Skip to main content
SpringerLink
Log in

Leucine-induced anabolic-catabolism: two sides of the same coin

  • Review Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Leucine is an essential nutrient with potent abilities to stimulate both muscle protein synthesis as well as increased oxidative metabolism supported by mitochondrial biogenesis. Few studies have simultaneously investigated anabolic and catabolic responses following leucine treatment with the exception of master regulator of cellular energetics, AMPK. The unique ability of leucine to stimulate both favorable anabolic and catabolic processes in highly metabolically active tissues suggests leucine consumption/supplementation may provide benefits beyond hypertrophic gains. This review highlights original investigations reporting leucine’s ability to stimulate both anabolic and catabolic processes in muscle. Additionally, this report discusses potential explanations for the simultaneous activation of two seemingly opposing processes, as well as the interplay between them. The role of cellular energetics is of undeniable importance in sustaining increased protein synthesis following leucine administration; however, the dependence of leucine-induced mitochondrial biogenesis on heightened energy expenditure from elevated protein synthesis remains to be defined experimentally.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

4E-BP1:

Eukaryotic translation initiation factor 4E-binding protein 1

AA:

Amino acid

ACC:

Acetyl-CoA carboxylase

ACOX1:

Acyl-CoA oxidase 1, palmitoyl

Akt/PKB:

Protein kinase B

AMPK:

5′ Adenosine monophosphate-activated protein kinase

AS160:

Akt substrate of 160 kDa

ATF4:

Activating transcription factor 4

CAMKII:

Calcium/calmodulin-dependent protein kinase II

CKD:

Chronic kidney disease

COX:

Cytochrome C oxidase subunit

CPT-1B:

Carnitine palmitoyltransferase 1

CrAT:

Carnitine O-acetyltransferase

CRP:

C-reactive protein

CytC:

Cytochrome C

EDL:

Extensor digitorum longus

EE:

Energy expenditure

eEF:

Eukaryotic translation elongation factor

eIF:

Eukaryotic translation initiation factor

ERK:

Extracellular signal-regulated kinase

F:

Female

FAS:

Fatty acid synthase

FFA:

Free fatty acid

FOXO1/3a:

Forkhead box O1/O3a

GβL:

G protein beta subunit-like

GCN2:

General control nonderepressible 2

GHR:

Growth hormone receptor

GLUT4:

Glucose transporter 4

GS:

Glycogen synthase

GSH/GSSG:

Glutathione

GSK3:

Glycogen synthase kinase 3

HbA1c:

Glycated hemoglobin

HOMAIR:

Homeostatic model assessment of insulin resistance

Hspd1:

Heat shock 60 kDa protein 1

hVps34:

Human vacuolar protein sorting 34

IGF-1:

Insulin-like growth factor 1

IGFBP:

Insulin-like growth factor-binding protein

IL-1β/6/15:

Interleukin-1β/6/15

IR:

Insulin receptor

IRS1:

Insulin receptor substrate 1

LAT1:

Large neutral amino acid transporter

LC3I/II:

Microtubule-associated protein 1A/1B-light chain 3 I/II

M:

Male

MAFbx:

Muscle atrophy F-box

MAPK:

Mitogen-activated protein kinase

MCAD:

Medium-chain acyl-CoA dehydrogenase

MCP1:

Monocyte chemotactic protein 1

MDA:

Malondialdehyde

MHCII:

Major histocompatibility complex class II

Mnk1:

MAP kinase-interacting serine/threonine-protein kinase 1

MnSOD:

Mitochondrial antioxidant manganese superoxide dismutase

mTOR:

Mammalian target of rapamycin

MuRF1:

Muscle RING finger 1

MAPK:

Mitogen-activated protein kinase

NAMPT:

Nicotinamide phosphoribosyltransferase

NO:

Nitric oxide

NRF:

Nuclear respiratory factor

OCR:

Oxygen consumption rate

PCr:

Creatine phosphate

PDK:

Phosphoinositide-dependent kinase

PGC-1α:

