{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T18:05:45Z","timestamp":1784311545536,"version":"3.55.0"},"reference-count":43,"publisher":"Portland Press Ltd.","issue":"21","license":[{"start":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T00:00:00Z","timestamp":1564012800000},"content-version":"vor","delay-in-days":636,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,11,1]]},"abstract":"<jats:p>Leucine modulates muscle protein synthesis (MPS), with potential to facilitate accrual\/maintenance of muscle mass. Animal models suggest that leucine boluses shortly after meals may prolong MPS and delay onset of a \u201cmuscle-full\u201d state. However, the effects of nutrient \u201ctop-ups\u201d in humans, and particularly older adults where deficits exist, have not been explored. We determined the effects of a leucine top-up after essential amino acid (EAA) feeding on anabolic signaling, MPS, and muscle energy metabolism in older men. During 13C6-phenylalanine infusion, 16 men (\u223c70 years) consumed 15 g of EAA with (n=8, FED + LEU) or without (n=8, FED) 3 g of leucine top-up 90 min later. Repeated blood and muscle sampling permitted measurement of fasting and postprandial plasma EAA, insulin, anabolic signaling including mTOR complex 1 (mTORC1) substrates, cellular ATP and phosphorylocreatine, and MPS. Oral EAA achieved rapid insulinemia (12.5 iU\u00b7ml\u22121 25 min post-feed), essential aminoacidemia (3000 \u03bcM, 45\u201365 min post-feed), and activation of mTORC1 signaling. Leucine top-up prolonged plasma EAA (2800 \u03bcM, 135 min) and leucine availability (1050 \u03bcM, 135 min post-feed). Fasting FSRs of 0.046 and 0.056%\u00b7h-1 (FED and FED + LEU respectively) increased to 0.085 and 0.085%\u00b7h-1 90\u2013180 min post-feed and returned to basal rates after 180 min in both groups. Phosphorylation of mTORC1 substrates returned to fasting levels 240 min post-feed in both groups. Feeding had limited effect on muscle high-energy phosphates, but did induce eukaryotic elongation factor 2 (eEF2) phosphorylation. We demonstrate the refractoriness of muscle to nutrient-led anabolic stimulation in the postprandial period; thus, leucine supplements should be taken outside of meals, or with meals containing suboptimal protein in terms of either amount or EAA composition.<\/jats:p>","DOI":"10.1042\/cs20171230","type":"journal-article","created":{"date-parts":[[2017,10,6]],"date-time":"2017-10-06T00:50:19Z","timestamp":1507251019000},"page":"2643-2653","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Human skeletal muscle is refractory to the anabolic effects of leucine during the postprandial muscle-full period in older men"],"prefix":"10.1042","volume":"131","author":[{"given":"W.\u00a0Kyle","family":"Mitchell","sequence":"first","affiliation":[{"name":"MRC-ARUK Centre for Musculoskeletal Ageing Research and NIHR Nottingham BRC, School of Medicine, Royal Derby Hospital, University of Nottingham, U.K."},{"name":"Department of Surgery, School of Medicine, Royal Derby Hospital, University of Nottingham, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethan\u00a0E.","family":"Phillips","sequence":"additional","affiliation":[{"name":"MRC-ARUK Centre for Musculoskeletal Ageing Research and NIHR Nottingham BRC, School of Medicine, Royal Derby Hospital, University of Nottingham, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Hill","sequence":"additional","affiliation":[{"name":"MRC\/ARUK Centre for Musculoskeletal Ageing Research and NIHR Nottingham BRC, School of Life Sciences, Queen\u2019s Medical Centre, Nottingham, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Greenhaff","sequence":"additional","affiliation":[{"name":"MRC\/ARUK Centre for Musculoskeletal Ageing Research and NIHR Nottingham BRC, School of Life Sciences, Queen\u2019s Medical Centre, Nottingham, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan\u00a0N.","family":"Lund","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, Royal Derby Hospital, University of Nottingham, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John\u00a0P.