Elevated corticosterone associated with food deprivation upregulates expression in rat skeletal muscle of the mTORC1 repressor, REDD1 - PubMed (original) (raw)

Elevated corticosterone associated with food deprivation upregulates expression in rat skeletal muscle of the mTORC1 repressor, REDD1

Nora K McGhee et al. J Nutr. 2009 May.

Abstract

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.

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Figures

FIGURE 1

FIGURE 1

REDD1 protein (A) and mRNA expression (B) in gastrocnemius muscle of rats that consumed food ad libitum (Fed), were food deprived for 18 h, or were refed for 45 min after an 18-h deprivation (Re-fed). Values are means ± SEM, n ± 6. Means without a common letter differ, P < 0.05.

FIGURE 2

FIGURE 2

Serum insulin level (A), S6K1 hyperphosphorylation (B), and S6K1 phosphorylation on Thr389 (C) in gastrocnemius muscle of control (gray bars) and diabetic (black bars) rats that consumed food ad libitum (Fed), were food deprived for 18 h, or were refed for 45 min after an 18-h deprivation (Re-fed). Values are means ± SEM, n = 5–6. Within diabetic and control groups, means without a common letter differ, P < 0.05. *Different from corresponding control, P < 0.05.

FIGURE 3

FIGURE 3

REDD1 protein (A) and mRNA expression (B) in gastrocnemius muscle of control (gray bars) and diabetic (black bars) rats that consumed food ad libitum (Fed), were food deprived for 18 h, or were refed for 45 min after an 18-h deprivation (Re-fed). Values are means ± SEM, n = 6. Within diabetic and control groups, means without a common letter differ, P < 0.05. *Different from corresponding control, P < 0.05.

FIGURE 4

FIGURE 4

Serum insulin concentration (A), Akt(Ser473) phosphorylation (B), and REDD1 expression (C) in gastrocnemius muscle of control and insulin-treated diabetic rats. Values are means ± SEM, n = 6. Means without a common letter differ, P < 0.05.

FIGURE 5

FIGURE 5

Serum corticosterone concentrations in fed and food-deprived control (A) or diabetic (B) rats. (B) Serum corticosterone concentrations were measured in serum from fed and food-deprived diabetic rats. Values are means ± SEM, n = 6. Means without a common letter differ, P < 0.05.

FIGURE 6

FIGURE 6

Serum corticosterone concentration is directly proportional to REDD1 mRNA expression in gastrocnemius of control (A) and diabetic (C) rats administered vehicle but not in control (B) or diabetic (D) rats administered RU486.

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