PPAR-gamma coactivator-1 alpha

PI3K:

Phosphatidylinositol-4,5-bisphosphate 3-kinase

PIP2:

Phosphatidylinositol-4,5-bisphosphate

PIP3:

Phosphatidylinositol-3,4,5-trisphosphate

PP2A:

Protein phosphatase 2

PPAR:

Peroxisome proliferator-activator receptor

PSMB7:

Proteasome subunit beta type-7

PRAS40:

Proline-rich Akt substrate of 40 kDa

REDD2:

Regulated in development and DNA damage responses 2

RER:

Respiratory exchange ratio

Rheb:

Ras-homolog enriched in the brain

RG:

Red gastrocnemius

RQ:

Respiratory quotient

S6:

Ribosomal protein 6

S6K:

Ribosomal S6 kinase

SD:

Sprague-Dawley

SIRT:

Sirtuin

SNAT2:

Sodium-coupled neutral amino acid transporter 2

T3:

Thyroid hormone 3,5,3′-triiodothyronine

TFAM:

Mitochondrial transcription factor A

TG:

Triglyceride

TNFα:

Tumor necrosis factor alpha

TSC:

Tuberous sclerosis

UBE2K:

Ubiquitin-conjugating enzyme E2K

UCHL1:

Ubiquitin carboxy-terminal hydrolase L1

UCP:

Uncoupling protein

ULK1:

Unc-51 like autophagy activating kinase 1

WG:

White gastrocnemius

References

  • Amat R, Planavila A, Chen SL, Iglesias R, Giralt M, Villarroya F (2009) SIRT1 Controls the Transcription of the Peroxisome Proliferator-activated Receptor-gamma Co-activator-1 alpha (PGC-1 alpha) Gene in Skeletal Muscle through the PGC-1 alpha Autoregulatory Loop and Interaction with MyoD. J Bio Chem 284:21872–21880

    Article  CAS  Google Scholar 

  • Areta JL, Hawley JA, Ye JM, Chan MH, Coffey VG (2014) Increasing leucine concentration stimulates mechanistic target of rapamycin signaling and cell growth in C2C12 skeletal muscle cells. Nutr Res 34:1000–1007

    Article  CAS  PubMed  Google Scholar 

  • Backer JM, Myers MG, Shoelson SE, Chin DJ, Sun XJ, Miralpeix M, Hu P, Margolis B, Skolnik EY, Schlessinger J (1992) Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J 11:3469–3479

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bae SS, Cho H, Mu J, Birnbaum MJ (2003) Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J Biol Chem 278:49530–49536

    Article  CAS  PubMed  Google Scholar 

  • Balage M, Dupont J, Mothe-Satney I, Tesseraud S, Mosoni L, Dardevet D (2011) Leucine supplementation in rats induced a delay in muscle IR/PI3K signaling pathway associated with overall impaired glucose tolerance. J Nutr Biochem 22:219–226

    Article  CAS  PubMed  Google Scholar 

  • Baum JI, O’Connor JC, Seyler JE, Anthony TG, Freund GG, Layman DK (2005) Leucine reduces the duration of insulin-induced PI 3-kinase activity in rat skeletal muscle. Am J Physiol Endocrinol Metab 288:E86–E91

    Article  CAS  PubMed  Google Scholar 

  • Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang MY, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342

    Article  CAS  PubMed  Google Scholar 

  • Bernard JR, Liao YH, Hara D, Ding Z, Chen CY, Nelson JL, Ivy JL (2011) An amino acid mixture improves glucose tolerance and insulin signaling in Sprague-Dawley rats. Am J Physiol Endocrinol Metab 300:E752–E760

    Article  CAS  PubMed  Google Scholar 

  • Binder E, Bermúdez-Silva FJ, André C, Elie M, Romero-Zerbo SY, Leste-Lasserre T, Belluomo I, Duchampt A, Clark S, Aubert A, Mezzullo M, Fanelli F, Pagotto U, Layé S, Mithieux G, Cota D (2013) Leucine supplementation protects from insulin resistance by regulating adiposity levels. PLoS ONE 8:e74705

