Abstract
Objective
To evaluate the causal effect of plasma omega-3 polyunsaturated fatty acids (PUFAs) on sarcopenia-related traits (lean mass, grip strength and walking pace) utilizing two-sample Mendelian randomization (MR) approach.
Methods
Based on genome-wide association study (GWAS) summary statistics, we performed two-sample MR applying the inverse variance weighted (IVW) as the primary method, supplemented with four additional sensitivity analyses. Furthermore, multivariable MR (MVMR) was applied to assess these associations independent of alcohol drinking, type 2 diabetes (T2D), triglycerides (TG), estimated glomerular filtration rate (eGFR) and C-reactive protein (CRP).
Results
In univariable MR, the IVW analysis suggested no significant causal effect of genetically determined plasma omega-3 PUFAs on fat-free mass (right leg: β = 0.01, 95% CI = −0.02 to 0.05, P = 0.375; left leg: β = 0.01, 95% CI = −0.02 to 0.04, P = 0.446; right arm: β = 0.01, 95% CI = −0.02 to 0.05, P = 0.376; left arm: β = 0.01, 95% CI = −0.02 to 0.04, P = 0.384; trunk:β = 0.02, 95% CI = −0.02 to 0.06, P = 0.283; whole: β = 0.01, 95% CI = −0.03 to 0.04, P = 0.631), grip strength (right hand: β = −0.01, 95% CI = −0.03 to 0.01, P = 0.387; left hand: β = −0.01, 95% CI = −0.02 to 0.01, P = 0.553) and walking pace (β = 0.00, 95% CI = −0.01 to 0.02, P = 0.575), and sensitive analysis generated similar non-significant results. Furthermore, the MVMR revealed no independent causal association.
Conclusions
Genetically determined plasma omega-3 PUFAs have no causal effect on sarcopenia-related traits.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout




Data availability
Data are available from the corresponding author upon reasonable request.
References
Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 2019;48:16–31.
Mayhew AJ, Amog K, Phillips S, Parise G, McNicholas PD, de Souza RJ, et al. The prevalence of sarcopenia in community-dwelling older adults, an exploration of differences between studies and within definitions: a systematic review and meta-analyses. Age Ageing. 2019;48:48–56.
Beaudart C, Rizzoli R, Bruyère O, Reginster JY, Biver E. Sarcopenia: burden and challenges for public health. Arch Public Health. 2014;72:45.
Morley JE, Argiles JM, Evans WJ, Bhasin S, Cella D, Deutz NE, et al. Nutritional recommendations for the management of sarcopenia. J Am Med Dir Assoc. 2010;11:391–6.
Ferguson EJ, Seigel JW, McGlory C. Omega-3 fatty acids and human skeletal muscle. Curr Opin Clin Nutr Metab Care. 2021;24:114–9.
Calder PC. Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans. 2017;45:1105–15.
Jeromson S, Mackenzie I, Doherty MK, Whitfield PD, Bell G, Dick J, et al. Lipid remodeling and an altered membrane-associated proteome may drive the differential effects of EPA and DHA treatment on skeletal muscle glucose uptake and protein accretion. Am J Physiol Endocrinol Metab. 2018;314:E605–19.
Dupont J, Dedeyne L, Dalle S, Koppo K, Gielen E. The role of omega-3 in the prevention and treatment of sarcopenia. Aging Clin Exp Res. 2019;31:825–36.
Zhang Y, Guo H, Liang J, Xiao W, Li Y. Relationship Between Dietary Omega-3 and Omega-6 Polyunsaturated Fatty Acids Level and Sarcopenia. A Meta-Analysis of Observational Studies. Front Nutr. 2021;8:738083.
Wong TC, Chen YT, Wu PY, Chen TW, Chen HH, Chen TH, et al. Ratio of Dietary n-6/n-3 Polyunsaturated fatty acids independently related to muscle mass decline in hemodialysis patients. PLoS One. 2015;10:e0140402.
de Branco FMS, Rossato LT, Rinaldi AEM, Azeredo CM, de Oliveira EP. Plasma omega-3 is not associated with appendicular muscle mass index in young and middle-aged individuals: Results from NHANES 2011-2012. Prostaglandins Leukot Ess Fat Acids. 2022;178:102412.
Bae YJ, Cui XS, Shin SH. Increased Omega-3 Fatty Acid Intake Is Associated with Low Grip Strength in Elderly Korean Females. Nutrients. 2022;14:2374.
Frison E, Boirie Y, Peuchant E, Tabue-Teguo M, Barberger-Gateau P, Féart C. Plasma fatty acid biomarkers are associated with gait speed in community-dwelling older adults: The Three-City-Bordeaux study. Clin Nutr. 2017;36:416–22.
Reinders I, Song X, Visser M, Eiriksdottir G, Gudnason V, Sigurdsson S, et al. Plasma phospholipid PUFAs are associated with greater muscle and knee extension strength but not with changes in muscle parameters in older adults. J Nutr. 2015;145:105–12.
Reinders I, Murphy RA, Song X, Visser M, Cotch MF, Lang TF, et al. Polyunsaturated fatty acids in relation to incident mobility disability and decline in gait speed; the Age, Gene/Environment Susceptibility-Reykjavik Study. Eur J Clin Nutr. 2015;69:489–93.
Lengelé L, Moehlinger P, Bruyère O, Locquet M, Reginster JY, Beaudart C. Association between Changes in Nutrient Intake and Changes in Muscle Strength and Physical Performance in the SarcoPhAge Cohort. Nutrients. 2020;12:3485.
