The journal of nutrition, health & aging

, Volume 22, Issue 4, pp 534–540 | Cite as

Sex Differences in the Associations between L-Arginine Pathway Metabolites, Skeletal Muscle Mass and Function, and their Responses to Resistance Exercise, in Old Age

  • M. da Boit
  • S. Tommasi
  • D. Elliot
  • A. Zinellu
  • S. Sotgia
  • R. Sibson
  • J. R. Meakin
  • R. M. Aspden
  • C. Carru
  • A. A. Mangoni
  • Stuart R. Gray



The current study was designed to explore the associations between L-arginine metabolites and muscle mass and function in old age, which are largely unknown.


The study used a randomised, double-blind, placebo-controlled design.


The study was carried out in a laboratory setting.


50 healthy older adults [median age 70 years (IQR 67-73); 27 males].


Participants undertook an 18-week resistance exercise program, and a nutritional intervention (fish oil vs. placebo).


Serum homoarginine, ornithine, citrulline, asymmetric dimethylarginine (ADMA), NG-monomethyl-L-arginine (L-NMMA), and symmetric dimethylarginine (SDMA), maximal voluntary contraction (MVC) and isokinetic torque of the knee extensors at 30° s-1 (MIT), muscle cross sectional area (MCSA) and quality (MQ) were measured at baseline and after the intervention.


No significant exercise-induced changes were observed in metabolite concentrations. There were significant sex differences in the associations between metabolites and muscle parameters. After adjusting for age, glomerular filtration rate and fish oil intervention, citrulline (P=0.002) and ornithine (P=0.022) were negatively associated with MCSA at baseline in males but not females. However, baseline citrulline was negatively correlated with exercise-induced changes in MVC (P=0.043) and MQ (P=0.026) amongst females. Furthermore, amongst males, baseline homoarginine was positively associated with exercise-induced changes in MVC (P=0.026), ADMA was negatively associated with changes in MIT (P=0.026), L-NMMA (p=0.048) and ornithine (P<0.001) were both positively associated with changes in MCSA, and ornithine was negatively associated with changes in MQ (P=0.039).


Therefore, barring citrulline, there are significant sex differences in the associations between L-arginine metabolites and muscle mass and function in healthy older adults. These metabolites might enhance sarcopenia risk stratification, and the success of exercise programs, in old age.

Key words

L-arginine metabolites muscle mass muscle function old age exercise 

Supplementary material

12603_2017_964_MOESM1_ESM.pdf (72 kb)
Supplementary section
12603_2017_964_MOESM2_ESM.pdf (73 kb)
Supplementary Table 1. Summary of quantitative parameters and analytical performance


