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Leucine and citrulline modulate muscle function in malnourished aged rats

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Abstract

Protein energy malnutrition in the elderly causes preferential loss of muscle mass which is associated with poor functional states. Leucine and citrulline are able to stimulate muscle protein synthesis in aged rats but no study has been undertaken to evaluate their effect on muscle function. Sprague–Dawley male rats aged 23 months were used in the experiment. Part of them were subjected to a dietary restriction for 12 weeks and then assigned to four groups: a group was euthanized (restricted group), and the others were refed for 1 week with either a leucine-, a citrulline-supplemented diet, or a standard diet. The other rats were fed ad libitum. Muscle mass and motor activity significantly increased during the refeeding with either leucine or citrulline (respectively, +51 and +37% for muscle mass, P < 0.05). The improvement of muscle mass and of motor activity induced by leucine and citrulline was highly associated with that of maximal tetanic isometric force (r = 0.769, P < 0.0001; r = 0.389, P < 0.05, respectively) but only leucine improved maximal tetanic isometric force (+101%, P < 0.05). In conclusion, this is the first study to demonstrate the ability of two amino acids (leucine and citrulline) to modulate muscle function.

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Abbreviations

AA:

Amino acids

Cit:

Citrulline

Leu:

Leucine

AL:

Ad libitum

R:

Restricted

NEAA:

Non-essential amino acids

isoN:

Isonitrogenous

TCA:

Trichloroacetic acid

References

  • Anthony JC, Lang CH, Crozier SJ, Anthony TG, MacLean DA, Kimball SR, Jefferson LS (2002) Contribution of insulin to the translational control of protein synthesis in skeletal muscle by leucine. Am J Physiol Endocrinol Metab 282:E1092–E1101

    PubMed  CAS  Google Scholar 

  • Beliaeff S, Bouchard DR, Hautier C, Brochu M, Dionne IJ (2008) Association between muscle mass and isometric muscle strength in well-functioning older men and women. J Aging Phys Act 16:484–493

    PubMed  Google Scholar 

  • Boirie Y, Gachon P, Beaufrere B (1997) Splanchnic and whole-body leucine kinetics in young and elderly men. Am J Clin Nutr 65:489–495

    PubMed  CAS  Google Scholar 

  • Bouillanne O, Morineau G, Dupont C, Coulombel I, Vincent JP, Nicolis I, Benazeth S, Cynober L, Aussel C (2005) Geriatric Nutritional Risk Index: a new index for evaluating at-risk elderly medical patients. Am J Clin Nutr 82:777–783

    PubMed  CAS  Google Scholar 

  • Capodaglio P, Capodaglio EM, Facioli M, Saibene F (2007) Long-term strength training for community-dwelling people over 75: impact on muscle function, functional ability and life style. Eur J Appl Physiol 100:535–542

    Article  PubMed  Google Scholar 

  • Chambon-Savanovitch C, Felgines C, Farges MC, Pernet P, Cezard J, Raul F, Cynober L, Vasson MP (1999) Severe dietary restriction initiated in aged rats: evidence for poor adaptation in terms of protein metabolism and intestinal functions. Eur J Clin Invest 29:504–511

    Article  PubMed  CAS  Google Scholar 

  • Chambon-Savanovitch C, Felgines C, Walrand S, Raul F, Zarrabian S, Meunier MT, Farges MC, Cynober L, Vasson MP (2001) A pancreatic extract-enriched diet improves the nutritional status of aged rats. J Nutr 131:813–819

    PubMed  CAS  Google Scholar 

  • Clark BC, Manini TM (2008) Sarcopenia ≠ dynapenia. J Gerontol A Biol Sci Med Sci 63:829–834

    Article  PubMed  Google Scholar 

  • Corcondilas A, Koroxenidis GT, Shepherd JT (1964) Effect of a brief contraction of forearm muscles on forearm blood flow. J Appl Physiol 19:142–146

    PubMed  CAS  Google Scholar 

  • Curis E, Nicolis I, Moinard C, Osowska S, Zerrouk N, Benazeth S, Cynober L (2005) Almost all about citrulline in mammals. Amino Acids 29:177–205

    Article  PubMed  CAS  Google Scholar 

  • Dardevet D, Sornet C, Bayle G, Prugnaud J, Pouyet C, Grizard J (2002) Postprandial stimulation of muscle protein synthesis in old rats can be restored by a leucine-supplemented meal. J Nutr 132:95–100