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bolster DR, Vary TC, Kimball SR, Jefferson LS (2004) Leucine regulates translation initiation in rat skeletal muscle via enhanced eIF4G phosphorylation. J Nutr 134:1704–1710

    CAS  PubMed  Google Scholar 

  • Brenmoehl JHA (2013) Dual control of mitochondrial biogenesis by sirtuin 1 and sirtuin 3. Mitochondrion 13:755–761

    Article  CAS  PubMed  Google Scholar 

  • Bruckbauer A, Zemel MB (2014) Synergistic effects of polyphenols and methylxanthines with Leucine on AMPK/Sirtuin-mediated metabolism in muscle cells and adipocytes. PLoS ONE 9:e89166

    Article  PubMed Central  PubMed  Google Scholar 

  • Bruckbauer A, Zemel MB, Thorpe T, Akula MR, Stuckey AC, Osborne D, Martin EB, Kennel S, Wall JS (2012) Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice. Nutr Metab (Lond) 9:77

    Article  CAS  Google Scholar 

  • Casperson SL, Sheffield-Moore M, Hewlings SJ, Paddon-Jones D (2012) Leucine supplementation chronically improves muscle protein synthesis in older adults consuming the RDA for protein. Clin Nutr 31:512–519

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen Y, Sood S, McIntire K, Roth R, Rabkin R (2011) Leucine-stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats. Am J Physiol Endocrinol Metab 301:E873–E881

    Article  CAS  PubMed  Google Scholar 

  • Cheng Y, Meng Q, Wang C, Li H, Huang Z, Chen S, Xiao F, Guo F (2010) Leucine deprivation decreases fat mass by stimulation of lipolysis in white adipose tissue and upregulation of uncoupling protein 1 (UCP1) in brown adipose tissue. Diabetes 59:17–25

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Coffey VG, Moore DR, Burd NA, Rerecich T, Stellingwerff T, Garnham AP, Phillips SM, Hawley JA (2011) Nutrient provision increases signalling and protein synthesis in human skeletal muscle after repeated sprints. Eur J Appl Physiol 111:1473–1483

    Article  CAS  PubMed  Google Scholar 

  • Corradetti MN, Guan KL (2006) Upstream of the mammalian target of rapamycin: do all roads pass through mTOR? Oncogene 25:6347–6360

    Article  CAS  PubMed  Google Scholar 

  • Costa Júnior JM, Rosa MR, Protzek AO, de Paula FM, Ferreira SM, Rezende LF, Vanzela EC, Zoppi CC, Silveira LR, Kettelhut IC, Boschero AC, de Oliveira CA, Carneira EM (2015) Leucine supplementation does not affect protein turnover and impairs the beneficial effects of endurance training on glucose homeostasis in healthy mice. Amino Acids 47:745–755

    Article  PubMed  Google Scholar 

  • Coughlan KA, Balon TW, Valentine RJ, Petrocelli R, Schultz V, Brandon A, Cooney GJ, Kraegen EW, Ruderman NB, Saha AK (2015) Nutrient Excess and AMPK Downregulation in Incubated Skeletal Muscle and Muscle of Glucose Infused Rats. PLoS ONE 10:e0127388

    Article  PubMed Central  PubMed  Google Scholar 

  • Deldicque L, Sanchez Canedo C, Horman S, De Potter I, Bertrand L, Hue L, Francaux M (2008) Antagonistic effects of leucine and glutamine on the mTOR pathway in myogenic C2C12 cells. Amino Acids 35:147–155

    Article  CAS  PubMed  Google Scholar 

  • Dodd KM, Tee AR (2012) Leucine and mTORC1: a complex relationship. Am J Physiol Endocrinol Metab 302:E1329–E1342

    Article  CAS  PubMed  Google Scholar 

  • Dreyer HC, Drummond MJ, Pennings B, Fujita S, Glynn EL, Chinkes DL, Dhanani S, Volpi E, Rasmussen BB (2008) Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle. Am J Physiol Endocrinol Metab 294:E392–E400