  1. 1.
    Baumgartner RN, Koehler KM, Gallagher D, Romero L, Heymsfield SB, Ross RR, Garry PJ, Lindeman RD. Epidemiology of sarcopenia among the elderly in New Mexico._Am J Epidemiol. Apr 1998;15;147(8):755–63.Google Scholar
  2. 2.
    O’Loughlin JL, Robitaille Y, Boivin JF, Suissa S. Incidence of and risk factors for falls and injurious falls among the community-dwelling elderly. Am J Epidemiol. Feb 1993;1;137(3):342–54.CrossRefPubMedGoogle Scholar
  3. 3.
    Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R. The healthcare costs of sarcopenia in the United States. J Am Geriatr Soc. Jan 2004;52(1):80–5. doi: 10.1111/j.1532-5415.2004.52014.x.CrossRefGoogle Scholar
  4. 4.
    Mitchell WK, Williams J, Atherton P, Larvin M, Lund J, Narici M. Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Front Physiol. 2012;3:260. doi: 10.3389/fphys.2012.00260.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Stamler JS, Meissner G. Physiology of nitric oxide in skeletal muscle. Physiol Rev. Jan; 2001;81(1):209–37.CrossRefGoogle Scholar
  6. 6.
    Viinikka L. Nitric oxide as a challenge for the clinical chemistry laboratory. Scand J Clin Lab Invest. Nov; 1996;56(7):577–81. doi: Scholar
  7. 7.
    Moali C, Boucher JL, Sari MA, Stuehr DJ, Mansuy D. Substrate specificity of NO synthases: detailed comparison of L-arginine, homo-L-arginine, their N omegahydroxy derivatives, and N omega-hydroxynor-L-arginine. Biochemistry. Jul 1998;21;37(29):10453–60. doi: 10.1021/bi980742t.CrossRefGoogle Scholar
  8. 8.
    Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol. Jun; 2004;24(6):1023–30. doi: ATV.0000128897.54893.26.CrossRefGoogle Scholar
  9. 9.
    Michel T. R is for arginine: metabolism of arginine takes off again, in new directions. Circulation. Sep 2013;24;128(13):1400–4. doi:10.1161/CIRCULATIONAHA.113.005924.CrossRefGoogle Scholar
  10. 10.
    Pilz S, Meinitzer A, Tomaschitz A, Kienreich K, Dobnig H, Schwarz M, Wagner D, Drechsler C, Piswanger-Sölkner C, März W, Fahrleitner-Pammer A. Associations of homoarginine with bone metabolism and density, muscle strength and mortality: cross-sectional and prospective data from 506 female nursing home patients. Osteoporos Int. Jan; 2013;24(1):377–81. doi: 10.1007/s00198-012-1950-9.CrossRefGoogle Scholar
  11. 11.
    Obayashi K, Saeki K, Maegawa T, Sakai T, Kitagawa M, Otaki N, Kataoka H, Kurumatani N. Association of Serum Asymmetric Dimethylarginine With Muscle Strength and Gait Speed: A Cross-Sectional Study of the HEIJO-KYO Cohort. J Bone Miner Res. May; 2016;31(5):1107–13. doi: 10.1002/jbmr.2773. Epub 2016 Jan20.CrossRefGoogle Scholar
  12. 12.
    Peterson MD, Rhea MR, Sen A, Gordon PM. Resistance exercise for muscular strength in older adults: a meta-analysis. Ageing Res Rev. Jul; 2010;9(3):226–37. doi: 10.1016/j.arr.2010.03.004.CrossRefGoogle Scholar
  13. 13.
    Campins L, Camps M, Riera A, Pleguezuelos E, Yebenes JC, Serra-Prat M. Oral Drugs Related with Muscle Wasting and Sarcopenia. A Review. Pharmacology. Aug 2016;31;99(1-2):1–8. doi: 10.1159/000448247.Google Scholar
  14. 14.
    Kalyani RR, Corriere M, Ferrucci L. Age-related and disease-related muscle loss: the effect of diabetes, obesity, and other diseases. Lancet Diabetes Endocrinol. Oct; 2014;2(10):819–29. doi: 10.1016/S2213-8587(14)70034-8.CrossRefGoogle Scholar
  15. 15.
    Da Boit M, Sibson R, Sivasubramaniam S, Meakin JR, Greig CA, Aspden RM, Thies F, Jeromson S, Hamilton DL, Speakman JR, Hambly C, Mangoni AA et al. Sex differences in the effect of fish oil supplementation on the adaptive response to resistance exercise training in older people: a randomized control trial. Am J Clin Nutr. Nov 2016;16. doi: 10.3945/ajcn.116.140780.Google Scholar
  16. 16.
    Da Boit M, Sibson R, Meakin JR, Aspden RM, Thies F, Mangoni AA, Gray SR. Sex differences in the response to resistance exercise training in older people. Physiol Rep. Jun; 2016;4(12). doi: 10.14814/phy2.12834.Google Scholar
  17. 17.
    Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. Mar 1999;16;130(6):461–70. doi: 10.7326/0003-4819-130-6-199903160-00002.Google Scholar
  18. 18.
    Mangoni AA, Zinellu A, Carru C, Attia JR, Mc Evoy M. Transsulfuration pathway thiols and methylated arginines: the Hunter Community Study. PLoS One. 2013;8(1):e54870. doi: Scholar