    PubMed  CAS  Google Scholar 

  • Deutz NE (2008) The 2007 ESPEN Sir David Cuthbertson Lecture: amino acids between and within organs. The glutamate-glutamine-citrulline-arginine pathway. Clin Nutr 27:321–327

    Article  PubMed  CAS  Google Scholar 

  • Felgines C, Savanovitch C, Farges MC, Cynober L, Vasson MP (1999) Protein metabolism in rats during long-term dietary restriction: influence of aging. JPEN J Parenter Enteral Nutr 23:32–37

    Article  PubMed  CAS  Google Scholar 

  • Fleury P, Eberhard R (1951) Determination of proteins by photometric, biuret method, according to the technique of Gornall. Ann Biol Clin (Paris) 9:453–466

    CAS  Google Scholar 

  • Frontera WR, Hughes VA, Lutz KJ, Evans WJ (1991) A cross-sectional study of muscle strength and mass in 45- to 78-yr-old men and women. J Appl Physiol 71:644–650

    PubMed  CAS  Google Scholar 

  • Gale CR, Martyn CN, Cooper C, Sayer AA (2007) Grip strength, body composition, and mortality. Int J Epidemiol 36:228–235

    Article  PubMed  Google Scholar 

  • Godard MP, Williamson DL, Trappe SW (2002) Oral amino-acid provision does not affect muscle strength or size gains in older men. Med Sci Sports Exerc 34:1126–1131

    Article  PubMed  CAS  Google Scholar 

  • Goodpaster BH, Park SW, Harris TB, Kritchevsky SB, Nevitt M, Schwartz AV, Simonsick EM, Tylavsky FA, Visser M, Newman AB (2006) The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J Gerontol A Biol Sci Med Sci 61:1059–1064

    Article  PubMed  Google Scholar 

  • Guillet C, Prod’homme M, Balage M, Gachon P, Giraudet C, Morin L, Grizard J, Boirie Y (2004) Impaired anabolic response of muscle protein synthesis is associated with S6K1 dysregulation in elderly humans. FASEB J 18:1586–1587

    PubMed  CAS  Google Scholar 

  • Harris T (1997) Muscle mass and strength: relation to function in population studies. J Nutr 127:1004S–1006S

    PubMed  CAS  Google Scholar 

  • HAS (2007) Stratégie de prise en charge en cas de dénutrition protéino-énergétique chez la personne âgée. www.hassanté.fr

  • Hebuterne X, Broussard JF, Rampal P (1995) Acute renutrition by cyclic enteral nutrition in elderly and younger patients. JAMA 273:638–643

    Article  PubMed  CAS  Google Scholar 

  • Hebuterne X, Schneider S, Peroux JL, Rampal P (1997) Effects of refeeding by cyclic enteral nutrition on body composition: comparative study of elderly and younger patients. Clin Nutr 16:283–289

    Article  PubMed  CAS  Google Scholar 

  • Hughes VA, Frontera WR, Wood M, Evans WJ, Dallal GE, Roubenoff R, Fiatarone Singh MA (2001) Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health. J Gerontol A Biol Sci Med Sci 56:B209–B217

    Article  PubMed  CAS  Google Scholar 

  • Jourdan M, Cynober L, Moinard C, Blanc MC, Neveux N, De Bandt JP, Aussel C (2007) Splanchnic sequestration of amino acids in aged rats: in vivo and ex vivo experiments using a model of isolated perfused liver. Am J Physiol Regul Integr Comp Physiol 294:748–755

    Article  Google Scholar 

  • Jourdan M, Nair KS, Ford C, Shimke J, Ali B, Will B, Marc J, Aussel C, Cynober L (2008) Citrulline stimulates muscle protein synthesis at the post-absorptive state in healthy subjects fed a low protein diet. Clin Nutr 3:11–12 (abstract)

    Google Scholar 

  • Kagansky N, Berner Y, Koren-Morag N, Perelman L, Knobler H, Levy S (2005) Poor nutritional habits are predictors of poor outcome in very old hospitalized patients. Am J Clin Nutr 82:784–791

    PubMed  CAS  Google Scholar 

  • Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR (2006) A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab 291:E381–E387

