The effect of long chain omega-3 polyunsaturated fatty acids on muscle mass and function in sarcopenia: A scoping systematic review and meta-analysis

Open AccessPublished:October 19, 2021DOI:https://doi.org/10.1016/j.clnesp.2021.10.011

      Summary

      Background & aims

      Sarcopenia is characterized by the progressive loss of skeletal muscle mass and function, which reduces mobility and quality of life. Risk factors for sarcopenia include advanced age, physical inactivity, obesity, and chronic diseases such as cancer or rheumatoid arthritis. Omega-3 long chain polyunsaturated fatty acids (LC PUFAs) might be associated with a reduction in risk of sarcopenia due to their anti-inflammatory effects.

      Methods

      We conducted a systematic review and meta-analysis to quantify the effects of omega-3 LC PUFAs on muscle mass, volume and function parameters. The National Library of Medicine's MEDLINE/PubMed database was searched on 9th October 2020 for randomized controlled trials that used omega-3 LC PUFAs as an intervention with muscle-related endpoints. A snowballing search to identify additional studies was completed on 23rd April 2021. The meta-analysis was conducted using meta-essentials worksheet 3. Bias was assessed using the Jadad scale.

      Results

      123 studies were identified with the systematic searches. Most studies were performed in disease populations, such as cancer or chronic obstructive pulmonary disease (COPD), or in healthy individuals after a fatiguing exercise bout. The endpoints lean body mass, skeletal muscle mass, mid-arm muscle circumference, handgrip strength, quadriceps maximal voluntary capacity (MVC), and 1-repetition maximum chest press were selected for meta-analysis based on the number of available studies; thus 66 studies were included in the quantitative synthesis. Using a random effects model and 2-tailed p-value, there was a significant relationship in favor of omega-3 LC PUFA supplementation for lean body mass (effect size 0.27, 95%CI 0.04 to 0.51), skeletal muscle mass (effect size 0.31, 95%CI 0.01 to 0.60) and quadriceps MVC (effect size 0.47, 95%CI 0.02 to 0.93).

      Conclusion

      The results indicate that there is a positive effect of omega-3 LC PUFA supplementation on overall body muscle mass and strength. Small study size and heterogeneity limit the applicability of these findings for sarcopenia prevention. Larger trials in populations at risk of sarcopenia would strengthen the evidence base.