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Du M, Shen QW, Zhu MJ, Ford SP (2007) Leucine stimulates mammalian target of rapamycin signaling in C2C12 myoblasts in part through inhibition of adenosine monophosphate-activated protein kinase. J Anim Sci 85:919–927

    Article  CAS  PubMed  Google Scholar 

  • Evans MJ, Scarpulla RC (1990) NRF-1—a transactivator of nuclear-encoded respiratory genes in animal cells. Genes Dev 4:1023–1034

    Article  CAS  PubMed  Google Scholar 

  • Filiputti E, Rafacho A, Araújo EP, Silveira LR, Trevisan A, Batista TM, Curi R, Velloso LA, Quesada I, Boschero AC, Carneiro EM (2010) Augmentation of insulin secretion by leucine supplementation in malnourished rats: possible involvement of the phosphatidylinositol 3-phosphate kinase/mammalian target protein of rapamycin pathway. Metabolism 59:635–644

    Article  CAS  PubMed  Google Scholar 

  • Fu L, Bruckbauer A, Li F, Cao Q, Cui X, Wu R, Shi H, Zemel MB, Xue B (2015a) Leucine amplifies the effects of metformin on insulin sensitivity and glycemic control in diet-induced obese mice. Metabolism 64:845–856

    Article  CAS  PubMed  Google Scholar 

  • Fu L, Li F, Bruckbauer A, Cao Q, Cui X, Wu R, Shi H, Xue B, Zemel MB (2015b) Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism. Diabetes Metab Syndr Obes 8:227–239

    PubMed Central  PubMed  Google Scholar 

  • Gannon NP, Conn CA, Vaughan RA (2015) Dietary stimulators of GLUT4 expression and translocation in skeletal muscle: a mini-review. Mol Nutr Food Res 59:48–64

    Article  CAS  PubMed  Google Scholar 

  • Gao X, Tian F, Wang X, Zhao J, Wan X, Zhang L, Wu C, Li N, Li J (2015) Leucine supplementation improves acquired growth hormone resistance in rats with protein-energy malnutrition. PLoS ONE 10:e0125023

    Article  PubMed Central  PubMed  Google Scholar 

  • Gil JH, Kim CK (2015) Effects of different doses of leucine ingestion following eight weeks of resistance exercise on protein synthesis and hypertrophy of skeletal muscle in rats. J Exerc Nutrition Biochem 19:31–38

    Article  PubMed Central  PubMed  Google Scholar 

  • Gingras AC, Raught B, Sonenberg N (2001) Regulation of translation initiation by FRAP/mTOR. Genes Dev 15:807–826

    Article  CAS  PubMed  Google Scholar 

  • Gleyzer N, Vercauteren K, Scarpulla RC (2005) Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol Cell Bio 25:1354–1366

    Article  CAS  Google Scholar 

  • Glynn EL, Fry CS, Drummond MJ, Timmerman KL, Dhanani S, Volpi Rasmussen BB (2010) Excess leucine intake enhances muscle anabolic signaling but not net protein anabolism in young men and women. J Nutr 140:1970–1976

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gordon JW, Rungi AA, Inagaki H, Hood DA (2001) Effects of contractile activity on mitochondrial transcription factor A expression in skeletal muscle. J Appl Physiol 90:389–396

    Article  CAS  PubMed  Google Scholar 

  • Gran P, Cameron-Smith D (2011) The actions of exogenous leucine on mTOR signalling and amino acid transporters in human myotubes. BMC Physiol 11:10

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Guo K, Yu YH, Hou J, Zhang Y (2010) Chronic leucine supplementation improves glycemic control in etiologically distinct mouse models of obesity and diabetes mellitus. Nutr Metab (Lond) 7:57

    Article  Google Scholar 

  • Holz MK, Ballif BA, Gygi SP, Blenis J (2005) mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123:569–580