    Article  PubMed  CAS  Google Scholar 

  • Laughlin MH, Armstrong RB (1982) Muscular blood flow distribution patterns as a function of running speed in rats. Am J Physiol 243:H296–H306

    PubMed  CAS  Google Scholar 

  • Liu CJ, Latham NK (2009) Progressive resistance strength training for improving physical function in older adults. Cochrane Database Syst Rev CD002759

  • Meneilly GS, Elliot T, Bryer-Ash M, Floras JS (1995) Insulin-mediated increase in blood flow is impaired in the elderly. J Clin Endocrinol Metab 80:1899–1903

    Article  PubMed  CAS  Google Scholar 

  • Milne AC, Potter J, Vivanti A, Avenell A (2009) Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database Syst Rev CD003288

  • Moinard C, Cynober L (2007) Citrulline: a new player in the control of nitrogen homeostasis. J Nutr 137:1621S–1625S

    PubMed  CAS  Google Scholar 

  • Moinard C, Dauge V, Cynober L (2004) Ornithine alpha-ketoglutarate supplementation influences motor activity in healthy rats. Clin Nutr 23:485–490

    Article  PubMed  CAS  Google Scholar 

  • Mosoni L, Houlier ML, Mirand PP, Bayle G, Grizard J (1993) Effect of amino acids alone or with insulin on muscle and liver protein synthesis in adult and old rats. Am J Physiol 264:E614–E620

    PubMed  CAS  Google Scholar 

  • Mosoni L, Valluy MC, Serrurier B, Prugnaud J, Obled C, Guezennec CY, Mirand PP (1995) Altered response of protein synthesis to nutritional state and endurance training in old rats. Am J Physiol 268:E328–E335

    PubMed  CAS  Google Scholar 

  • Newman AB, Haggerty CL, Goodpaster B, Harris T, Kritchevsky S, Nevitt M, Miles TP, Visser M (2003) Strength and muscle quality in a well-functioning cohort of older adults: the Health, Aging and Body Composition Study. J Am Geriatr Soc 51:323–330

    Article  PubMed  Google Scholar 

  • Newman AB, Kupelian V, Visser M, Simonsick EM, Goodpaster BH, Kritchevsky SB, Tylavsky FA, Rubin SM, Harris TB (2006) Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort. J Gerontol A Biol Sci Med Sci 61:72–77

    Article  PubMed  Google Scholar 

  • Osowska S, Duchemann T, Walrand S, Paillard A, Boirie Y, Cynober L, Moinard C (2006) Citrulline modulates muscle protein metabolism in old malnourished rats. Am J Physiol Endocrinol Metab 291:E582–E586

    Article  PubMed  CAS  Google Scholar 

  • Persson M, Hytter-Landahl A, Brismar K, Cederholm T (2007) Nutritional supplementation and dietary advice in geriatric patients at risk of malnutrition. Clin Nutr 26:216–224

    Article  PubMed  CAS  Google Scholar 

  • Radegran G, Saltin B (1998) Muscle blood flow at onset of dynamic exercise in humans. Am J Physiol 274:H314–H322

    PubMed  CAS  Google Scholar 

  • Rasmussen BB, Fujita S, Wolfe RR, Mittendorfer B, Roy M, Rowe VL, Volpi E (2006) Insulin resistance of muscle protein metabolism in aging. FASEB J 20:768–769

    PubMed  CAS  Google Scholar 

  • Rieu I, Sornet C, Bayle G, Prugnaud J, Pouyet C, Balage M, Papet I, Grizard J, Dardevet D (2003) Leucine-supplemented meal feeding for ten days beneficially affects postprandial muscle protein synthesis in old rats. J Nutr 133:1198–1205

    PubMed  CAS  Google Scholar 

  • Rieu I, Balage M, Sornet C, Debras E, Ripes S, Rochon-Bonhomme C, Pouyet C, Grizard J, Dardevet D (2007) Increased availability of leucine with leucine-rich whey proteins improves postprandial muscle protein synthesis in aging rats. Nutrition 23:323–331

    Article  PubMed  CAS  Google Scholar 

  • Rolland Y, Vellas B (2009) Sarcopenia. Rev Med Interne 30:150–160

    Article  PubMed  CAS  Google Scholar 

  • Ruiz JR, Sui X, Lobelo F, Morrow JR Jr, Jackson AW, Sjostrom M, Blair SN (2008) Association between muscular strength and mortality in men: prospective cohort study. BMJ 337:a439