      Keywords

      1. Introduction

      Muscle mass and function are essential to good health and quality of life. A number of conditions can result in loss of muscle and its quality and function, including sarcopenia, cachexia, and muscle disuse atrophy. Sarcopenia has been defined as “a progressive and generalized skeletal muscle disorder that is associated with increased likelihood of adverse outcomes including falls, fractures, physical disability and mortality” [
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • Boirie Y.
      • Bruyere O.
      • Cederholm T.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      ]. Sarcopenia is considered primarily a disease of aging and is characterized by the progressive loss of skeletal muscle mass and function. Secondary sarcopenia can be classified according to causes related to inactivity, disease or malnutrition [
      • Cruz-Jentoft A.J.
      • Baeyens J.P.
      • Bauer J.M.
      • Boirie Y.
      • Cederholm T.
      • Landi F.
      • et al.
      Sarcopenia: European consensus on definition and diagnosis: report of the European working group on sarcopenia in older people.
      ]. Inactivity from extended bed rest, a sedentary lifestyle, or zero gravity causes a rapid decline in muscle mass and quality, and a loss of muscle function. Diseases that are associated with sarcopenia have a strong inflammatory component and include cancer and its treatment, chronic obstructive pulmonary disease (COPD), heart failure and type 2 diabetes mellitus [
      • Kim S.H.
      • Shin M.J.
      • Shin Y.B.
      • Kim K.U.
      Sarcopenia associated with chronic obstructive pulmonary disease.
      ].
      Sarcopenia is associated with a decline in functional capacity of the muscle, which leads to physical disability, lower quality of life, and an increased risk of death [
      • Santilli V.
      • Bernetti A.
      • Mangone M.
      • Paoloni M.
      Clinical definition of sarcopenia.
      ]. Patients with sarcopenia cause significantly higher healthcare costs related to longer hospital stays and a greater need for residential living facilities [
      • Mijnarends D.M.
      • Schols J.M.G.A.
      • Halfens R.J.G.
      • Meijers J.M.M.
      • Luiking Y.C.
      • Verlaan S.
      • et al.
      Burden-of-illness of Dutch community-dwelling older adults with sarcopenia: health related outcomes and costs.
      ,
      • Bruyère O.
      • Beaudart C.
      • Ethgen O.
      • Reginster J.-Y.
      • Locquet M.
      The health economics burden of sarcopenia: a systematic review.
      ]. Events such as falls are more likely in patients with sarcopenia, who frequently also have immune system dysfunctions and hence have an increased risk for infection especially after surgery [
      • Nelke C.
      • Dziewas R.
      • Minnerup J.
      • Meuth S.G.
      • Ruck T.
      Skeletal muscle as potential central link between sarcopenia and immune senescence.
      ]. Sarcopenia ultimately increases healthcare expenditure across different care settings [
      • Norman K.
      • Otten L.
      Financial impact of sarcopenia or low muscle mass - a short review.
      ].
      The latest working group operational definition of sarcopenia from 2019 primarily uses low muscle strength to identify probable sarcopenia, and low muscle quantity or quality is required for a diagnosis [
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • Boirie Y.
      • Bruyere O.
      • Cederholm T.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      ]. The new criteria mark a shift from prior definitions of sarcopenia with low skeletal muscle mass and a measure of muscle function (for example, walking speed) or additionally muscle strength, particularly handgrip strength being used for diagnosis [
      • Santilli V.
      • Bernetti A.
      • Mangone M.
      • Paoloni M.
      Clinical definition of sarcopenia.
      ]. Due to technological limitations in measuring muscle quantity and quality, muscle strength was now considered a more reliable indicator of sarcopenia [
      • Cruz-Jentoft A.J.
      • Bahat G.
      • Bauer J.
      • Boirie Y.
      • Bruyere O.
      • Cederholm T.
      • et al.
      Sarcopenia: revised European consensus on definition and diagnosis.
      ].
      Studies in community-dwelling older adults show sarcopenia prevalence is approximately 10% [
      • Mayhew A.J.
      • Amog K.
      • Phillips S.
      • Parise G.
      • McNicholas P.D.
      • de Souza R.J.
      • 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.
      ,
      • Shafiee G.
      • Keshtkar A.
      • Soltani A.
      • Ahadi Z.
      • Larijani B.
      • Heshmat R.
      Prevalence of sarcopenia in the world: a systematic review and meta- analysis of general population studies.
      ,
      • Makizako H.
      • Nakai Y.
      • Tomioka K.
      • Taniguchi Y.
      Prevalence of sarcopenia defined using the Asia Working Group for Sarcopenia criteria in Japanese community-dwelling older adults: a systematic review and meta-analysis.
      ]. Hospitalized and institutionalized older adults have an even higher prevalence of sarcopenia [
      • Shen Y.
      • Chen J.
      • Chen X.
      • Hou L.
      • Lin X.
      • Yang M.
      Prevalence and associated factors of sarcopenia in nursing home residents: a systematic review and meta-analysis.
      ,
      • Papadopoulou S.K.
      • Tsintavis P.
      • Potsaki P.
      • Papandreou D.
      Differences in the prevalence of sarcopenia in community-dwelling, nursing home and hospitalized individuals. A systematic review and meta-analysis.
      ,
      • Ligthart-Melis G.C.
      • Luiking Y.C.
      • Kakourou A.
      • Cederholm T.
      • Maier A.B.
      • de van der Schueren M.A.E.
      Frailty, sarcopenia, and malnutrition frequently (Co-)occur in hospitalized older adults: a systematic review and meta-analysis.
      ]. Comprehensive studies show that sarcopenia prevalence increases with age and can vary by sex. For example, in a nutritional survey conducted in the US of 4984 adults aged over 60 years, sarcopenia prevalence was lower in males than females, with a significantly higher prevalence in those aged over 80 years compared to younger age groups [
      • Batsis J.A.
      • Mackenzie T.A.
      • Lopez-Jimenez F.
      • Bartels S.J.
      Sarcopenia, sarcopenic obesity, and functional impairments in older adults: National Health and Nutrition Examination Surveys 1999-2004.
      ]. Assessment of general sarcopenia prevalence in free-living or patient populations is hampered by the sarcopenia definition and measurement instrument used, which can estimate widely variable prevalence within the same population [
      • Liu X.
      • Hou L.
      • Zhao W.
      • Xia X.
      • Hu F.
      • Zhang G.
      • et al.
      The comparison of sarcopenia diagnostic criteria using AWGS 2019 with the other five criteria in West China.
      ].
      While the precise mechanisms whereby progressive muscle loss occurs are not yet fully understood, it is believed to be a multi-factorial process with a range of causes. Five main factors are believed to be involved in the development of sarcopenia [
      • Liguori I.
      • Russo G.
      • Aran L.
      • Bulli G.
      • Curcio F.
      • Della-Morte D.
      • et al.
      Sarcopenia: assessment of disease burden and strategies to improve outcomes.
      ]:
      • 1.
        Neuromuscular degeneration
      • 2.
        Changes in muscle protein turnover
      • 3.
        Changes in hormone levels and sensitivity
      • 4.
        Chronic inflammation and oxidative stress
      • 5.
        Behavior and lifestyle factors
      Neuromuscular degeneration involves related processes of muscle fiber atrophy, a decrease in the number of alpha-motor neurons, the replacement of muscle by fibrous connective tissue, and the infiltration of muscle tissue with adipocytes [
      • Liguori I.
      • Russo G.
      • Aran L.
      • Bulli G.
      • Curcio F.
      • Della-Morte D.
      • et al.
      Sarcopenia: assessment of disease burden and strategies to improve outcomes.
      ,
      • Carlson B.M.
      The biology of long-term denervated skeletal muscle.
      ]. Skeletal muscle undergoes repeated cycles of denervation and enervation during adult life. Structural changes to the neuromuscular junction lead to enervation failure and the gradual increase in permanently denervated muscle fibers [
      • Aare S.
      • Spendiff S.
      • Vuda M.
      • Elkrief D.
      • Perez A.
      • Wu Q.
      • et al.
      Failed reinnervation in aging skeletal muscle.
      ,
      • Anagnostou M.E.
      • Hepple R.T.
      Mitochondrial mechanisms of neuromuscular junction degeneration with aging.
      ]. Preferential atrophy of fast-twitch (type II) muscle fibers due to aging is thought to be primarily responsible for a loss of function and strength [
      • Wiedmer P.
      • Jung T.
      • Castro J.P.
      • Pomatto L.C.D.
      • Sun P.Y.
      • Davies K.J.A.
      • et al.
      Sarcopenia - molecular mechanisms and open questions.
      ].
      The balance between muscle protein synthesis and degradation affects overall turnover. While this allows adaptation to changes in nutrition, metabolism and physical activity, poor homeostasis, which results from a reduction in protein synthesis and a shift towards proteolysis, is believed to contribute to muscle loss in aging [
      • Wiedmer P.
      • Jung T.
      • Castro J.P.
      • Pomatto L.C.D.
      • Sun P.Y.
      • Davies K.J.A.
      • et al.
      Sarcopenia - molecular mechanisms and open questions.
      ]. Both increased muscle protein degradation and a blunted anabolic response to stimuli such as hyperinsulinemia are thought to contribute to sarcopenia [
      • Liguori I.
      • Russo G.
      • Aran L.
      • Bulli G.
      • Curcio F.
      • Della-Morte D.
      • et al.
      Sarcopenia: assessment of disease burden and strategies to improve outcomes.
      ].
      Insulin-like growth factor 1 (IGF-1) is, besides insulin, the main anabolic signaling molecule. Muscle hypertrophy and protein synthesis is stimulated by the binding of IGF-1 and insulin to their receptors in the muscle cell membrane, activating the phosphatidylinositide 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway, initiating the anabolic process. Muscle protein synthesis can also be stimulated via activation of mTOR complex 1 by amino acids. In addition, insulin has a direct effect on muscle cells, stimulating their growth as well as the uptake of glucose. Myocytes become less sensitive to the anabolic effects of insulin as they age [
      • Wiedmer P.
      • Jung T.
      • Castro J.P.
      • Pomatto L.C.D.
      • Sun P.Y.
      • Davies K.J.A.
      • et al.
      Sarcopenia - molecular mechanisms and open questions.
      ]. Exercise is another strong stimulant for muscle protein synthesis, acting through multiple pathways including the mTOR pathway, as reviewed elsewhere [
      • McGlory C.
      • Devries M.C.
      • Phillips S.M.
      Skeletal muscle and resistance exercise training; the role of protein synthesis in recovery and remodeling.
      ].
      Muscle wasting diseases are linked to inflammation. It is assumed that chronic, low-grade inflammation tends to increase due to aging, while chronic or serious disease and their treatments can cause an inflammatory cascade. Elevated concentrations of pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor-necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) link inflammation to change that occurs in aging [
      • Nelke C.
      • Dziewas R.
      • Minnerup J.
      • Meuth S.G.
      • Ruck T.
      Skeletal muscle as potential central link between sarcopenia and immune senescence.
      ]. For example, IL-6 and TNF-α contribute to a reduced effect of insulin on protein synthesis by interfering with the insulin signaling cascade [
      • Franceschi C.
      • Campisi J.
      Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.
      ].
      Both nutrition and physical activity impact sarcopenia by regulating muscle (protein) turnover, singularly and together [
      • Cruz-Jentoft A.J.
      • Landi F.
      • Schneider S.M.
      • Zuniga C.
      • Arai H.
      • Boirie Y.
      • et al.
      Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS).
      ]. Short or extended periods of inactivity or low food, especially protein, intake will encourage muscle atrophy, while adequate nutrient intakes in conjunction with physical activity will stimulate increases in muscle mass [
      • Liguori I.
      • Russo G.
      • Aran L.
      • Bulli G.
      • Curcio F.
      • Della-Morte D.
      • et al.
      Sarcopenia: assessment of disease burden and strategies to improve outcomes.
      ]. Thus a central role for exercise in preventing sarcopenia and muscle senescence is suggested [
      • Nelke C.
      • Dziewas R.
      • Minnerup J.
      • Meuth S.G.
      • Ruck T.
      Skeletal muscle as potential central link between sarcopenia and immune senescence.
      ]. Protein and amino acid intake during a meal will promote an anabolic response to improve or maintain muscle mass [
      • Baum J.I.
      • Kim I.-Y.
      • Wolfe R.R.
      Protein consumption and the elderly: what is the optimal level of intake?.
      ]. Protein intake recommendations for elderly individuals vary but are generally considered to be higher than for younger individuals [
      • Baum J.I.
      • Kim I.-Y.
      • Wolfe R.R.
      Protein consumption and the elderly: what is the optimal level of intake?.
      ]. Both, protein intake and exercise also affect the sensitivity of cells to insulin, and are linked directly and indirectly to inflammation. For example, the transient increase in reactive oxidative species from exercise causes an adaptive anti-inflammatory response that has a net effect of reducing chronic inflammation [
      • Kolodziej F.
      • O'Halloran K.D.
      Re-evaluating the oxidative phenotype: can endurance exercise save the western world?.
      ]. Exercise also assists in creating an energy deficit that could indirectly reduce chronic inflammation through a reduction in body adipose tissue mass [
      • Kolodziej F.
      • O'Halloran K.D.
      Re-evaluating the oxidative phenotype: can endurance exercise save the western world?.
      ].