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, Royal Derby Hospital, University of Nottingham, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbie","family":"Rankin","sequence":"additional","affiliation":[{"name":"MRC-ARUK Centre for Musculoskeletal Ageing Research and NIHR Nottingham BRC, School of Medicine, Royal Derby Hospital, University of Nottingham, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel\u00a0J.","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"MRC-ARUK Centre for Musculoskeletal Ageing Research and NIHR Nottingham BRC, School of Medicine, Royal Derby Hospital, University of Nottingham, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Smith","sequence":"additional","affiliation":[{"name":"MRC-ARUK Centre for Musculoskeletal Ageing Research and NIHR Nottingham BRC, School of Medicine, Royal Derby Hospital, University of Nottingham, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip\u00a0J.","family":"Atherton","sequence":"additional","affiliation":[{"name":"MRC-ARUK Centre for Musculoskeletal Ageing Research and NIHR Nottingham BRC, School of Medicine, Royal Derby Hospital, University of Nottingham, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2017,10,27]]},"reference":[{"key":"2019102412383234500_B1","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1113\/jphysiol.2011.225003","article-title":"Muscle protein synthesis in response to nutrition and exercise","volume":"590","author":"Atherton","year":"2012","journal-title":"J. Physiol."},{"key":"2019102412383234500_B2","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1096\/fj.04-2640fje","article-title":"Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle","volume":"19","author":"Cuthbertson","year":"2005","journal-title":"FASEB J."},{"key":"2019102412383234500_B3","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1016\/j.jada.2009.06.369","article-title":"A moderate serving of high-quality protein maximally stimulates skeletal muscle protein synthesis in young and elderly subjects","volume":"109","author":"Symons","year":"2009","journal-title":"J. Am. Diet. Assoc."},{"key":"2019102412383234500_B4","doi-asserted-by":"publisher","first-page":"E1056","DOI":"10.1152\/ajpendo.00481.2014","article-title":"Intake of low-dose leucine-rich essential amino acids stimulates muscle anabolism equivalently to bolus whey protein in older women at rest and after exercise","volume":"308","author":"Bukhari","year":"2015","journal-title":"Am. J. Physiol. \u2013 Endocrinol. Metab."},{"key":"2019102412383234500_B5","first-page":"1080","article-title":"Muscle full effect after oral protein: Time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling","volume":"92","author":"Atherton","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"2019102412383234500_B6","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1111\/j.1469-7793.2001.0575f.x","article-title":"Latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids","volume":"532","author":"Bohe","year":"2001","journal-title":"J. Physiol."},{"key":"2019102412383234500_B7","first-page":"207","article-title":"A dose- rather than delivery profile-dependent mechanism regulates the \u2018muscle-full\u2019 effect in response to oral essential amino acid intake in young men","volume":"145","author":"Mitchell","year":"2015","journal-title":"J. Nutr."},{"key":"2019102412383234500_B8","first-page":"E450","article-title":"The impact of delivery profile of essential amino acids upon skeletal muscle protein synthesis in older men: clinical efficacy of pulse vs. bolus supply","volume":"309","author":"Mitchell","year":"2015","journal-title":"Am. J. Physiol. \u2013 Endocrinol. Metab."},{"key":"2019102412383234500_B9","first-page":"E372","article-title":"Flooding with L-[1-13C]leucine stimulates human muscle protein incorporation of continuously infused L-[1-13C]valine","volume":"262","author":"Smith","year":"1992","journal-title":"Am. J. Physiol."},{"key":"2019102412383234500_B10","first-page":"E73","article-title":"Effects of flooding amino acids on incorporation of labeled amino acids into human muscle protein","volume":"275","author":"Smith","year":"1998","journal-title":"Am. J. Physiol."},{"key":"2019102412383234500_B11","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0955-2863(98)00087-4","article-title":"Nonessential amino acids are not necessary to stimulate net muscle protein synthesis in healthy volunteers","volume":"10","author":"Tipton","year":"1999","journal-title":"J. Nutr. Biochem."},{"key":"2019102412383234500_B12","first-page":"987","article-title":"Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus","volume":"57","author":"Wahren","year":"1976","journal-title":"J. Clin. Invest."