  19. 19.
    Delmonico MJ, Harris TB, Visser M, Park SW, Conroy MB, Velasquez-Mieyer P, Boudreau R, Manini TM, Nevitt M, Newman AB, Goodpaster BH. Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am J Clin Nutr. Dec; 2009;90(6):1579–85. doi: 10.3945/ajcn.2009.28047.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Roshanravan B, Patel KV, Robinson-Cohen C, de Boer IH, O’Hare AM, Ferrucci L, Himmelfarb J, Kestenbaum B. Creatinine clearance, walking speed, and muscle atrophy: a cohort study. Am J Kidney Dis. May; 2015;65(5):737–47. doi: 10.1053/j.ajkd.2014.10.016.CrossRefPubMedGoogle Scholar
  21. 21.
    Wadham C, Mangoni AA. Dimethylarginine dimethylaminohydrolase regulation: a novel therapeutic target in cardiovascular disease. Expert Opin Drug Metab Toxicol. Mar; 2009;5(3):303–19. doi: 10.1517/17425250902785172.CrossRefGoogle Scholar
  22. 22.
    Jenkinson CP, Grody WW, Cederbaum SD. Comparative properties of arginases. Comp Biochem Physiol B Biochem Mol Biol. May; 1996;114(1):107–32.CrossRefGoogle Scholar
  23. 23.
    Caldwell RB, Toque HA, Narayanan SP, Caldwell RW. Arginase: an old enzyme with new tricks. Trends Pharmacol Sci. Jun; 2015;36(6):395–405. doi: 10.1016/ Scholar
  24. 24.
    Timmerman KL, Volpi E. Endothelial function and the regulation of muscle protein anabolism in older adults. Nutr Metab Cardiovasc Dis. Dec; 2013;23 Suppl 1:S44–50. doi: 10.1016/j.numecd.2012.03.013.CrossRefGoogle Scholar
  25. 25.
    Cullen ME, Yuen AH, Felkin LE, Smolenski RT, Hall JL, Grindle S, Miller LW, Birks EJ, Yacoub MH, Barton PJ. Myocardial expression of the arginine:glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis. Circulation. Jul 2006;4;114(1 Suppl):116–20. doi: 10.1161/CIRCULATIONAHA.105.000448.Google Scholar
  26. 26.
    Davids M, Ndika JD, Salomons GS, Blom HJ, Teerlink T. Promiscuous activity of arginine:glycine amidinotransferase is responsible for the synthesis of the novel cardiovascular risk factor homoarginine. FEBS Lett. Oct 2012;19;586(20):3653–7. doi: 10.1016/j.febslet.2012.08.020.CrossRefGoogle Scholar
  27. 27.
    Devries MC, Phillips SM. Creatine supplementation during resistance training in older adults-a meta-analysis. Med Sci Sports Exerc. Jun; 2014;46(6):1194–203. doi: 10.1249/MSS.0000000000000220.CrossRefGoogle Scholar
  28. 28.
    Atzler D, Appelbaum S, Cordts K, Ojeda FM, Wild PS, Munzel T, Blankenberg S, Böger RH, Blettner M, Beutel ME, Pfeiffer N, Zeller T, Lackner KJ, Schwedhelm E. Reference intervals of plasma homoarginine from the German Gutenberg Health Study. Clin Chem Lab Med. Jul 2016;1;54(7):1231–7. doi: 10.1515/cclm-2015-0785.Google Scholar
  29. 29.
    Hoberman HD, Sims EA, Engstrom WW. The effect of methyltestosterone on the rate of synthesis of creatine. J Biol Chem. Mar; 1948;173(1):111–6.Google Scholar
  30. 30.
    Bentur OS, Schwartz D, Chernichovski T, Ingbir M, Weinstein T, Chernin G, Schwartz IF. Estradiol augments while progesterone inhibits arginine transport in human endothelial cells through modulation of cationic amino acid transporter-1. Am J Physiol Regul Integr Comp Physiol. Aug 2015;15;309(4):R421–7. doi: 10.1152/ajpregu.00532.2014.CrossRefGoogle Scholar

Copyright information

© Serdi and Springer-Verlag France SAS, part of Springer Nature 2017

Authors and Affiliations

  • M. da Boit
    • 1
  • S. Tommasi
    • 2
  • D. Elliot
    • 2
  • A. Zinellu
    • 3
  • S. Sotgia
    • 3
  • R. Sibson
    • 4
  • J. R. Meakin
    • 5
  • R. M. Aspden
    • 4
  • C. Carru
    • 3
    • 6
  • A. A. Mangoni
    • 2
  • Stuart R. Gray
    • 7
    • 8
  1. 1.Department of Life SciencesUniversity of DerbyDerbyUK
  2. 2.Department of Clinical Pharmacology, School of MedicineFlinders UniversityAdelaideAustralia
  3. 3.Department of Biomedical SciencesUniversity of SassariSassariItaly
  4. 4.Institute of Medical SciencesUniversity of AberdeenAberdeenUK
  5. 5.Exeter MR Research CentreUniversity of ExeterExeterUK
  6. 6.Quality Control UnitUniversity Hospital (AOUSS)SassariItaly
  7. 7.Institute of Cardiovascular and Medical SciencesUniversity of GlasgowGlasgowUK
  8. 8.BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical SciencesUniversity of GlasgowScotlandUK

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