      1.1 Omega-3 LC PUFA and effects on mechanisms of sarcopenia

      The main bioactive omega-3 LC PUFAs are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are present in seafood and in the oil extracted from seafood (“fish oil”), as well as in krill oil and some algal oils [
      • Calder P.C.
      Very long-chain n-3 fatty acids and human health: fact, fiction and the future.
      ]. EPA and DHA can also be bio-synthesised from alpha-linolenic acid (ALA) which is found in many foods of plant origin, but this conversion process is considered to be poor in humans [
      • Baker E.J.
      • Miles E.A.
      • Burdge G.C.
      • Yaqoob P.
      • Calder P.C.
      Metabolism and functional effects of plant-derived omega-3 fatty acids in humans.
      ]. The main sources of EPA and DHA in the diet include fish and seafood, fortified foods, and dietary supplements. For patients with sarcopenia, fish oils can be incorporated into oral nutrition supplements and enteral feeds. Once consumed, EPA and DHA are incorporated into cell membranes, including inflammatory immune cells [
      • Calder P.C.
      Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance.
      ,
      • Calder P.C.
      Omega-3 fatty acids and inflammatory processes: from molecules to man.
      ,
      • Calder P.C.
      N-3 PUFA and inflammation: from membrane to nucleus and from bench to bedside.
      ] and the sarcolemma of skeletal muscle fibers [
      • Smith G.I.
      • Atherton P.
      • Reeds D.N.
      • Mohammed B.S.
      • Rankin D.
      • Rennie M.J.
      • et al.
      Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia-hyperaminoacidaemia in healthy young and middle-aged men and women.
      ,
      • McGlory C.
      • Galloway S.D.
      • Hamilton D.L.
      • McClintock C.
      • Breen L.
      • Dick J.R.
      • et al.
      Temporal changes in human skeletal muscle and blood lipid composition with fish oil supplementation.
      ]. This incorporation is linked to their biological activity in the regulation of inflammation [
      • Calder P.C.
      Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance.
      ,
      • Calder P.C.
      Omega-3 fatty acids and inflammatory processes: from molecules to man.
      ,
      • Calder P.C.
      N-3 PUFA and inflammation: from membrane to nucleus and from bench to bedside.
      ]. EPA and DHA reduce the production of inflammatory eicosanoids (prostaglandins, thromboxanes, leukotrienes) from the omega-6 PUFA arachidonic acid [
      • Calder P.C.
      Eicosanoids.
      ] and act as substrates for production of alternative chemical mediators that down-regulate (resolve) inflammation (resolvins, protectins, maresins) [
      • Serhan C.N.
      • Chiang N.
      Resolution phase lipid mediators of inflammation: agonists of resolution.
      ,
      • Serhan C.N.
      • Chiang N.
      • Dalli J.
      The resolution code of acute inflammation: novel pro-resolving lipid mediators in resolution.
      ,
      • Serhan C.N.
      Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology.
      ]. Through these, and other membrane-mediated events, EPA and DHA alter both intracellular and intercellular signals. Within cells this leads to altered patterns of inflammatory gene expression and protein production [
      • Calder P.C.
      Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance.
      ,
      • Calder P.C.
      Omega-3 fatty acids and inflammatory processes: from molecules to man.
      ,
      • Calder P.C.
      N-3 PUFA and inflammation: from membrane to nucleus and from bench to bedside.
      ]. The net result is decreased production of inflammatory cytokines, chemokines, adhesion molecules, proteases and enzymes related to inflammation [
      • Calder P.C.
      Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance.
      ,
      • Calder P.C.
      Omega-3 fatty acids and inflammatory processes: from molecules to man.
      ,
      • Calder P.C.
      N-3 PUFA and inflammation: from membrane to nucleus and from bench to bedside.
      ]. The anti-inflammatory and inflammation resolving effects of EPA and DHA are relevant to both prevention and treatment of muscle wasting [
      • McGlory C.
      • Galloway S.D.
      • Hamilton D.L.
      • McClintock C.
      • Breen L.
      • Dick J.R.
      • et al.
      Temporal changes in human skeletal muscle and blood lipid composition with fish oil supplementation.
      ].
      The aim of this systematic review was to identify the effects of omega-3 LC PUFAs on endpoints related to muscle mass and muscle function (described in Table 1).
      Table 1Clinical endpoints related to muscle mass and muscle function.
      Lean body mass
      Lean body mass (LBM), also called fat free mass, is the difference between total body weight and body fat weight. It provides only an approximate estimate of muscle mass because the weight of organs and bone is also included in this measure. LBM is measured using dual-energy x-ray absorptiometry (DEXA), magnetic resonance imaging (MRI) or bioelectrical impedance analysis (BIA).
      Skeletal muscle mass
      Skeletal muscle mass (SMM) is a more sensitive indicator of body functional muscle mass than lean body mass. International definitions of sarcopenia relate to a loss of SMM [
      • Cruz-Jentoft A.J.
      • Landi F.
      • Schneider S.M.
      • Zuniga C.
      • Arai H.
      • Boirie Y.
      • et al.
      Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS).
      ]. SMM is measured using DEXA, MRI, computed tomography (CT) or BIA, with MRI and CT being the gold standards because they can measure muscle tissue more accurately than other techniques [
      • Liguori I.
      • Russo G.
      • Aran L.
      • Bulli G.
      • Curcio F.
      • Della-Morte D.
      • et al.
      Sarcopenia: assessment of disease burden and strategies to improve outcomes.
      ]. However, DEXA has become more popular in the last decade through its ease of use, lower cost and radiation exposure, and wider availability [
      • Clark B.C.
      • Tavoian D.
      • Goodpaster B.H.
      • Cawthon P.M.
      • Hansen R.D.
      • Manini T.M.
      Comment on: "Pitfalls in the measurement of muscle mass: a need for a reference standard" by Buckinx et al.
      ].
      Mid-Arm Muscle Circumference
      Mid-arm muscle circumference (MAMC) is a measure of somatic protein reserves, and therefore estimates the quantity of fat and muscle mass in the body [
      • Tian X.
      • Chen Y.
      • Yang Z.K.
      • Qu Z.
      • Dong J.
      Novel equations for estimating lean body mass in patients with chronic kidney disease.
      ,
      • Lambell K.J.
      • Earthman C.P.
      • Tierney A.C.
      • Goh G.S.
      • Forsyth A.
      • King S.J.
      How does muscularity assessed by bedside methods compare to computed tomography muscle area at intensive care unit admission? A pilot prospective cross-sectional study.
      ]. The measure is based on several assumptions for its reliability. It is assumed that the circumference of the upper arm is representative for the rest of the body; however unequal fat distribution throughout the body may affect the measure's predictability. Conditions that cause swelling in the upper body such as oedema affect the measurement, as does immobility. The measurement is simple to perform using a tape measure.
      Handgrip strength
      A useful functional marker of muscle function is handgrip strength, which predicts the ability to perform everyday activities. Handgrip strength peaks around the age of 40 years and thereafter declines, and is a good predictor of age-related functional outcomes [
      • Massy-Westropp N.M.
      • Gill T.K.
      • Taylor A.W.
      • Bohannon R.W.
      • Hill C.L.
      Hand Grip Strength: age and gender stratified normative data in a population-based study.
      ]. A dynamometer measures static force exerted by the hand, and a standardized protocol is available to position subjects for repeated measures [
      • Massy-Westropp N.M.
      • Gill T.K.
      • Taylor A.W.
      • Bohannon R.W.
      • Hill C.L.
      Hand Grip Strength: age and gender stratified normative data in a population-based study.
      ]. Handgrip strength is considered to be a robust measure, even with different assessors or dynamometers. The measurement device is portable and low-cost, and it can be implemented in large studies and surveys.
      Quadriceps Maximal Voluntary Capacity
      Various strength tests are available that estimate the functional capacity of skeletal muscle. Gait, balance and mobility require adequate lower limb strength, which can be measured using the quadriceps maximal voluntary capacity (MVC). Quadriceps MVC appears to decline at a greater rate than handgrip strength across the spectrum of aging [
      • Samuel D.
      • Wilson K.
      • Martin H.J.
      • Allen R.
      • Sayer A.A.
      • Stokes M.
      Age-associated changes in hand grip and quadriceps muscle strength ratios in healthy adults.
      ]. A strength testing chair is used for the test, which can be applied to measure both knee extensors and flexors, although the quadriceps are responsible for knee extension.
      1-Repetition Maximum Chest Press
      The 1-repetition maximum (1RM) chest press is a measure of the strength of the chest muscles [
      • Niewiadomski W.
      • Laskowska D.
      • Gąsiorowska A.
      • Cybulski G.
      • Strasz A.
      • Langfort J.
      Determination and prediction of one repetition maximum (1RM): safety considerations.
      ]. It is defined as the maximum weight a subject can press with one repetition using a barbell lying in a supine position on a horizontal bench. While the predictive value of the measurement has not been investigated often in regards to sarcopenia, it is considered to be a gold standard measurement of muscle strength [
      • Dos Santos W.
      • Siqueira G.
      • Martins W.
      • Vieira A.
      • Schincaglia R.
      • Gentil P.
      • et al.
      Reliability and agreement of the 10-repetition maximum test in breast cancer survivors.
      ]. Strength training programs can be tailored to individuals' strength as a percentage of the 1RM chest press, which is important for exercise in older adults [
      • Fragala M.S.
      • Cadore E.L.
      • Dorgo S.
      • Izquierdo M.
      • Kraemer W.J.
      • Peterson M.D.
      • et al.
      Resistance training for older adults: position statement from the National Strength and Conditioning Association.
      ].