    Article  CAS  PubMed  Google Scholar 

  • Iwanaka N, Egawa T, Satoubu N, Karaike K, Ma X, Masuda S, Hayashi T (2010) Leucine modulates contraction- and insulin-stimulated glucose transport and upstream signaling events in rat skeletal muscle. J Appl Physiol 108:274–282

    Article  CAS  PubMed  Google Scholar 

  • Jager S, Handschin C, Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1 alpha. Proc Natl Acad Sci USA 104:12017–12022

    Article  PubMed Central  PubMed  Google Scholar 

  • Kasuga M, Karlsson FA, Kahn CR (1982a) Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science 215:185–187

    Article  CAS  PubMed  Google Scholar 

  • Kasuga M, Zick Y, Blith DL, Karlsson FA, Häring HU, Kahn CR (1982b) Insulin stimulation of phosphorylation of the beta subunit of the insulin receptor. Formation of both phosphoserine and phosphotyrosine. J Biol Chem 257:9891–9894

    CAS  PubMed  Google Scholar 

  • Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM (2003) GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11:895–904

    Article  CAS  PubMed  Google Scholar 

  • Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1 alpha. Cell 127:1109–1122

    Article  CAS  PubMed  Google Scholar 

  • Lang CH, Frost RA, Bronson SK, Lynch CJ, Vary TC (2010) Skeletal muscle protein balance in mTOR heterozygous mice in response to inflammation and leucine. Am J Physiol Endocrinol Metab 298:E1283–E1294

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Li H, Xu M, Lee J, He C, Xie Z (2012) Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice. Am J Physiol Endocrinol Metab 303:E1234–E1244

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Li X, Wang X, Liu R, Ma Y, Guo H, Hao L, Yao P, Liu L, Sun X, He K, Cao W, Yang X (2013) Chronic leucine supplementation increases body weight and insulin sensitivity in rats on high-fat diet likely by promoting insulin signaling in insulin-target tissues. Mol Nutr Food Res 57:1067–1079

    Article  CAS  PubMed  Google Scholar 

  • Liang C, Bruckbauer A, Zemel MB (2010) Leucine modulation of sirtuins and AMPK in adipocytes and myotubes. FASEB J 24:E1283–E1294

    Article  Google Scholar 

  • Liang C, Curry BJ, Brown PL, Zemel MB (2014) Leucine Modulates Mitochondrial Biogenesis and SIRT1-AMPK Signaling in C2C12 Myotubes. J Nutr Metab 2014:239750

    Article  PubMed Central  PubMed  Google Scholar 

  • Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (2005) Rheb binds and regulates the mTOR kinase. Curr Biol 15:702–713

    Article  CAS  PubMed  Google Scholar 

  • LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 11:32–50

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Luo JQ, Chen DW, Yu B (2013) Upregulation of amino acid transporter expression induced by l-leucine availability in L6 myotubes is associated with ATF4 signaling through mTORC1-dependent mechanism. Nutrition 29:284–290

    Article  CAS  PubMed  Google Scholar 

  • Macotela Y, Emanuelli B, Bång AM, Espinoza DO, Boucher J, Beebe K, Gall W, Kahn CR (2011) Dietary leucine–an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS ONE 6:e21187

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mao X, Zeng X, Wang J, Qiao S (2011) Leucine promotes leptin receptor expression in mouse C2C12 myotubes through the mTOR pathway. Mol Biol Rep 38:3201–3206

    Article  CAS  PubMed  Google Scholar 

  • McIntire KL, Chen Y, Sood S, Rabkin R (2014) Acute uremia suppresses leucine-induced signal transduction in skeletal muscle. Kidney Int 85:374–382

    Article  CAS  PubMed  Google Scholar 

  • Mieulet V, Roceri M, Espeillac C, Sotiropoulos A, Ohanna M, Oorschot V, Klumperman J, Sandri M, Pende M (2007) S6 kinase inactivation impairs growth and translational target phosphorylation in muscle cells maintaining proper regulation of protein turnover. Am J Physiol Cell Physiol 293:C712–C722

