Skip to main content
SpringerLink
Log in

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

  • Published:
The journal of nutrition, health & aging

Abstract

Objectives

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.

Design

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

Setting

The study was carried out in a laboratory setting.

Participants

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

Intervention

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

Measurements

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.

Results

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).

Conclusion

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.

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

Similar content being viewed by others

References

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Stamler JS, Meissner G. Physiology of nitric oxide in skeletal muscle. Physiol Rev. Jan; 2001;81(1):209–37.

    Article  CAS  Google Scholar 

  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: https://doi.org/10.3109/00365519609090591.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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: https://doi.org/10.1161/01. ATV.0000128897.54893.26.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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. 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.

    Article  Google Scholar 

  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.

  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. 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. 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: https://doi.org/10.1371/journal.pone.0054870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  22. Jenkinson CP, Grody WW, Cederbaum SD. Comparative properties of arginases. Comp Biochem Physiol B Biochem Mol Biol. May; 1996;114(1):107–32.

    Article  CAS  Google Scholar 

  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/j.tips.2015.03.006.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    CAS  Google Scholar 

  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.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Life Sciences, University of Derby, Derby, UK

    M. da Boit

  2. Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide, Australia

    S. Tommasi, D. Elliot & A. A. Mangoni

  3. Department of Biomedical Sciences, University of Sassari, Sassari, Italy

    A. Zinellu, S. Sotgia & C. Carru

  4. Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK

    R. Sibson & R. M. Aspden

  5. Exeter MR Research Centre, University of Exeter, Exeter, UK

    J. R. Meakin

  6. Quality Control Unit, University Hospital (AOUSS), Sassari, Italy

    C. Carru

  7. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

    Stuart R. Gray

  8. BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland, G12 8TA, UK

    Stuart R. Gray

Authors
  1. M. da Boit
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Tommasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Elliot
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Zinellu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Sotgia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. Sibson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. R. Meakin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. M. Aspden
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. Carru
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A. A. Mangoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stuart R. Gray
    View author publications

    You can also search for this author in PubMed Google Scholar

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

da Boit, M., Tommasi, S., Elliot, D. et al. Sex Differences in the Associations between L-Arginine Pathway Metabolites, Skeletal Muscle Mass and Function, and their Responses to Resistance Exercise, in Old Age. J Nutr Health Aging 22, 534–540 (2018). https://doi.org/10.1007/s12603-017-0964-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12603-017-0964-6

Key words

Search

Navigation