},{"key":"2019102412383234500_B13","first-page":"E407","article-title":"Removal of infused amino acids by splanchnic and leg tissues in humans","volume":"250","author":"Gelfand","year":"1986","journal-title":"Am. J. Physiol."},{"key":"2019102412383234500_B14","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/B978-0-12-802167-5.00009-8","article-title":"Feeding modulation of amino acid utilization: role of insulin and amino acids in skeletal muscle","author":"Atherton","year":"2016","journal-title":"The Molecular Nutrition of Amino Acids and Proteins"},{"key":"2019102412383234500_B15","first-page":"43","article-title":"Sestrin2 is a leucine sensor for the mTORC1 pathway","volume":"351","author":"Wolfson","year":"2016","journal-title":"Science"},{"key":"2019102412383234500_B16","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.cell.2012.02.044","article-title":"Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway","volume":"149","author":"Han","year":"2012","journal-title":"Cell"},{"key":"2019102412383234500_B17","first-page":"35","article-title":"Bolus ingestion of individual branched-chain amino acids alters plasma amino acid profiles in young healthy men","volume":"3","author":"Matsumoto","year":"2014","journal-title":"Springerplus"},{"key":"2019102412383234500_B18","first-page":"2911","article-title":"Effects of leucine and its metabolite \u03b2-hydroxy-\u03b2-methylbutyrate on human skeletal muscle protein metabolism","volume":"591","author":"Wilkinson","year":"2013","journal-title":"J. Physiol."},{"key":"2019102412383234500_B19","first-page":"276","article-title":"Leucine supplementation of a low-protein mixed macronutrient beverage enhances myofibrillar protein synthesis in young men: a double-blind, randomized trial","volume":"99","author":"Churchward-Venne","year":"2014","journal-title":"Am. J. Clin. Nutr."},{"key":"2019102412383234500_B20","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-015-2109-8","article-title":"Leucine-induced anabolic-catabolism: two sides of the same coin","author":"Gannon","year":"2015","journal-title":"Amino Acids"},{"key":"2019102412383234500_B21"},{"key":"2019102412383234500_B22","first-page":"1103","article-title":"The leucine content of a complete meal directs peak activation but not duration of skeletal muscle protein synthesis and mammalian target of rapamycin signaling in rats","volume":"139","author":"Norton","year":"2009","journal-title":"J. Nutr."},{"key":"2019102412383234500_B23","first-page":"E1236","article-title":"Leucine or carbohydrate supplementation reduces AMPK and eEF2 phosphorylation and extends postprandial muscle protein synthesis in rats","volume":"301","author":"Wilson","year":"2011","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2019102412383234500_B24","first-page":"E992","article-title":"Amino acid absorption and subsequent muscle protein accretion following graded intakes of whey protein in elderly men","volume":"302","author":"Pennings","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2019102412383234500_B25","doi-asserted-by":"crossref","first-page":"E21","DOI":"10.1152\/ajpendo.00382.2014","article-title":"Quantity of dietary protein intake, but not pattern of intake, affects net protein balance primarily through differences in protein synthesis in older adults","volume":"308","author":"Kim","year":"2015","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2019102412383234500_B26","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/0026-0495(81)90074-3","article-title":"Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man","volume":"30","author":"Abumrad","year":"1981","journal-title":"Metabolism"},{"key":"2019102412383234500_B27","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1136\/jnnp.50.11.1461","article-title":"Conchotome and needle percutaneous biopsy of skeletal muscle","volume":"50","author":"Dietrichson","year":"1987","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"2019102412383234500_B28","first-page":"E203","article-title":"Precursor pools of protein synthesis: a stable isotope study in a swine model","volume":"267","author":"Baumann","year":"1994","journal-title":"Am. J. Physiol."},{"key":"2019102412383234500_B29","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3109\/00365517409082477","article-title":"Glycogen, glycolytic intermediates and high-energy phosphates determined in biopsy samples of musculus quadriceps femoris of man at rest. Methods and variance of values","volume":"33","author":"Harris","year":"1974","journal-title":"Scand. J. Clin. Lab. Invest."