Nutrient-Induced Stimulation of Protein Synthesis in Mouse Skeletal Muscle Is Limited by the mTORC1 Repressor REDD1

• DOI: 10.3945/jn.114.207621
• Publication Date: 2015-02-26T17:42:36Z
• Authors: Bradley S Gordon; David L Williamson; Charles H Lang; Leonard S Jefferson; Scot R Kimball
• Keywords: Male; Mice, Knockout; 0303 health sciences; TOR Serine-Threonine Kinases; Muscle Proteins; Cell Cycle Proteins; Mechanistic Target of Rapamycin Complex 1; Phosphoproteins; Mice; 03 medical and health sciences; Gene Expression Regulation; Multiprotein Complexes; Protein Biosynthesis; Animals; Micronutrients; Eukaryotic Initiation Factors; Phosphorylation; Carrier Proteins; Muscle, Skeletal; Adaptor Proteins, Signal Transducing; Signal Transduction; Transcription Factors

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.The objective was to examine the role of REDD1 in limiting the response of muscle protein synthesis and mTORC1 signaling to a nutrient stimulus.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.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.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.