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1 Department of Cell Biology, Harvard Medical School, Boston, MA, USA
2 Department of Biochemical Science and Technology, Kagoshima University, Korimoto, Kagoshima, Japan
* To whom correspondence should be addressed. E-mail: alfred_goldberg{at}hms.harvard.edu.
Muscle atrophy results primarily from accelerated protein degradation and is associated with increased expression of two muscle-specific ubiquitin-ligases, atrogin-1 and MuRF1. Glucocorticoids are essential for many types of muscle atrophy, and their effects are opposite to IGF-1 and insulin, which promote growth. In myotubes, dexamethasone inhibited growth and enhanced the breakdown of long-lived cell proteins, especially of myofibrillar proteins (as measured by 3-methylhistidine release), while also increasing atrogin-1 and MuRF1 mRNA. Conversely, IGF-1 suppressed protein degradation and prevented the dexamethasone-induced increase in proteolysis. IGF-1 rapidly reduced atrogin-1 expression within one hour by blocking mRNA synthesis without affecting mRNA degradation, while IGF-1 decreased MuRF1 mRNA slowly. IGF-1 and insulin also blocked the dexamethasone induction of these ubiquitin-ligases and several other atrophy-related genes ("atrogenes"). The changes in overall proteolysis with dexamethasone and IGF-1 correlated tightly with the changes in atrogin-1 mRNA content, but not with the changes in MuRF1 mRNA. IGF-1 activates the PI3-kinase/Akt pathway and inhibition of this pathway (but not the calcineurin/NFAT or MEK/ERK pathways) increased proteolysis and atrogin-1 mRNA expression. Thus, an important component of growth stimulation by IGF-1, through the PI3-kinase/Akt pathway, is its ability to rapidly suppress transcription of the atrophy-related E3, atrogin-1, other atrogenes, and degradation of myofibrillar proteins.
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