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Biochemical, Molecular, and Genetic Mechanisms

Elevated Corticosterone Associated with Food Deprivation Upregulates Expression in Rat Skeletal Muscle of the mTORC1 Repressor, REDD1^1,2,3

Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033

Food deprivation induces a repression of protein synthesis in skeletal muscle in part due to reduced signaling through the mammalian target of rapamycin complex 1 (mTORC1). Previous studies have identified upregulated expression of the protein Regulated in DNA Damage and Development (REDD1) as an important mechanism in the regulation of mTORC1 activity in response to a variety of stresses. Our goal in this investigation was to determine whether modulation of REDD1 expression occurs in response to food deprivation and refeeding, and, if it does, to ascertain if changes in REDD1 expression correlate with altered mTORC1 signaling. As expected, mTORC1 signaling was repressed after 18 h of food deprivation compared with freely-fed control rats and quickly recovered after refeeding for 45 min. Food deprivation caused a dramatic rise in REDD1 mRNA and protein expression; refeeding resulted in a reduction to baseline. Food deprivation is characterized by low-serum insulin and elevated glucocorticoid concentrations. Therefore, initially, alloxan-induced type I diabetes was used to minimize the food deprivation- and refeeding-induced changes in insulin. Although diabetic rats exhibited upregulated REDD1 expression compared with nondiabetic controls, there was no direct correlation between REDD1 mRNA expression and serum insulin levels, and insulin treatment of diabetic rats did not affect REDD1 expression. In contrast, serum corticosterone levels correlated directly with REDD1 mRNA expression (r = 0.68; P = 0.01). Moreover, inhibiting corticosterone-mediated signaling via administration of the glucocorticoid receptor antagonist RU486 blocked both the food deprivation- and diabetes-induced increase in REDD1 mRNA expression. Overall, the results demonstrate that changes in REDD1 expression likely contribute to the regulation of mTORC1 signaling during food deprivation and refeeding.

^* To whom correspondence should be addressed. E-mail: skimball{at}psu.edu.

Manuscript received 18 September 2008. Initial review completed 9 October 2008. Revision accepted 6 February 2009.