Abstract
Background
Exercise and protein ingestion preserve muscle mass during moderate energy deficits.
Objective
To determine the molecular mechanisms by which exercise and protein ingestion may spare muscle mass during severe energy deficit (5500 kcal/day).
Design
Fifteen overweight, but otherwise healthy men, underwent a pre-test (PRE), caloric restriction (3.2 kcals/kg body weight/day) + exercise (45 min one-arm cranking + 8 h walking) for 4 days (CRE), followed by a control diet (CD) for 3 days, with a caloric content similar to pre-intervention while exercise was reduced to less than 10,000 steps per day. During CRE, participants ingested either whey protein (PRO, n = 8) or sucrose (SU, n = 7) (0.8 g/kg body weight/day). Muscle biopsies were obtained from the trained and untrained deltoid, and vastus lateralis.
Results
Following CRE and CD, serum concentrations of leptin, insulin, and testosterone were reduced, whereas cortisol and the catabolic index (cortisol/total testosterone) increased. The Akt/mTor/p70S6K pathway and total eIF2α were unchanged, while total 4E-BP1 and Thr37/464E-BP1 were higher. After CRE, plasma BCAA and EAA were elevated, with a greater response in PRO group, and total GSK3β, pSer9GSK3β, pSer51eIF2α, and pSer51eIF2α/total eIF2α were reduced, with a greater response of pSer9GSK3β in the PRO group. The changes in signaling were associated with the changes in leptin, insulin, amino acids, cortisol, cortisol/total testosterone, and lean mass.
Conclusions
During severe energy deficit, pSer9GSK3β levels are reduced and human skeletal muscle becomes refractory to the anabolic effects of whey protein ingestion, regardless of contractile activity. These effects are associated with the changes in lean mass and serum insulin, testosterone, and cortisol concentrations.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Chaston TB, Dixon JB, O’Brien PE. Changes in fat-free mass during significant weight loss: a systematic review. Int J Obes. 2007;31:743–50.
Pasiakos SM, Cao JJ, Margolis LM, Sauter ER, Whigham LD, McClung JP, et al. Effects of high-protein diets on fat-free mass and muscle protein synthesis following weight loss: a randomized controlled trial. FASEB J. 2013;27:3837–47.
Blomstrand E, Eliasson J, Karlsson HK, Kohnke R. Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. J Nutr. 2006;136:269S–73S.
Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1–22.
Vendelbo MH, Clasen BF, Treebak JT, Moller L, Krusenstjerna-Hafstrom T, Madsen M, et al. Insulin resistance after a 72-h fast is associated with impaired AS160 phosphorylation and accumulation of lipid and glycogen in human skeletal muscle. Am J Physiol Endocrinol Metab. 2012;302:E190–200.
Biolo G, Ciocchi B, Stulle M, Piccoli A, Lorenzon S, Dal Mas V, et al. Metabolic consequences of physical inactivity. J Ren Nutr. 2005;15:49–53.
Carbone JW, McClung JP, Pasiakos SM. Skeletal muscle responses to negative energy balance: effects of dietary protein. Adv Nutr. 2012;3:119–26.
Karl JP, Smith TJ, Wilson MA, Bukhari AS, Pasiakos SM, McClung HL, et al. Altered metabolic homeostasis is associated with appetite regulation during and following 48-h of severe energy deprivation in adults. Metabolism. 2016;65:416–27.
Guerra B, Santana A, Fuentes T, Delgado-Guerra S, Cabrera-Socorro A, Dorado C, et al. Leptin receptors in human skeletal muscle. J Appl Physiol. 2007;102:1786–92.
Egerman MA, Glass DJ. Signaling pathways controlling skeletal muscle mass. Crit Rev Biochem Mol Biol. 2014;49:59–68.
Frame S, Cohen P. GSK3 takes centre stage more than 20 years after its discovery. Biochem J. 2001;359:1–16.
Baird TD, Wek RC. Eukaryotic initiation factor 2 phosphorylation and translational control in metabolism. Adv Nutr. 2012;3:307–21.
Calbet JA, Ponce-Gonzalez JG, Perez-Suarez I, de la Calle Herrero J, Holmberg HC. A time-efficient reduction of fat mass in 4 days with exercise and caloric restriction. Scand J Med Sci Sports. 2015;25:223–33.
Calbet JAL, Ponce-Gonzalez JG, Calle-Herrero J, Perez-Suarez I, Martin-Rincon M, Santana A, et al. Exercise preserves lean mass and performance during severe energy deficit: the role of exercise volume and dietary protein content. Front Physiol. 2017;8:483.
Calbet JA, Dorado C, Diaz-Herrera P, Rodriguez-Rodriguez LP. High femoral bone mineral content and density in male football (soccer) players. Med Sci Sports Exerc. 2001;33:1682–7.
Craig CL, Marshall AL, Sjöström M, Bauman AE, Booth ML, Ainsworth BE, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc. 2003;35:1381–95.
Perez-Suarez I, Ponce-Gonzalez JG, de La Calle-Herrero J, Losa-Reyna J, Martin-Rincon M, Morales-Alamo D, et al. Severe energy deficit upregulates leptin receptors, leptin signaling, and PTP1B in human skeletal muscle. J Appl Physiol. 2017;123:1276–87.
Garcia-Carrizo F, Nozhenko Y, Palou A, Rodriguez AM. Leptin effect on acetylation and phosphorylation of pgc1alpha in muscle cells associated with AMPK and Akt activation in high-glucose medium. J of cellular physiology. J Cell Physiol. 2016;231:641–9.
Kohn AD, Kovacina KS, Roth RA. Insulin stimulates the kinase activity of RAC-PK, a pleckstrin homology domain containing ser/thr kinase. EMBO J. 1995;14:4288–95.
