Severe energy deficit at high altitude inhibits skeletal muscle mTORC1-mediated anabolic signaling without increased ubiquitin proteasome activity

Lee M Margolis; John W Carbone; Claire E Berryman; Christopher T Carrigan; Nancy E Murphy; Arny A Ferrando; Andrew J Young; Stefan M Pasiakos

doi:10.1096/fj.201800163RR

Severe energy deficit at high altitude inhibits skeletal muscle mTORC1-mediated anabolic signaling without increased ubiquitin proteasome activity

FASEB J. 2018 Jun 7:fj201800163RR. doi: 10.1096/fj.201800163RR. Online ahead of print.

Authors

Lee M Margolis^{1

2}, John W Carbone^{2

3}, Claire E Berryman^{1

2}, Christopher T Carrigan¹, Nancy E Murphy¹, Arny A Ferrando⁴, Andrew J Young^{1

2}, Stefan M Pasiakos¹

Affiliations

¹ Military Nutrition Division, U.S. Army Research Institute of Environmental Medicine, Natick, Massachusetts, USA.
² Oak Ridge Institute of Science and Education, Oak Ridge, Tennessee, USA.
³ School of Health Sciences, Eastern Michigan University, Ypsilanti, Michigan, USA.
⁴ Department of Geriatrics, The Center for Translational Research in Aging and Longevity, Donald W. Reynolds Institute of Aging, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

PMID: 29878853
DOI: 10.1096/fj.201800163RR

Abstract

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.

Keywords: REDD1; hypoxia; proteolysis; rpS6; weight loss.