    Article  CAS  PubMed  Google Scholar 

  • Moberg M, Apró W, Ohlsson I, Pontén M, Villanueva A, Ekblom B, Blomstrand E (2014) Absence of leucine in an essential amino acid supplement reduces activation of mTORC1 signalling following resistance exercise in young females. Appl Physiol Nutr Metab 39:183–194

    Article  CAS  PubMed  Google Scholar 

  • Morato PN, Lollo PC, Moura CS, Batista TM, Carneiro EM, Amaya-Farfan J (2013) A dipeptide and an amino acid present in whey protein hydrolysate increase translocation of GLUT-4 to the plasma membrane in Wistar rats. Food Chem 139:853–859

    Article  CAS  PubMed  Google Scholar 

  • Mordier S, Deval C, Béchet D, Tassa A, Ferrara M (2000) Leucine limitation induces autophagy and activation of lysosome-dependent proteolysis in C2C12 myotubes through a mammalian target of rapamycin-independent signaling pathway. J Biol Chem 275:29900–29906

    Article  CAS  PubMed  Google Scholar 

  • Murgas Torrazza R, Suryawan A, Gazzaneo MC, Orellana RA, Frank JW, Nguyen HV, Fiorotto ML, El-Kadi S, Davis TA (2010) Leucine supplementation of a low-protein meal increases skeletal muscle and visceral tissue protein synthesis in neonatal pigs by stimulating mTOR-dependent translation initiation. J Nutr 140:2145–2152

    Article  PubMed Central  PubMed  Google Scholar 

  • Nakai N, Kawano F, Terada M, Oke Y, Ohira T, Ohira Y (2008) Effects of peroxisome proliferator-activated receptor alpha (PPARalpha) agonists on leucine-induced phosphorylation of translational targets in C2C12 cells. Biochim Biophys Acta 1780:1101–1105

    Article  CAS  PubMed  Google Scholar 

  • Nicastro H, Zanchi NE, da Luz CR, de Moraes WM, Ramona P, de Siqueira Filho MA, Chaves DF, Medeiros A, Brum PC, Dardevet D, Lancha AH (2012) Effects of leucine supplementation and resistance exercise on dexamethasone-induced muscle atrophy and insulin resistance in rats. Nutrition 28:465–471

    Article  CAS  PubMed  Google Scholar 

  • Nishitani S, Matsumura T, Fujitani S, Sonaka I, Miura Y, Yagasaki K (2002) Leucine promotes glucose uptake in skeletal muscles of rats. Biochem Biophys Res Commun 299:693–696

    Article  CAS  PubMed  Google Scholar 

  • Nishitani S, Takehana K, Fujitani S, Sonaka I (2005) Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol 288:G1292–G1300

    Article  CAS  PubMed  Google Scholar 

  • Noatsch A, Petzke KJ, Millrose MK, Klaus S (2011) Body weight and energy homeostasis was not affected in C57BL/6 mice fed high whey protein or leucine-supplemented low-fat diets. Eur J Nutr 50:479–488

    Article  CAS  PubMed  Google Scholar 

  • Pasiakos SM, McClung HL, McClung JP, Margolis LM, Andersen NE, Cloutier GJ, Pikosky MA, Rood JC, Fielding RA, Young AJ (2011) Leucine-enriched essential amino acid supplementation during moderate steady state exercise enhances postexercise muscle protein synthesis. Am J Clin Nutr 94:809–818

    Article  CAS  PubMed  Google Scholar 

  • Pereira MG, Baptista IL, Carlassara EO, Moriscot AS, Aoki MS, Miyabara EH (2014) Leucine supplementation improves skeletal muscle regeneration after cryolesion in rats. PLoS ONE 9:e85283