    Article  PubMed  Google Scholar 

  • Seiler WO (2001) Clinical pictures of malnutrition in ill elderly subjects. Nutrition 17:496–498

    Article  PubMed  CAS  Google Scholar 

  • Sullivan DH, Walls RC, Boop MM (1995) Protein-energy undernutrition and the risk of mortality within one year of hospital discharge: a follow-up study. J Am Geriatr Soc 43:507–512

    PubMed  CAS  Google Scholar 

  • Timmerman KL, Lee JL, Fujita S, Dhanani S, Dreyer HC, Fry CS, Drummond MJ, Sheffield-Moore M, Rasmussen BB, Volpi E (2010) Pharmacological vasodilation improves insulin-stimulated muscle protein anabolism but not glucose utilization in older adults. Diabetes. doi:10.2337/db10-0415

  • Verhoeven S, Vanschoonbeek K, Verdijk LB, Koopman R, Wodzig WK, Dendale P, van Loon LJ (2009) Long-term leucine supplementation does not increase muscle mass or strength in healthy elderly men. Am J Clin Nutr 89:1468–1475

    Article  PubMed  CAS  Google Scholar 

  • Vignaud A, Noirez P, Besse S, Rieu M, Barritault D, Ferry A (2003) Recovery of slow skeletal muscle after injury in the senescent rat. Exp Gerontol 38:529–537

    Article  PubMed  CAS  Google Scholar 

  • Volpi E, Sheffield-Moore M, Rasmussen BB, Wolfe RR (2001) Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA 286:1206–1212

    Article  PubMed  CAS  Google Scholar 

  • Walrand S, Chambon-Savanovitch C, Felgines C, Chassagne J, Raul F, Normand B, Farges MC, Beaufrere B, Vasson MP, Cynober L (2000) Aging: a barrier to renutrition? Nutritional and immunologic evidence in rats. Am J Clin Nutr 72:816–824

    PubMed  CAS  Google Scholar 

  • Zangarelli A, Chanseaume E, Morio B, Brugere C, Mosoni L, Rousset P, Giraudet C, Patrac V, Gachon P, Boirie Y, Walrand S (2006) Synergistic effects of caloric restriction with maintained protein intake on skeletal muscle performance in 21-month-old rats: a mitochondria-mediated pathway. FASEB J 20:2439–2450

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Dr Nathalie Neveux and Ms Julie Marc for their technical support.

Conflict of interest

CF, LC and CM are share holders of Citrage company. Other authors do not declare any conflict of interest.

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Authors and Affiliations

  1. Département de Biologie Expérimentale, Métabolique et Clinique (EA 4466), Faculté de Pharmacie, Université Paris Descartes, 75 270, Paris Cedex 06, France

    Cécile Faure, Agathe Raynaud-Simon, Luc Cynober, Christian Aussel & Christophe Moinard

  2. Département de Gériatrie, Hôpital Universitaire Bichat, AP-HP, 75 877, Paris Cedex 18, France

    Agathe Raynaud-Simon

  3. INSERM U974, CNRS UMR7215, Institut de Myologie, 75 013, Paris, France

    Arnaud Ferry

  4. INSERM U952, CNRS UMR 7224, UPMC, Université Pierre et Marie Curie, 75 252, Paris Cedex 05, France

    Valérie Daugé

  5. Service Interhospitalier de Biochimie, Hôpitaux Cochin et Hôtel Dieu, AP-HP, 75 181, Paris Cedex 04, France

    Luc Cynober

  6. Service Interhospitalier de Biologie, Hôpital Emile Roux, AP-HP, 94 456, Limeil-Brévannes, France

    Christian Aussel

Authors
  1. Cécile Faure
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  2. Agathe Raynaud-Simon
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  3. Arnaud Ferry
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  4. Valérie Daugé
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  5. Luc Cynober
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  6. Christian Aussel
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  7. Christophe Moinard
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Correspondence to Christophe Moinard.

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Faure, C., Raynaud-Simon, A., Ferry, A. et al. Leucine and citrulline modulate muscle function in malnourished aged rats. Amino Acids 42, 1425–1433 (2012). https://doi.org/10.1007/s00726-011-0841-2

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  • DOI: https://doi.org/10.1007/s00726-011-0841-2

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