      2. Materials & methods

      2.1 Data sources and searching strategy

      The National Library of Medicine's MEDLINE/PubMed database was searched for primary research articles reporting clinical trials or potentially relevant observational studies reporting relationships between omega-3 LC PUFA supplementation and a measure of muscle strength, function, volume, fatigue or quality. The search terms were “omega-3 and muscle”. As this was an exploratory review, search filters were not applied. The search was conducted on 9th October 2020. The searching strategy was not registered as it was a scoping systematic review, which are recommended not to be registered [
      ]. Articles were assessed for inclusion based on being a clinical study performed using an omega-3 supplement, and including a muscle-related endpoint, and the decision recorded in a Microsoft Excel spreadsheet. The initial screening was performed by JB. After screening abstracts of potentially relevant articles, the full-text was accessed for inclusion into the meta-analysis. A snowballing search of the reference lists of included articles was conducted to identify further articles that may have been missed in the MEDLINE/PubMed search [
      • Lam C.N.
      • Watt A.E.
      • Isenring E.A.
      • de van der Schueren M.A.E.
      • van der Meij B.S.
      The effect of oral omega-3 polyunsaturated fatty acid supplementation on muscle maintenance and quality of life in patients with cancer: a systematic review and meta-analysis.
      ]. The snowballing search was conducted by JB, BT and IW, and the results logged in a Microsoft Excel spreadsheet. The snowballing search was completed on 23rd April 2021.

      2.2 Data extraction and quality assessment

      The Jadad scale was used to assess study quality at the individual study level [
      • Jadad A.R.
      • Moore R.A.
      • Carroll D.
      • Jenkinson C.
      • Reynolds D.J.
      • Gavaghan D.J.
      • et al.
      Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
      ]. A five-point score was assigned to each study based on blinding, randomization, and reporting of dropouts. Studies that had a score of 4 or 5 had a low risk of bias, whereas those with scores of 3 or less were considered to be at high risk of bias. Study meta-data included number of participants, intervention type, dose, control type, study population information (adult/elderly, healthy/diseased), and intervention length. Potentially relevant endpoints fell under the following topics: muscle fatigue, muscle volume, muscle strength, muscle quality, and inflammation marker (see Supplemental Table 2 for the list of endpoints extracted). At this stage, the categories muscle fatigue and muscle quality were taken out of the analysis because the low number of studies and diverse endpoints precluded meta-analysis. Inflammation markers were also removed as they could not be adequately included as an explanatory variable in the meta-analysis at the study level. Information extracted related to the endpoints included the number of subjects in each intervention group, the change in parameter from baseline for all intervention groups, or mean difference, and standard deviation.

      2.3 Data synthesis and statistical analysis

      Based on the number of studies obtained for each endpoint, a meta-analysis was conducted for LBM, SMM, mid-arm muscle circumference, handgrip strength, quadriceps MVC and 1RM chest press using the Meta Essentials worksheet 3 for continuous data, which allows for the use of raw data (means, standard deviations and sample size) or for tests of differences to be used [
      • Suurmond R.
      • van Rhee H.
      • Hak T.
      Introduction, comparison, and validation of meta-essentials: a free and simple tool for meta-analysis.
      ]. We used the change in parameters between the final measurement and baseline. For studies that included a fatiguing exercise bout or had planned surgery as part of the study design, we included data comparing the parameter change after supplementation between baseline and before the event to avoid the effect of acute inflammation on the parameter in question. For all analyses, standardized mean differences are reported. We used the random effects model, two-sided p-value and Hedge's g measure of effect size to give a more conservative estimate for the meta-analysis. Analyses were performed to determine the effect of healthy/disease subgroups and adult/elderly sub-groups, and dose. Publication bias in the meta-analysis was assessed by visually inspecting the funnel plot and heterogeneity with the I2 statistic. When the funnel plot indicated that certain studies were outliers, their effect was investigated by removing them from the meta-analysis to determine the effect on the outcome as a sensitivity analysis.

      3. Results

      We identified 1933 abstracts, of which 1823 were excluded, leaving 110 articles for potential inclusion. 18 articles were excluded after assessment of the full text (9 observational studies, 8 with non-relevant endpoints, one non-English article). From the 92 included articles, a snowball search was conducted, which identified a further 31 articles. These 123 articles underwent a bias assessment. Four articles were found to report sub-studies of studies already included. Thus, 119 articles were included in the qualitative assessment. After studies with endpoints in the categories muscle fatigue, muscle quality and inflammation were removed, 66 articles were selected for quantitative synthesis (meta-analysis) and are listed in Supplemental Table 1. The results of the article selection process are presented in a PRISMA flow chart (Fig. 1).
      Fig. 1
      Fig. 1PRISMA flow diagram of study inclusion.