    Article  PubMed Central  PubMed  Google Scholar 

  • Peyrollier K, Hajduch E, Blair AS, Hyde R, Hundal HS (2000) l-leucine availability regulates phosphatidylinositol 3-kinase, p70 S6 kinase and glycogen synthase kinase-3 activity in L6 muscle cells: evidence for the involvement of the mammalian target of rapamycin (mTOR) pathway in the l-leucine-induced up-regulation of system A amino acid transport. Biochem J 350(Pt 2):361–368

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pruznak AM, Kazi AA, Frost RA, Vary TC, Lang CH (2008) Activation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside prevents leucine-stimulated protein synthesis in rat skeletal muscle. J Nutr 138:1887–1894

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ribeiro CB, Christofoletti DC, Pezolato VA, de Cássia MDR, Prestes J, Tibana RA, Pereira EC, de Sousa NIV, Durigan JL, da Silva CA (2015) Leucine minimizes denervation-induced skeletal muscle atrophy of rats through akt/mtor signaling pathways. Front Physiol 6:73

    Article  PubMed Central  PubMed  Google Scholar 

  • Ruvinsky I, Meyuhas O (2006) Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci 31:342–348

    Article  CAS  PubMed  Google Scholar 

  • Sadiq F, Hazlerigg DG, Lomax MA (2007) Amino acids and insulin act additively to regulate components of the ubiquitin-proteasome pathway in C2C12 myotubes. BMC Mol Biol 8:23

    Article  PubMed Central  PubMed  Google Scholar 

  • Saha AK, Xu XJ, Lawson E, Deoliveira R, Brandon AE, Kraegen EW, Ruderman NB (2010) Downregulation of AMPK accompanies leucine- and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle. Diabetes 59:2426–2434

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Salles J, Chanet A, Giraudet C, Patrac V, Pierre P, Jourdan M, Luiking YC, Verlaan S, Migné C, Boirie Y, Walrand S (2013) 1,25(OH)2-vitamin D3 enhances the stimulating effect of leucine and insulin on protein synthesis rate through Akt/PKB and mTOR mediated pathways in murine C2C12 skeletal myotubes. Mol Nutr Food Res 57:2137–2146

    Article  CAS  PubMed  Google Scholar 

  • Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296–1302

    Article  CAS  PubMed  Google Scholar 

  • Scarpulla RC (2002) Transcriptional activators and coactivators in the nuclear control of mitochondrial function in mammalian cells. Gene 286:81–89

    Article  CAS  PubMed  Google Scholar 

  • Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813:1269–1278

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shah OJ, Anthony JC, Kimball SR, Jefferson LS (2000) 4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle. Am J Physiol Endocrinol Metab 279:E715–E729

    CAS  PubMed  Google Scholar 

  • Smith EM, Finn SG, Tee AR, Browne GJ, Proud CG (2005) The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J Biol Chem 280:18717–18727

    Article  CAS  PubMed  Google Scholar 

  • Sun X, Zemel MB (2007) Leucine and calcium regulate fat metabolism and energy partitioning in murine adipocytes and muscle cells. Lipids 42:297–305

    Article  CAS  PubMed  Google Scholar 

  • Sun X, Zemel MB (2009) Leucine modulation of mitochondrial mass and oxygen consumption in skeletal muscle cells and adipocytes. Nutr Metab (Lond) 6:26

    Article  Google Scholar 

  • Suryawan A, Jeyapalan AS, Orellana RA, Wilson FA, Nguyen HV, Davis TA (2008) Leucine stimulates protein synthesis in skeletal muscle of neonatal pigs by enhancing mTORC1 activation. Am J Physiol Endocrinol Metab 295:E868–E875

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Suryawan A, Torrazza RM, Gazzaneo MC, Orellana RA, Fiorotto ML, El-Kadi SW, Srivastava N, Nguyen HV, Davis TA (2012) Enteral leucine supplementation increases protein synthesis in skeletal and cardiac muscles and visceral tissues of neonatal pigs through mTORC1-dependent pathways. Pediatr Res 71:324–331

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Talvas J, Obled A, Fafournoux P, Mordier S (2006) Regulation of protein synthesis by leucine starvation involves distinct mechanisms in mouse C2C12 myoblasts and myotubes. J Nutr 136:1466–1471