},{"key":"2019102412383234500_B30","first-page":"4","article-title":"An overview of technical considerations for Western blotting applications to physiological research","volume":"27","author":"Bass","year":"2017","journal-title":"Scand. J. Med. Sci. Sports"},{"key":"2019102412383234500_B31","first-page":"828S","article-title":"Human skeletal muscle protein metabolism responses to amino acid nutrition","volume":"7","author":"Mitchell","year":"2016","journal-title":"Adv. Nutr."},{"key":"2019102412383234500_B32","first-page":"260","article-title":"Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review","volume":"3","author":"Mitchell","year":"2012","journal-title":"Front. Physiol."},{"key":"2019102412383234500_B33","first-page":"888","article-title":"Enriching a protein drink with leucine augments muscle protein synthesis after resistance exercise in young and older men","volume":"36","author":"Atherton","year":"2017","journal-title":"Clin. Nutr."},{"key":"2019102412383234500_B34","first-page":"E595","article-title":"Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle","volume":"295","author":"Greenhaff","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2019102412383234500_B35","first-page":"1723","article-title":"Post-meal responses of elongation factor 2 (eEF2) and adenosine monophosphate-activated protein kinase (AMPK) to leucine and carbohydrate supplements for regulating protein synthesis duration and energy homeostasis in rat skeletal muscle","volume":"4","author":"Wilson","year":"2012","journal-title":"Nutrients"},{"key":"2019102412383234500_B36","first-page":"275","article-title":"An acetyl group deficit limits mitochondrial ATP production at the onset of exercise","volume":"30","author":"Greenhaff","year":"2002","journal-title":"Biochem. Soc. Trans."},{"key":"2019102412383234500_B37","first-page":"43","article-title":"Regulation and roles of elongation factor 2 kinase","author":"Proud","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"2019102412383234500_B38","first-page":"212","article-title":"Direct and indirect activation of eukaryotic elongation factor 2 kinase by AMP-activated protein kinase","volume":"36","author":"Johanns","year":"2017","journal-title":"Cell. Signal."},{"key":"2019102412383234500_B39","first-page":"320","article-title":"ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions","volume":"68","author":"Roux","year":"2004","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"2019102412383234500_B40","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.1128\/MCB.24.7.2986-2997.2004","article-title":"A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin","volume":"24","author":"Browne","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"2019102412383234500_B41","first-page":"67","article-title":"Leucine content of dietary proteins is a determinant of postprandial skeletal muscle protein synthesis in adult rats","volume":"9","author":"Norton","year":"2012","journal-title":"Nutr. Metab. (Lond)"},{"key":"2019102412383234500_B42","first-page":"486","article-title":"Measurement of muscle protein fractional synthetic rate by capillary gas chromatography\/combustion isotope ratio mass spectrometry","volume":"21","author":"Yarasheski","year":"1992","journal-title":"Biol. Mass Spectrom."},{"key":"2019102412383234500_B43","first-page":"264","article-title":"Stimulation of muscle protein synthesis by prolonged parenteral infusion of leucine is dependent on amino acid availability in neonatal pigs","volume":"140","author":"Wilson","year":"2010","journal-title":"J. Nutr."}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/portlandpress.com\/clinsci\/article-pdf\/131\/21\/2643\/445948\/cs-2017-1230.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/portlandpress.com\/clinsci\/article-pdf\/131\/21\/2643\/445948\/cs-2017-1230.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,10,24]],"date-time":"2019-10-24T19:47:52Z","timestamp":1571946472000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/131\/21\/2643\/71655\/Human-skeletal-muscle-is-refractory-to-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,27]]},"references-count":43,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2017,11,1]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20171230","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,27]]}}}