      3.1 Lean body mass

      We found 35 articles reporting the results of intervention studies with omega-3 LC PUFAs and lean body mass (measured in kg). 8 studies were excluded: one study did not have a control group without omega-3 LC PUFAs [
      • Cerchietti L.C.
      • Navigante A.H.
      • Castro M.A.
      Effects of eicosapentaenoic and docosahexaenoic n-3 fatty acids from fish oil and preferential Cox-2 inhibition on systemic syndromes in patients with advanced lung cancer.
      ], four did not report LBM at both baseline and end of the intervention [
      • Edholm P.
      • Strandberg E.
      • Kadi F.
      Lower limb explosive strength capacity in elderly women: effects of resistance training and healthy diet.
      ,
      • Haugaard S.B.
      • Vaag A.
      • Mu H.
      • Madsbad S.
      Skeletal muscle structural lipids improve during weight-maintenance after a very low calorie dietary intervention.
      ,
      • Lalia A.Z.
      • Dasari S.
      • Robinson M.M.
      • Abid H.
      • Morse D.M.
      • Klaus K.A.
      • et al.
      Influence of omega-3 fatty acids on skeletal muscle protein metabolism and mitochondrial bioenergetics in older adults.
      ,
      • Deger S.M.
      • Hung A.M.
      • Ellis C.D.
      • Booker C.
      • Bian A.
      • Chen G.
      • et al.
      High dose omega-3 fatty acid administration and skeletal muscle protein turnover in maintenance hemodialysis patients.
      ], one reported LBM in g/kg body weight [
      • Rodriguez-Cruz M.
      • Atilano-Miguel S.
      • Barbosa-Cortes L.
      • Bernabe-Garcia M.
      • Almeida-Becerril T.
      • Cardenas-Conejo A.
      • et al.
      Evidence of muscle loss delay and improvement of hyperinsulinemia and insulin resistance in Duchenne muscular dystrophy supplemented with omega-3 fatty acids: a randomized study.
      ], one did not include a measure of variability [
      • Aoyama T.
      • Yoshikawa T.
      • Ida S.
      • Cho H.
      • Sakamaki K.
      • Ito Y.
      • et al.
      Effects of perioperative Eicosapentaenoic acid-enriched oral nutritional supplement on lean body mass after total gastrectomy for gastric cancer.
      ], and one reported change as a beta-coefficient [
      • van der Meij B.S.
      • Langius J.A.
      • Smit E.F.
      • Spreeuwenberg M.D.
      • von Blomberg B.M.
      • Heijboer A.C.
      • et al.
      Oral nutritional supplements containing (n-3) polyunsaturated fatty acids affect the nutritional status of patients with stage III non-small cell lung cancer during multimodality treatment.
      ]. One study reported results separately for males and females [
      • Cornish S.M.
      • Chilibeck P.D.
      Alpha-linolenic acid supplementation and resistance training in older adults.
      ], and another included two different omega-3 LC PUFA doses [
      • Fearon K.C.
      • Barber M.D.
      • Moses A.G.
      • Ahmedzai S.H.
      • Taylor G.S.
      • Tisdale M.J.
      • et al.
      Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia.
      ] and results were therefore analyzed along these strata in the meta-analysis. Thus, 29 comparisons were included in total. Studies were conducted in both healthy and diseased groups, most commonly patients with cancer. Reported dosing ranged from 600 to 4000 mg per day EPA plus DHA. One study used high dose ALA as the intervention [
      • Cornish S.M.
      • Chilibeck P.D.
      Alpha-linolenic acid supplementation and resistance training in older adults.
      ], and in one study omega-3 LC PUFAs were part of a multi-ingredient supplement that included whey protein, creatine, calcium and vitamin D [
      • Snijders T.
      • Bell K.E.
      • Nederveen J.P.
      • Saddler N.I.
      • Mazara N.
      • Kumbhare D.A.
      • et al.
      Ingestion of a multi-ingredient supplement does not alter exercise-induced satellite cell responses in older men.
      ]. Another study compared two doses containing a different ratio of omega-3 LC PUFAs; therefore, the dose reported in Table 2 is the difference between the low and high dose of omega-3 LC PUFAs [
      • de Luis D.A.
      • Izaola O.
      • Aller R.
      • Cuellar L.
      • Terroba M.C.
      A randomized clinical trial with oral Immunonutrition (omega3-enhanced formula vs. arginine-enhanced formula) in ambulatory head and neck cancer patients.
      ]. A cluster of studies used an oral nutritional supplement including 2200 mg EPA [
      • Hanai N.
      • Terada H.
      • Hirakawa H.
      • Suzuki H.
      • Nishikawa D.
      • Beppu S.
      • et al.
      Prospective randomized investigation implementing immunonutritional therapy using a nutritional supplement with a high blend ratio of ω-3 fatty acids during the perioperative period for head and neck carcinomas.
      ,
      • Healy L.A.
      • Ryan A.
      • Doyle S.L.
      • Éb N.B.
      • 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.
      ,
      • Moses A.W.
      • Slater C.
      • Preston T.
      • Barber M.D.
      • Fearon K.C.
      Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids.
      ,
      • Ryan A.M.
      • Reynolds J.V.
      • Healy L.
      • Byrne M.
      • Moore J.
      • Brannelly N.
      • et al.
      Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: results of a double-blinded randomized controlled trial.
      ,
      • Sánchez-Lara K.
      • Turcott J.G.
      • Juárez-Hernández E.
      • Nuñez-Valencia C.
      • Villanueva G.
      • Guevara P.
      • et al.
      Effects of an oral nutritional supplement containing eicosapentaenoic acid on nutritional and clinical outcomes in patients with advanced non-small cell lung cancer: randomised trial.
      ]; this supplement also includes DHA (785 or 1100 mg depending upon the region) but this is often not specified [
      Abbott Laboratories
      Prosure datasheet version 7.
      ]. In total, 2101 subjects were included in the meta-analysis. Due to the relatively large number of participants, no study contributed more than 4% to the overall results. Results were derived from studies at both low and high risk of bias (Table 2).
      Table 2Included studies reporting on lean body mass (LBM).
      Study first author & yearIntervention: Change in LBM, mean (SE)Control: Change in LBM, mean (SE)Difference: Intervention- controlWeighting in the meta-analysisSubgroup studiedReported omega-3 PUFA dose (/day)Bias riskRef.
      Calder 20180.07 (0.14)−0.03 (0.15)3.47%COPD2000 mg EPA + DHALow[
      • Calder P.C.
      • Laviano A.
      • Lonnqvist F.
      • Muscaritoli M.
      • Ohlander M.
      • Schols A.
      Targeted medical nutrition for cachexia in chronic obstructive pulmonary disease: a randomized, controlled trial.
      ]
      Cornish 20180.5 (6.2)0.7 (5.9)3.16%Healthy1980 mg EPA, 990 mg DHALow[
      • Cornish S.M.
      • Myrie S.B.
      • Bugera E.M.
      • Chase J.E.
      • Turczyn D.
      • Pinder M.
      Omega-3 supplementation with resistance training does not improve body composition or lower biomarkers of inflammation more so than resistance training alone in older men.
      ]
      Cornish 2009 (male)1.2 (7.1)0.4 (7.2)3.16%Healthy14,000 (ALA)Low[
      • Cornish S.M.
      • Chilibeck P.D.
      Alpha-linolenic acid supplementation and resistance training in older adults.
      ]
      Cornish 2009 (female)0.7 (5)0.4 (5)3.30%Healthy14,000 (ALA)Low
      Couet 19970.2 (0.66)−0.24 (0.46)2.61%Healthy1100 mg EPA, 700 mg DHAHigh[
      • Couet C.
      • Delarue J.
      • Ritz P.
      • Antoine J.M.
      • Lamisse F.
      Effect of dietary fish oil on body fat mass and basal fat oxidation in healthy adults.
      ]
      Damiot 2019−0.3 (1.6)−0.3 (1.6)3.07%Healthy1100 mg EPA, 1000 mg DHAHigh[
      • Damiot A.
      • Demangel R.
      • Noone J.
      • Chery I.
      • Zahariev A.
      • Normand S.
      • et al.
      A nutrient cocktail prevents lipid metabolism alterations induced by 20 days of daily steps reduction and fructose overfeeding: result from a randomized study.
      ]
      de Luis 2005−1.0 (8.7)0.8 (8.2)3.76%Head and neck cancer720 mg EPA
      (difference with low omega-3 group). ∗This study used a branded Oral Nutrition Supplement known to contain 440 mg DHA in addition to 990 mg EPA per serving [67].
      High[
      • de Luis D.A.
      • Izaola O.
      • Aller R.
      • Cuellar L.
      • Terroba M.C.
      A randomized clinical trial with oral Immunonutrition (omega3-enhanced formula vs. arginine-enhanced formula) in ambulatory head and neck cancer patients.
      ]
      Fearon 20030.54 (0.3)0.24 (0.4)3.99%Cancer cachexia2200 mg EPA, 960 mg DHALow[
      • Fearon K.C.
      • Von Meyenfeldt M.F.
      • Moses A.G.
