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Disuse-induced muscle atrophy is accompanied by a blunted postprandial response of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Conflicting observations exist as to whether postabsorptive mTORC1 pathway activation is also blunted by disuse and plays a role in atrophy. It is unknown whether changes in habitual protein intake alter mTORC1 regulatory proteins and how they may contribute to the development of anabolic resistance. The primary objective of this study was to characterize the downstream responsiveness of skeletal muscle mTORC1 activation and its upstream regulatory factors, following 14 days of lower limb disuse in middle-aged men (45-60 yr). The participants were further randomized to receive daily supplementation of 20 g/d of protein ( n = 12; milk protein concentrate) or isocaloric carbohydrate placebo ( n = 13). Immobilization reduced postabsorptive skeletal muscle phosphorylation of the mTORC1 downstream targets, 4E-BP1, P70S6K, and ribosomal protein S6 (RPS6), with phosphorylation of the latter two decreasing to a greater extent in the placebo, compared with the protein supplementation groups (37% ± 13% vs. 14% ± 11% and 38% ± 20% vs. 25% ± 8%, respectively). Sestrin2 protein was also downregulated following immobilization irrespective of supplement group, despite a corresponding increase in its mRNA content. This decrease in Sestrin2 protein was negatively correlated with the immobilization-induced change in the in silico-predicted regulator miR-23b-3p. No other measured upstream proteins were altered by immobilization or supplementation. Immobilization downregulated postabsorptive mTORC1 pathway activation, and 20 g/day of protein supplementation attenuated the decrease in phosphorylation of targets regulating muscle protein synthesis.

Oxidative stress induced by acute exercise may regulate exercise training-induced adaptations that improve metabolic health. One of the central transcription regulatory targets of reactive oxygen species (ROS) is Nrf2 (nuclear factor erythroid-derived 2-like 2, or NFE2L2). Here, we investigated whether global deficiency of Nrf2 in mice would impact exercise training-induced changes in glucose and lipid homeostasis. We report that following 6 wk of treadmill exercise training, Nrf2-deficient mice have elevated fasting plasma triglycerides and free fatty acids and higher blood glucose levels following a meal despite having a similar fat mass to wild-type controls. This impaired glucose homeostasis appears to be related to reduced insulin sensitivity primarily in adipose and liver tissue, and although a clear mechanism was not evident, Nrf2-deficient mice had increased markers of hepatic oxidative stress and stress-related kinase activation in white adipose tissue (WAT) without overt inflammation alteration in WAT or modulation of hepatic and WAT fibroblast growth factor 21 gene expression. Our results suggest that Nrf2 facilitates exercise training-induced improvements in glucose homeostasis; however, further research is required to determine whether this occurs through direct regulation of exercise adaptations or via the maintenance of redox balance during training.