I suppressed protein degradation and prevented the Dex-induced increase in proteolysis. IGF-I rapidly reduced atrogin-1 expression within 1 h by blocking mRNA synthesis without affecting mRNA degradation, whereas IGF-I decreased MuRF1 mRNA slowly. IGF-I and insulin also blocked Dex induction of these E3s and several other atrophy-related genes ("atrogenes"). Changes in overall proteolysis with Dex and IGF-I correlated tightly with changes in atrogin-1 mRNA content, but not with changes in MuRF1 mRNA. IGF-I activates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, and inhibition of this pathway [but not the calcineurin-nuclear factor of activated T cell (NFAT) or the MEK-ERK pathway] increased proteolysis and atrogin-1 mRNA expression. Thus an important component of growth stimulation by IGF-I, through the PI3K-Akt pathway, is its ability to rapidly suppress transcription of the atrophy-related E3 atrogin-1 and other atrogenes and degradation of myofibrillar proteins.

glucocorticoids; 3-methylhistidine; insulin; phosphatidylinositol 3-kinase-Akt pathway


Address for reprint requests and other correspondence: A. L. Goldberg, Dept. of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115 (E-mail: alfred_goldberg{at}hms.harvard.edu)




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