The mTORC1 Repressor REDD1 Governs Nutrient Induced Stimulation of Protein Synthesis in Skeletal Muscle

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 skeletal muscle during various atrophic conditions and diminished under hypertrophic conditions. Therefore, the question arises as to what extent REDD1 governs nutrient‐induced stimulation of protein synthesis. To address this question, REDD1+/+ and REDD1‐/‐ mice were fasted for 16 hr and randomized to remain fasted or re‐fed for 15 min or 60 min. All mice were sacrificed 15 min following cessation of the re‐feeding periods and analyses were performed on the tibialis anterior. In fasted mice, protein synthesis and mTORC1 signaling (as assessed by changes in phosphorylation of mTOR at Ser2448, p70S6K1 at Thr389, and 4E‐BP1 at Ser65) were significantly lower in REDD1+/+ compared to REDD1‐/‐ mice. Thirty min after the start of re‐feeding, protein synthesis in REDD1+/+ mice was elevated by 28% to a value similar to that observed in fasted REDD1‐/‐ mice, and was accompanied by an activation of mTORC1 signaling. Even though re‐feeding in REDD1‐/‐ mice did not further stimulate protein synthesis, mTORC1 signaling was significantly elevated above the values measured in re‐fed REDD1+/+ mice. Seventy‐five min post re‐feeding, REDD1 expression in REDD1+/+ mice was reduced to nearly undetectable levels, and protein synthesis and mTORC1 signaling were not different between re‐fed REDD1+/+ mice and REDD1‐/‐ mice. In conclusion, these results support a model in which REDD1 expression governs the magnitude of anabolic signaling in skeletal muscle. Supported by NIH grant DK15658 (LSJ)