      • Van Geenen R.
      • Roy A.
      • Gouma D.J.
      • et al.
      Effect of a protein and energy dense N-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial.
      ]
      Fearon 2006 - high dose0.1 (0.61)4.07%Cancer cachexia4000 mg EPALow[
      • Fearon K.C.
      • Barber M.D.
      • Moses A.G.
      • Ahmedzai S.H.
      • Taylor G.S.
      • Tisdale M.J.
      • et al.
      Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia.
      ]
      Fearon 2006 - low dose−0.9 (0.61)4.04%Cancer cachexia2000 mg EPALow
      Haidari 20190.40 (0.4)−1.10 (0.9)3.21%Colorectal cancer108 mg EPA, 500 mg DHA, 52 mg otherLow[
      • Haidari F.
      • Abiri B.
      • Iravani M.
      • Ahmadi-Angali K.
      • Vafa M.
      Randomized study of the effect of vitamin D and omega-3 fatty acids cosupplementation as adjuvant chemotherapy on inflammation and nutritional status in colorectal cancer patients.
      ]
      Hanai 20181.00 (8.0)0.20 (7.0)3.30%Head and neck cancer2112 mg EPA∗High[
      • Hanai N.
      • Terada H.
      • Hirakawa H.
      • Suzuki H.
      • Nishikawa D.
      • Beppu S.
      • et al.
      Prospective randomized investigation implementing immunonutritional therapy using a nutritional supplement with a high blend ratio of ω-3 fatty acids during the perioperative period for head and neck carcinomas.
      ]
      Hayward 20161.133 (2)0.38 (1)3.22%Healthy540 mg EPA, 360 mg DHAHigh[
      • Hayward S.
      • Wilborn C.D.
      • Taylor L.W.
      • Urbina S.L.
      • Outlaw J.J.
      • Foster C.A.
      • et al.
      Effects of a high protein and omega-3-enriched diet with or without creatine supplementation on markers of soreness and inflammation during 5 consecutive days of high volume resistance exercise in females.
      ]
      Healy 20172 (18)3.1 (18)4.00%Esophageal cancer2200 mg EPA preoperatively, 2300 mg EPA post-operatively∗Low[
      • Healy L.A.
      • Ryan A.
      • Doyle S.L.
      • Éb N.B.
      • 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.
      ]
      Hossain 2020704 (893)3.67%Colorectal cancer3000 mg EPALow[
      • Hossain T.
      • Phillips B.E.
      • Doleman B.
      • Lund J.N.
      • Williams J.P.
      A double-blind randomized controlled trial of the effects of eicosapentaenoic acid supplementation on muscle inflammation and physical function in patients undergoing colorectal cancer resection.
      ]
      Jannas-Vela 2020−0.5 (3.7)−0.7 (3.9)3.13%Healthy2000 mg EPA, 1000 mg DHALow[
      • Jannas-Vela S.
      • Klingel S.L.
      • Cervone D.T.
      • Wickham K.A.
      • Heigenhauser G.J.F.
      • Mutch D.M.
      • et al.
      Resting metabolic rate and skeletal muscle SERCA and Na(+)/K(+) ATPase activities are not affected by fish oil supplementation in healthy older adults.
      ]
      Krzymińska-Siemaszko 2015−0.17 (6.9)0.04 (7.5)3.38%Healthy660 mg EPA, 440 mg DHA + 200 mg other omega-3 fatty acidsHigh[
      • Logan S.L.
      • Spriet L.L.
      Omega-3 fatty acid supplementation for 12 weeks increases resting and exercise metabolic rate in healthy community-dwelling older females.
      ]
      Logan 20151.6 (1.3)0.6 (1.5)3.15%Disease2000 mg EPA, 1000 mg DHAHigh[
      • Shirai Y.
      • Okugawa Y.
      • Hishida A.
      • Ogawa A.
      • Okamoto K.
      • Shintani M.
      • et al.
      Fish oil-enriched nutrition combined with systemic chemotherapy for gastrointestinal cancer patients with cancer cachexia.
      ]
      Moses 20040.3 (0.5)0.6 (0.8)3.13%Cancer cachexia2200 mg EPA∗Low[
      • Moses A.W.
      • Slater C.
      • Preston T.
      • Barber M.D.
      • Fearon K.C.
      Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids.
      ]
      Noreen 20100.5 (0.5)−0.1 (1.2)3.53%Healthy1600 mg EPA, 800 mg DHALow[
      • Noreen E.E.
      • Sass M.J.
      • Crowe M.L.
      • Pabon V.A.
      • Brandauer J.
      • Averill L.K.
      Effects of supplemental fish oil on resting metabolic rate, body composition, and salivary cortisol in healthy adults.
      ]
      Ogasawara 20181.8 (6.5)0.5 (6.9)3.56%COPD1100 mg EPA∗Low[
      • Ogasawara T.
      • Marui S.
      • Miura E.
      • Sugiura M.
      • Matsuyama W.
      • Aoshima Y.
      • et al.
      Effect of eicosapentaenoic acid on prevention of lean body mass depletion in patients with exacerbation of chronic obstructive pulmonary disease: a prospective randomized controlled trial.
      ]
      Paixao 2017−0.50 (4.5)−0.10 (6.8)3.46%Breast cancer940 mg EPA, 780 mg DHALow[
      • Paixão E.
      • Oliveira A.C.M.
      • Pizato N.
      • Muniz-Junqueira M.I.
      • Magalhães K.G.
      • Nakano E.Y.
      • et al.
      The effects of EPA and DHA enriched fish oil on nutritional and immunological markers of treatment naïve breast cancer patients: a randomized double-blind controlled trial.
      ]
      Philpott 2019−1.4 (0.4)−1.2 (0.4)3.04%Healthy∼2000 mg EPA, ∼2000 mg DHAHigh[
      • Philpott J.D.
      • Bootsma N.J.
      • Rodriguez-Sanchez N.
      • Hamilton D.L.
      • MacKinlay E.
      • Dick J.
      • et al.
      Influence of fish oil-derived n-3 fatty acid supplementation on changes in body composition and muscle strength during short-term weight loss in resistance-trained men.
      ]
      Ryan 20090.3 (3.7)−1.9 (3.7)3.62%Esophageal cancer2200 mg EPA∗Low[
      • Ryan A.M.
      • Reynolds J.V.
      • Healy L.
      • Byrne M.
      • Moore J.
      • Brannelly N.
      • et al.
      Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: results of a double-blinded randomized controlled trial.
      ]
      Sanchez-Lara 20141.6 (5)−2 (6)3.83%Lung cancerTwo servings of Prosure∗High[
      • Sánchez-Lara K.
      • Turcott J.G.
      • Juárez-Hernández E.
      • Nuñez-Valencia C.
      • Villanueva G.
      • Guevara P.
      • et al.
      Effects of an oral nutritional supplement containing eicosapentaenoic acid on nutritional and clinical outcomes in patients with advanced non-small cell lung cancer: randomised trial.
      ]
      Shirai 20172.3 (7.1)0.5 (8.2)3.88%Healthy1100 mg EPA, 500 mg DHA∗High[
      • Krzyminska-Siemaszko R.
      • Czepulis N.
      • Lewandowicz M.
      • Zasadzka E.
      • Suwalska A.
      • Witowski J.
      • et al.
      The effect of a 12-week omega-3 supplementation on body composition, muscle strength and physical performance in elderly individuals with decreased muscle mass.
      ]
      Snijders 20181.2 (1.4)−0.3 (2.1)3.21%Healthy700 mg EPA, 450 mg DHAHigh[
      • Snijders T.
      • Bell K.E.
      • Nederveen J.P.
      • Saddler N.I.
      • Mazara N.
      • Kumbhare D.A.
      • et al.
      Ingestion of a multi-ingredient supplement does not alter exercise-induced satellite cell responses in older men.
      ]
      Solís-Martínez 2018−0.20 (3.8)−1.30 (3.6)3.71%COPD2000 mg EPAHigh[
      • Solís-Martínez O.
      • Plasa-Carvalho V.
      • Phillips-Sixtos G.
      • Trujillo-Cabrera Y.
      • Hernández-Cuellar A.
      • Queipo-García G.E.
      • et al.
      Effect of eicosapentaenoic acid on body composition and inflammation markers in patients with head and neck squamous cell cancer from a public hospital in Mexico.
      ]
      Sugawara 20102.40 (3.9)−0.30 (2.0)3.32%Lung cancer2940High[
      • Sugawara K.
      • Takahashi H.
      • Kasai C.
      • Kiyokawa N.
      • Watanabe T.
      • Fujii S.
      • et al.
      Effects of nutritional supplementation combined with low-intensity exercise in malnourished patients with COPD.
      ]
      a (difference with low omega-3 group). ∗This study used a branded Oral Nutrition Supplement known to contain 440 mg DHA in addition to 990 mg EPA per serving [
      Abbott Laboratories
      Prosure datasheet version 7.
      ].
      The Forest plot summarizing the results of the meta-analysis of omega-3 LC PUFAs on LBM is presented in Fig. 2. There was a significant increase in lean body mass with omega-3 LC PUFAs (mean difference: 0.27, 95% CI: 0.04 to 0.051, p = 0.018). The sub-group analysis on healthy or patient populations also showed a significant increase in LBM in healthy subjects (mean difference: 0.28, 95% CI: 0.07 to 0.48) but not for disease groups (mainly cancer patients), which showed a non-significant effect of similar magnitude (mean difference: 0.27, 95% CI: −0.05 to 0.60). There was no significant effect of omega-3 LC PUFA dose and excluding the study that used the ALA intervention did not affect the results. Based on the funnel plot and publication bias tests, there was moderate heterogeneity (I2 = 89%, p < 0.001), and asymmetry was not particularly evident (Egger regression P = 0.07).
      Fig. 2
      Fig. 2Forest plot of random-effects meta-analysis on effect of omega-3 LC PUFA supplementation on lean body mass.

