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Muscle loss at high altitude (HA) is attributable to energy deficit and a potential dysregulation of anabolic signaling. Exercise and protein ingestion can attenuate the effects of energy deficit on muscle at sea level (SL). Whether these effects are observed when energy deficit occurs at HA is unknown. To address this, muscle obtained from lowlanders ( n = 8 males) at SL, acute HA (3 h, 4300 m), and chronic HA (21 d, -1766 kcal/d energy balance) before [baseline (Base)] and after 80 min of aerobic exercise followed by a 2-mile time trial [postexercise (Post)] and 3 h into recovery (Rec) after ingesting whey protein (25 g) were analyzed using standard molecular techniques. At SL, Post, and REC, p-mechanistic target of rapamycin (mTOR) Ser2448 , p-p70 ribosomal protein S6 kinase (p70S6K) Ser424/421 , and p-ribosomal protein S6 (rpS6) Ser235/236 were similar and higher ( P < 0.05) than Base. At acute HA, Post p-mTOR Ser2448 and Post and REC p-p70S6K Ser424/421 were not different from Base and lower than SL ( P < 0.05). At chronic HA, Post and Rec p-mTOR Ser2448 and p-p70S6K Ser424/421 were not different from Base and lower than SL, and, independent of time, p-rpS6 Ser235/236 was lower than SL ( P < 0.05). Post proteasome activity was lower ( P < 0.05) than Base and Rec, independent of phase. Our findings suggest that HA exposure induces muscle anabolic resistance that is exacerbated by energy deficit during acclimatization, with no change in proteolysis.-Margolis, L. M., Carbone, J. W., Berryman, C. E., Carrigan, C. T., Murphy, N. E., Ferrando, A. A., Young, A. J., Pasiakos, S. M. Severe energy deficit at high altitude inhibits skeletal muscle mTORC1-mediated anabolic signaling without increased ubiquitin proteasome activity.

This study was undertaken to characterize the ubiquitin proteasome system (UPS) response to varied dietary protein intake, energy deficit (ED), and consumption of a mixed meal. A randomized, controlled trial of 39 adults consuming protein at 0.8 (recommended dietary allowance [RDA]), 1.6 (2×-RDA), or 2.4 (3×-RDA) g · kg(-1) · d(-1) for 31 d. A 10-d weight maintenance (WM) period was followed by 21 d of 40% ED. Ubiquitin (Ub)-mediated proteolysis and associated gene expression were assessed in the postabsorptive (fasted) and postprandial (fed; 480 kcal, 20 g protein) states after WM and ED by using muscle biopsies, fluorescence-based assays, immunoblot analysis, and real-time qRT-PCR. In the assessment of UPS responses to varied protein intakes, ED, and feeding, the RDA, WM, and fasted measures served as appropriate controls. ED resulted in the up-regulation of UPS-associated gene expression, as mRNA expression of the atrogenes muscle RING finger-1 (MuRF1) and atrogin-1 were 1.2- and 1.3-fold higher (P<0.05) for ED than for WM. However, mixed-meal consumption attenuated UPS-mediated proteolysis, independent of energy status or dietary protein, as the activities of the 26S proteasome subunits β1, β2, and β5 were lower (P<0.05) for fed than for fasted. Muscle protein ubiquitylation was also 45% lower (P<0.05) for fed than for fasted, regardless of dietary protein and energy manipulations. Independent of habitual protein intake and despite increased MuRF1 and atrogin-1 mRNA expression during ED, consuming a protein-containing mixed meal attenuates Ub-mediated proteolysis.