    CAS  PubMed  Google Scholar 

  • Tsien C, Davuluri G, Singh D, Allawy A, Ten Have GA, Thapaliya S, Schulze JM, Barnes D, McCullough AJ, Engelen MP, Deutz NE, Dasarathy S (2015) Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis. Hepatology 61:2018–2029

    Article  CAS  PubMed  Google Scholar 

  • Vary TC, Deiter G, Lynch CJ (2007) Rapamycin limits formation of active eukaryotic initiation factor 4F complex following meal feeding in rat hearts. J Nutr 137:1857–1862

    CAS  PubMed  Google Scholar 

  • Vaughan RA, Garcia-Smith R, Gannon NP, Bisoffi M, Trujillo KA, Conn CA (2013a) Leucine Treatment Enhances Oxidative Capacity Through Complete Carbohydrate Oxidation and Increased Mitochondrial Density in Skeletal Muscle Cells. Amino Acids 45:901–911

    Article  CAS  PubMed  Google Scholar 

  • Vaughan RA, Mermier CM, Bisoffi M, Trujillo KA, Conn CA (2013b) Dietary Stimulators of the PGC-1 Superfamily and Mitochondrial Biosynthesis in Skeletal Muscle. A Mini-Review. J Physiol Biochem 70:271–284

    Article  PubMed  Google Scholar 

  • Virbasius JV, Scarpulla RC (1994) Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors—a potential regulatory link between nuclear and mitochondrial gene-expression in organelle biogenesis. Proc Natl Acad Sci USA 91:1309–1313

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang X, Proud CG (2006) The mTOR pathway in the control of protein synthesis. Physiology (Bethesda) 21:362–369

    Article  CAS  Google Scholar 

  • Wang Q, Somwar R, Bilan PJ, Liu Z, Jin J, Woodgett JR, Klip A (1999) Protein kinase B/Akt participates in GLUT4 translocation by insulin in L6 myoblasts. Mol Cell Biol 19:4008–4018

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wilson FA, Suryawan A, Gazzaneo MC, Orellana RA, Nguyen HV, Davis TA (2010) Stimulation of muscle protein synthesis by prolonged parenteral infusion of leucine is dependent on amino acid availability in neonatal pigs. J Nutr 140:264–270

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wilson FA, Suryawan A, Orellana RA, Gazzaneo MC, Nguyen HV, Davis TA (2011) Differential effects of long-term leucine infusion on tissue protein synthesis in neonatal pigs. Amino Acids 40:157–165

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yin Y, Yao K, Liu Z, Gong M, Ruan Z, Deng D, Tan B, Wu G (2010) Supplementing l-leucine to a low-protein diet increases tissue protein synthesis in weanling pigs. Amino Acids 39:1477–1486

    Article  CAS  PubMed  Google Scholar 

  • Yoshizawa F, Mochizuki S, Sugahara K (2013) Differential dose response of mTOR signaling to oral administration of leucine in skeletal muscle and liver of rats. Biosci Biotechnol Biochem 77:839–842

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Guo K, LeBlanc RE, Loh D, Schwartz GJ, Yu YH (2007) Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes 56:1647–1654

    Article  CAS  PubMed  Google Scholar 

  • Zong HH, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI (2002) AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci USA 99:15983–15987

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

No funding was received for this work.

Author information

Authors and Affiliations

  1. School of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA

    Nicholas P. Gannon

  2. Department of Exercise Science, High Point University, 833 Montlieu Ave, High Point, NC, 27262-3598, USA

    Roger A. Vaughan

Authors
  1. Nicholas P. Gannon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roger A. Vaughan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roger A. Vaughan.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Handling Editor: C.-A. A. Hu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gannon, N.P., Vaughan, R.A. Leucine-induced anabolic-catabolism: two sides of the same coin. Amino Acids 48, 321–336 (2016). https://doi.org/10.1007/s00726-015-2109-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-015-2109-8

Keywords

Search

Navigation