      3.2 Skeletal muscle mass

      We found 9 articles reporting the results of intervention studies with omega-3 LC PUFAs on skeletal muscle mass (SMM). We excluded one study for not including a control group [
      • Abe K.
      • Uwagawa T.
      • Haruki K.
      • Takano Y.
      • Onda S.
      • Sakamoto T.
      • et al.
      Effects of omega-3 fatty acid supplementation in patients with bile duct or pancreatic cancer undergoing chemotherapy.
      ], so the final analysis included 8 studies with data on 406 subjects (Table 3). Most studies were performed in populations such as patients with COPD, cancer or morbid obesity. All studies used supplements containing both EPA and DHA. The studies were all small, recruiting between 14 and 38 subjects per treatment arm. Five studies had a low risk of bias.
      Table 3Included studies reporting skeletal muscle mass (SMM).
      Study first author and yearIntervention: Change in SMM, mean (SE)Control: Change in SMM, mean (SE)Weighting in the meta-analysisSubgroup studiedReported omega-3 PUFA dose (mg/day)Bias riskRef.
      Akita 2019−0.2 (5.3)−0.8 (5.8)14.5%DiseaseTwo servings of Prosure
      This study used a branded Oral Nutrition Supplement known to contain 440 mg DHA in addition to 990 mg EPA per serving [67].
      High[
      • Akita H.
      • Takahashi H.
      • Asukai K.
      • Tomokuni A.
      • Wada H.
      • Marukawa S.
      • et al.
      The utility of nutritional supportive care with an eicosapentaenoic acid (EPA)-enriched nutrition agent during pre-operative chemoradiotherapy for pancreatic cancer: prospective randomized control study.
      ]
      Aredes 2019−3.44 (7.5)−3.16 (6.3)11.1%Disease2000 mg EPA, 450 mg DHALow[
      • Aredes M.A.
      • da Camara A.O.
      • de Paula N.S.
      • Fraga K.Y.D.
      • do Carmo M.
      • Chaves G.V.
      Efficacy of omega-3 supplementation on nutritional status, skeletal muscle, and chemoradiotherapy toxicity in cervical cancer patients: a randomized, triple-blind, clinical trial conducted in a middle-income country.
      ]
      Bakker 20190.6 (3.72)−3 (3.11)12.6%Disease1680 mg EPA, 380 mg DHAHigh[
      • Bakker N.
      • van den Helder R.S.
      • Geenen R.W.F.
      • Hunfeld M.A.
      • Cense H.A.
      • Demirkiran A.
      • et al.
      Four weeks of preoperative omega-3 fatty acids reduce liver volume: a randomised controlled trial.
      ]
      Calder 20180.02 (0.05)−0.1 (0.5)11.0%Disease2000 mg DHA + EPALow[
      • Calder P.C.
      • Laviano A.
      • Lonnqvist F.
      • Muscaritoli M.
      • Ohlander M.
      • Schols A.
      Targeted medical nutrition for cachexia in chronic obstructive pulmonary disease: a randomized, controlled trial.
      ]
      Dad'ová 20200.2 (3.7)0 (5.4)13.8%Healthy125 mg EPA, 105 mg DHALow[
      • Daďová K.
      • Petr M.
      • Šteffl M.
      • Sontáková L.
      • Chlumský M.
      • Matouš M.
      • et al.
      Effect of Calanus oil supplementation and 16 week exercise program on selected fitness parameters in older women.
      ]
      Krzymińska-Siemaszko 20150.08 (1.0)0.06 (1.0)9.58%Healthy660 mg EPA, 440 mg DHA + 200 mg other omega-3 fatty acidsHigh[
      • Krzyminska-Siemaszko R.
      • Czepulis N.
      • Lewandowicz M.
      • Zasadzka E.
      • Suwalska A.
      • Witowski J.
      • et al.
      The effect of a 12-week omega-3 supplementation on body composition, muscle strength and physical performance in elderly individuals with decreased muscle mass.
      ]
      Ogasawara 20180.2 (1.0)−0.3 (1.5)11.8%Disease1100 mg EPA
      This study used a branded Oral Nutrition Supplement known to contain 440 mg DHA in addition to 990 mg EPA per serving [67].
      Low[
      • Ogasawara T.
      • Marui S.
      • Miura E.
      • Sugiura M.
      • Matsuyama W.
      • Aoshima Y.
      • et al.
      Effect of eicosapentaenoic acid on prevention of lean body mass depletion in patients with exacerbation of chronic obstructive pulmonary disease: a prospective randomized controlled trial.
      ]
      van de Bool 20170.6 (0.6)0.3 (0.6)15.6%Disease500 mg EPA, 237 mg DHALow[
      • van de Bool C.
      • Rutten E.P.A.
      • van Helvoort A.
      • Franssen F.M.E.
      • Wouters E.F.M.
      • Schols A.
      A randomized clinical trial investigating the efficacy of targeted nutrition as adjunct to exercise training in COPD.
      ]
      a This study used a branded Oral Nutrition Supplement known to contain 440 mg DHA in addition to 990 mg EPA per serving [
      Abbott Laboratories
      Prosure datasheet version 7.
      ].
      The Forest plot summarizing the random-effects meta-analysis of omega-3 LC PUFAs on SMM is presented as Fig. 3. There was a significant increase in SMM in the omega-3 LC PUFA intervention group compared to control (mean difference 0.31, 95% CI 0.01 to 0.60, p = 0.013). Due to the small number of studies, dose and sub-group analyses were not performed. The I2 value of 36% indicated moderate heterogeneity. No publication bias was evident from the funnel plot or Egger's regression (p = 0.6).
      Fig. 3
      Fig. 3Forest plot of random-effects meta-analysis on effect of omega-3 LC PUFA supplementation on skeletal muscle mass.