Nilsson MI, Mikhail A, Lan L, Di Carlo A, Hamilton B, Barnard K, et al. A Five-Ingredient Nutritional Supplement and Home-Based Resistance Exercise Improve Lean Mass and Strength in Free-Living Elderly. Nutrients. 2020;12:2391.
Strandberg E, Edholm P, Ponsot E, Wåhlin-Larsson B, Hellmén E, Nilsson A, et al. Influence of combined resistance training and healthy diet on muscle mass in healthy elderly women: a randomized controlled trial. J Appl Physiol. 1985;2015:918–925.
Strike SC, Carlisle A, Gibson EL, Dyall SC. A High Omega-3 Fatty Acid Multinutrient Supplement Benefits Cognition and Mobility in Older Women: A Randomized, Double-blind, Placebo-controlled Pilot Study. J Gerontol A Biol Sci Med Sci. 2016;71:236–42.
Rolland Y, Barreto PS, Maltais M, Guyonnet S, Cantet C, Andrieu S, et al. Effect of Long-Term Omega 3 Polyunsaturated Fatty Acid Supplementation with or without Multidomain Lifestyle Intervention on Muscle Strength in Older Adults: Secondary Analysis of the Multidomain Alzheimer Preventive Trial (MAPT). Nutrients. 2019;11:1931.
Healy LA, Ryan A, Doyle SL, Bhuachalla ÉBN, Cushen S, Segurado R, et al. Does Prolonged Enteral Feeding With Supplemental Omega-3 Fatty Acids Impact on Recovery Post-esophagectomy: Results of a Randomized Double-Blind Trial. Ann Surg. 2017;266:720–8.
Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27:1133–63.
Smith GD, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32:1–22.
Staley JR, Blackshaw J, Kamat MA, Ellis S, Surendran P, Sun BB, et al. PhenoScanner: a database of human genotype-phenotype associations. Bioinformatics. 2016;32:3207–9.
Kettunen J, Demirkan A, Würtz P, Draisma HH, Haller T, Rawal R, et al. Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. Nat Commun. 2016;7:11122.
Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 2015;12:e1001779.
Visser M, Fuerst T, Lang T, Salamone L, Harris TB. Validity of fan-beam dual-energy X-ray absorptiometry for measuring fat-free mass and leg muscle mass. Health, Aging, and Body Composition Study-Dual-Energy X-ray Absorptiometry and Body Composition Working Group. J Appl Physiol. 1985;1999:1513–1520.
Roberts HC, Denison HJ, Martin HJ, Patel HP, Syddall H, Cooper C, et al. A review of the measurement of grip strength in clinical and epidemiological studies: towards a standardised approach. Age Ageing. 2011;40:423–9.
Wind AE, Takken T, Helders PJ, Engelbert RH. Is grip strength a predictor for total muscle strength in healthy children, adolescents, and young adults? Eur J Pediatr. 2010;169:281–7.
Xue A, Wu Y, Zhu Z, Zhang F, Kemper KE, Zheng Z, et al. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun. 2018;9:2941.
Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–83.
Pattaro C, Teumer A, Gorski M, Chu AY, Li M, Mijatovic V, et al. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Nat Commun. 2016;7:10023.
Ligthart S, Vaez A, Võsa U, Stathopoulou MG, de Vries PS, Prins BP, et al. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. Am J Hum Genet. 2018;103:691–706.
Glymour MM, Tchetgen Tchetgen EJ, Robins JM. Credible Mendelian randomization studies: approaches for evaluating the instrumental variable assumptions. Am J Epidemiol. 2012;175:332–9.
Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40:755–64.
Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44:512–25.
Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32:377–89.
Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016;40:304–14.
Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017;46:1985–98.
Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50:693–8.
Burgess S, Thompson SG. Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects. Am J Epidemiol. 2015;181:251–60.
Dalle S, Rossmeislova L, Koppo K. The Role of Inflammation in Age-Related Sarcopenia. Front Physiol. 2017;8:1045.
Gerling CJ, Mukai K, Chabowski A, Heigenhauser GJF, Holloway GP, Spriet LL, et al. Incorporation of Omega-3 Fatty Acids Into Human Skeletal Muscle Sarcolemmal and Mitochondrial Membranes Following 12 Weeks of Fish Oil Supplementation. Front Physiol. 2019;10:348.
Santo André HC, Esteves GP, Barreto GHC, Longhini F, Dolan E, Benatti FB. The Influence of n-3PUFA Supplementation on Muscle Strength, Mass, and Function: A Systematic Review and Meta-Analysis. Adv Nutr. 2023;14:115–27.
Cornish SM, Cordingley DM, Shaw KA, Forbes SC, Leonhardt T, Bristol A, et al. Effects of Omega-3 Supplementation Alone and Combined with Resistance Exercise on Skeletal Muscle in Older Adults: A Systematic Review and Meta-Analysis. Nutrients. 2022;14:2221.
Acknowledgements
We sincerely thank all investigators for sharing the genome-wide association studies (GWASs) summary statistic data.
Funding
This work was supported by Zhejiang Provincial Natural Science Foundation of China (Grant No. LY20H260001).
Author information
Authors and Affiliations
Contributions
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. LN (zhanglina@nbu.edu.cn), YF (fymaiyifeng@nbu.edu.cn) and HC (cenhan@nbu.edu.cn) had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conception and design: TJ, LN, YF, and HC; Acquisition of data: TJ, QM, ZZ, WM, and HC; Analysis and interpretation of data: TJ, QM, ZZ, WM, LN, YF, and HC.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Jin, T., Wang, M., Zeng, Z. et al. Causal associations of plasma omega-3 polyunsaturated fatty acids with sarcopenia-related traits: a two-sample Mendelian randomization study. Eur J Clin Nutr (2023). https://doi.org/10.1038/s41430-023-01339-y
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41430-023-01339-y