Nutrient-induced stimulation of protein synthesis in mouse skeletal muscle is limited by the mTORC1 repressor REDD1

Abstract

Background: In skeletal muscle, the nutrient-induced stimulation of protein synthesis requires signaling through the mechanistic target of rapamycin complex 1 (mTORC1). Expression of the repressor of mTORC1 signaling, regulated in development and DNA damage 1 (REDD1), is elevated in muscle during various atrophic conditions and diminished under hypertrophic conditions. The question arises as to what extent REDD1 limits the nutrient-induced stimulation of protein synthesis. Objective: The objective was to examine the role of REDD1 in limiting the response of muscle protein synthesis and mTORC1 signaling to a nutrient stimulus. Methods: Wild type REDD1 gene (REDD1 +/+) and disruption in the REDD1 gene (REDD1 -/-) mice were feed deprived for 16 h and randomized to remain feed deprived or refed for 15 or 60 min. The tibialis anterior was then removed for analysis of protein synthesis and mTORC1 signaling. Results: In feed-deprived mice, protein synthesis and mTORC1 signaling were significantly lower in REDD1 +/+ than in REDD1 -/- mice. Thirty minutes after the start of refeeding, protein synthesis in REDD1 +/+ mice was stimulated by 28%, reaching a value similar to that observed in feed-deprived REDD1 -/- mice, and was accompanied by increased phosphorylation of mTOR (Ser2448), p70S6K1 (Thr389), and 4E-BP1 (Ser65) by 81%, 167%, and 207%, respectively. In refed REDD1 -/- mice, phosphorylation of mTOR (Ser2448), p70S6K1 (Thr389), and 4E-BP1 (Ser65) were significantly augmented above the values observed in refed REDD1 +/+ mice by 258%, 405%, and 401%, respectively, although protein synthesis was not coordinately increased. Seventy-five minutes after refeeding, REDD1 expression in REDD1 +/+ mice was reduced (-15% of feed-deprived REDD1 +/+ values), and protein synthesis and mTORC1 signaling were not different between refed REDD1 +/+ mice and REDD1 -/- mice. Conclusions: The results show that REDD1 expression limits protein synthesis in mouse skeletal muscle by inhibiting mTORC1 signaling during periods of feed deprivation and that a reduction in its expression is necessary for maximal stimulation of protein synthesis in response to refeeding.