White JP, Gao S, Puppa MJ, Sato S, Welle SL, Carson JA. Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle. Mol Cell Endocrinol. 2013;365:174–86.
Proud CG. Regulation of protein synthesis by insulin. Biochem Soc Trans. 2006;34:213–6.
Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, et al. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell. 2005;19:159–70.
Huo X, Liu S, Shao T, Hua H, Kong Q, Wang J, et al. GSK3 protein positively regulates type I insulin-like growth factor receptor through forkhead transcription factors FOXO1/3/4. J Biol Chem. 2014;289:24759–70.
Pennings B, Boirie Y, Senden JM, Gijsen AP, Kuipers H, van Loon LJ. Whey protein stimulates postprandial muscle protein accretion more effectively than do casein and casein hydrolysate in older men. Am J Clin Nutr. 2011;93:997–1005.
Witard OC, Jackman SR, Breen L, Smith K, Selby A, Tipton KD. Myofibrillar muscle protein synthesis rates subsequent to a meal in response to increasing doses of whey protein at rest and after resistance exercise. Am J Clin Nutr. 2014;99:86–95.
Hector AJ, McGlory C, Damas F, Mazara N, Baker SK, Phillips SM. Pronounced energy restriction with elevated protein intake results in no change in proteolysis and reductions in skeletal muscle protein synthesis that are mitigated by resistance exercise. FASEB J. 2018;32:265–75.
Watts AG, Donovan CM. Sweet talk in the brain: glucosensing, neural networks, and hypoglycemic counterregulation. Front Neuroendocrinol. 2010;31:32–43.
Diaz-Rua R, Keijer J, Palou A, van Schothorst EM, Oliver P. Long-term intake of a high-protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats. J Nutr Biochem. 2017;46:39–48.
Liu Z, Jahn LA, Long W, Fryburg DA, Wei L, Barrett EJ. Branched chain amino acids activate messenger ribonucleic acid translation regulatory proteins in human skeletal muscle, and glucocorticoids blunt this action. J Clin Endocrinol Metab. 2001;86:2136–43.
Shah OJ, Anthony JC, Kimball SR, Jefferson LS. Glucocorticoids oppose translational control by leucine in skeletal muscle. Am J Physiol Endocrinol Metab. 2000;279:E1185–90.
Rannels DE, Rannels SR, Li JB, Pegg AE, Morgan HE, Jefferson LS. Effects of glucocorticoids on peptide chain initiation in heart and skeletal muscle. Adv Myocardiol. 1980;1:493–501.
Kostyo JL, Redmond AF. Role of protein synthesis in the inhibitory action of adrenal steroid hormones on amino acid transport by muscle. Endocrinology. 1966;79:531–40.
Shimizu N, Yoshikawa N, Ito N, Maruyama T, Suzuki Y, Takeda S, et al. Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle. Cell Metab. 2011;13:170–82.
Shah OJ, Kimball SR, Jefferson LS. Acute attenuation of translation initiation and protein synthesis by glucocorticoids in skeletal muscle. Am J Physiol Endocrinol Metab. 2000;278:E76–82.
Zheng B, Ohkawa S, Li H, Roberts-Wilson TK, Price SR. FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy. FASEB J. 2010;24:2660–9.
Frost RA, Lang CH. Multifaceted role of insulin-like growth factors and mammalian target of rapamycin in skeletal muscle. Endocrinol Metab Clin North Am. 2012;41:297–322, vi.
Schakman O, Kalista S, Bertrand L, Lause P, Verniers J, Ketelslegers JM, et al. Role of Akt/GSK-3beta/beta-catenin transduction pathway in the muscle anti-atrophy action of insulin-like growth factor-I in glucocorticoid-treated rats. Endocrinology. 2008;149:3900–8.
Arounleut P, Bowser M, Upadhyay S, Shi XM, Fulzele S, Johnson MH, et al. Absence of functional leptin receptor isoforms in the POUND (Lepr(db/lb)) mouse is associated with muscle atrophy and altered myoblast proliferation and differentiation. PLoS ONE. 2013;8:e72330.
Brinkoetter M, Magkos F, Vamvini M, Mantzoros CS. Leptin treatment reduces body fat but does not affect lean body mass or the myostatin-follistatin-activin axis in lean hypoleptinemic women. Am J Physiol Endocrinol Metab. 2011;301:E99–104.
Moon HS, Huh JY, Dincer F, Schneider BE, Hasselgren PO, Mantzoros CS. Identification and saturable nature of signaling pathways induced by metreleptin in humans: comparative evaluation of in vivo, ex vivo, and in vitro administration. Diabetes. 2015;64:828–39.
Fernandez-Elias VE, Ortega JF, Nelson RK, Mora-Rodriguez R. Relationship between muscle water and glycogen recovery after prolonged exercise in the heat in humans. Eur J Appl Physiol. 2015;115:1919–26.
Acknowledgements
We offer special thanks to José Navarro de Tuero for his excellent technical assistance and to Tobias Lopez Jessen for his help editing the English version of the manuscript.
Funding
This study was financed by grants from the Ministerio de Economía y Competitividad (PI14/01509 and FEDER), ULPGC: ULPAPD-08/01-4, and Östersund municipality.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Martin-Rincon, M., Perez-Suarez, I., Pérez-López, A. et al. Protein synthesis signaling in skeletal muscle is refractory to whey protein ingestion during a severe energy deficit evoked by prolonged exercise and caloric restriction. Int J Obes 43, 872–882 (2019). https://doi.org/10.1038/s41366-018-0174-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41366-018-0174-2
This article is cited by
-
Caloric restriction induces anabolic resistance to resistance exercise
European Journal of Applied Physiology (2020)