      3.3 Mid-arm muscle circumference

      We found 11 articles reporting the results of intervention studies with omega-3 LC PUFAs on mid-arm muscle circumference (MAMC) as an outcome measure. One study was excluded because MAMC was not compared between treatment groups [
      • Lenn J.
      • Uhl T.
      • Mattacola C.
      • Boissonneault G.
      • Yates J.
      • Ibrahim W.
      • et al.
      The effects of fish oil and isoflavones on delayed onset muscle soreness.
      ], one because results were not reported as absolute values [
      • Ochi E.
      • Tsuchiya Y.
      • Yanagimoto K.
      Effect of eicosapentaenoic acids-rich fish oil supplementation on motor nerve function after eccentric contractions.
      ], and one because post-intervention MAMC was not reported. The 8 included studies were performed in healthy adults and in diseased populations (various cancer patients and maintenance dialysis), and 355 subjects were included overall (Table 4). The small number of studies meant that we did not perform a sub-group analysis nor investigate the effect of dose on the study outcomes.
      Table 4Included studies of mid-arm muscle circumference (MAMC).
      Study first author and yearIntervention: Change in MAMC, mean (SE)Control: Change in MAMC, mean (SE)Weighting in the meta-analysisSubgroup studiedReported omega-3 PUFA dose (/day)Bias riskRef.
      Chagas 20170.60 (3.7)−0.10 (2.3)10.9%Leukemia/lymphoma367 mg EPA, 243 mg DHAHigh[
      • Chagas T.R.
      • Borges D.S.
      • de Oliveira P.F.
      • Mocellin M.C.
      • Barbosa A.M.
      • Camargo C.Q.
      • et al.
      Oral fish oil positively influences nutritional-inflammatory risk in patients with haematological malignancies during chemotherapy with an impact on long-term survival: a randomised clinical trial.
      ]
      Corder 20160.4 (1.1)0.5 (1.5)11.7%Healthy3000 mg DHALow[
      • Corder K.E.
      • Newsham K.R.
      • McDaniel J.L.
      • Ezekiel U.R.
      • Weiss E.P.
      Effects of short-term docosahexaenoic acid supplementation on markers of inflammation after eccentric strength exercise in women.
      ]
      De Luis 20050.3 (3.9)0.3 (3.1)14.3%Head and neck cancer720 mg EPA (difference with low omega-3 group)High[
      • de Luis D.A.
      • Izaola O.
      • Aller R.
      • Cuellar L.
      • Terroba M.C.
      A randomized clinical trial with oral Immunonutrition (omega3-enhanced formula vs. arginine-enhanced formula) in ambulatory head and neck cancer patients.
      ]
      Feijó 2019−0.3 (0.87)−0.7 (1.0)14.3%Gastric cancer3200 mg EPA + DHA
      This study used a branded Oral Nutrition Supplement known to contain 440 mg DHA in addition to 990 mg EPA per serving [67].
      High[
      • Feijó P.M.
      • Rodrigues V.D.
      • Viana M.S.
      • Dos Santos M.P.
      • Abdelhay E.
      • Viola J.P.
      • et al.
      Effects of ω-3 supplementation on the nutritional status, immune, and inflammatory profiles of gastric cancer patients: a randomized controlled trial.
      ]
      Fietkau 20130.39 (0.67)−0.83 (0.73)13.4%Head and neck cancer2000 mg EPA, 850 mg DHALow[
      • Fietkau R.
      • Lewitzki V.
      • Kuhnt T.
      • Hölscher T.
      • Hess C.F.
      • Berger B.
      • et al.
      A disease-specific enteral nutrition formula improves nutritional status and functional performance in patients with head and neck and esophageal cancer undergoing chemoradiotherapy: results of a randomized, controlled, multicenter trial.
      ]
      Gharekhani 20141.5 (4.2)1.1 (2.1)13.2%Maintenance dialysis1080 mg EPA, 720 mg DHAHigh[
      • Gharekhani A.
      • Khatami M.R.
      • Dashti-Khavidaki S.
      • Razeghi E.
      • Abdollahi A.
      • Hashemi-Nazari S.S.
      • et al.
      Effects of oral supplementation with omega-3 fatty acids on nutritional state and inflammatory markers in maintenance hemodialysis patients.
      ]
      Jouris 20110.3 (1.0)0.6 (1.1)11.0%Healthy2000 mg EPA, 1000 mg DHAHigh[
      • Gharekhani A.
      • Khatami M.R.
      • Dashti-Khavidaki S.
      • Razeghi E.
      • Abdollahi A.
      • Hashemi-Nazari S.S.
      • et al.
      Effects of oral supplementation with omega-3 fatty acids on nutritional state and inflammatory markers in maintenance hemodialysis patients.
      ]
      Tsuchiya 20190.45 (1.5)0.34 (1.7)11.3%Healthy600 mg EPA and 260 mg DHAHigh[
      • Tsuchiya Y.
      • Yanagimoto K.
      • Ueda H.
      • Ochi E.
      Supplementation of eicosapentaenoic acid-rich fish oil attenuates muscle stiffness after eccentric contractions of human elbow flexors.
      ]
      a This study used a branded Oral Nutrition Supplement known to contain 440 mg DHA in addition to 990 mg EPA per serving [
      Abbott Laboratories
      Prosure datasheet version 7.
      ].
      The Forest plot summarizing the random-effects meta-analysis of omega-3 LC PUFAs on MAMC is presented in Fig. 4. There was a positive, non-significant relationship found between omega-3 LC PUFA supplementation and MAMC (effect size 0.30, 95% CI -0.23 to 0.83). There was substantial heterogeneity (I2 = 77.6%, p < 0.001) and the Egger regression statistic was non-significant (p = 0.58), indicating that the data were not asymmetric. Only two studies were at low risk of bias for this analysis.
      Fig. 4
      Fig. 4Forest plot of random-effects meta-analysis on effect of omega-3 LC PUFA supplementation on mid-arm muscle circumference.

      3.4 Handgrip strength

      We found 14 articles reporting the results of intervention studies with omega-3 LC PUFAs on handgrip strength. One study did not report the results of the handgrip strength test except that there was no significant difference between treatment groups [
      • Calder P.C.
      • Laviano A.
      • Lonnqvist F.
      • Muscaritoli M.
      • Ohlander M.
      • Schols A.
      Targeted medical nutrition for cachexia in chronic obstructive pulmonary disease: a randomized, controlled trial.
      ], and another was excluded as both treatment arms included the same dose of omega-3 LC PUFAs [
      • Cerchietti L.C.
      • Navigante A.H.
      • Castro M.A.
      Effects of eicosapentaenoic and docosahexaenoic n-3 fatty acids from fish oil and preferential Cox-2 inhibition on systemic syndromes in patients with advanced lung cancer.
      ]. The 12 included studies used for the meta-analysis are listed in Table 5, reporting results from 1437 participants overall. Studies were performed in healthy subjects and diseased populations, and studies included a similar number of subjects with the exception of the study reported by Rolland with 800 subjects randomized to either omega-3 LC PUFAs or placebo [
      • Rolland Y.
      • Barreto P.S.
      • 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).
      ]. This study used a 2 × 2 factorial design for which a comparison was available only for the omega-3 LC PUFA versus placebo groups and not for the combinations with the multi-domain intervention. The total dose of omega-3 LC PUFAs was relatively high (1000–3400 mg/d) for most studies. Three studies had a high risk of bias.
      Table 5Included studies of hand grip strength.
      Study first author and yearIntervention: Change in handgrip strength, mean (SE)Control: Change in handgrip strength, mean (SE)Difference: Intervention - controlWeighting in the meta-analysisSubgroup studiedReported omega-3 PUFA dose (mg/day)Bias riskRef.
      Berbert 200551 (53)6 (34)8.61%Rheumatoid arthritis1800 mg EPA, 1200 mg DHAHigh[
      • Berbert A.A.
      • Kondo C.R.
      • Almendra C.L.
      • Matsuo T.
      • Dichi I.
      Supplementation of fish oil and olive oil in patients with rheumatoid arthritis.
      ]
      Dad'ova 20201 (2)0.9 (2.3)8.78%Healthy125 mg EPA, 105 mg DHALow[
      • Daďová K.
      • Petr M.
      • Šteffl M.
      • Sontáková L.
      • Chlumský M.
      • Matouš M.
      • et al.
      Effect of Calanus oil supplementation and 16 week exercise program on selected fitness parameters in older women.
      ]
      Fietkau 2013−1.57 (0.96)−2.72 (0.99)8.89%Head, neck and esophageal cancer2000 mg EPA, 850 mg DHALow[
      • Fietkau R.
      • Lewitzki V.
      • Kuhnt T.
      • Hölscher T.
      • Hess C.F.
      • Berger B.
      • et al.
      A disease-specific enteral nutrition formula improves nutritional status and functional performance in patients with head and neck and esophageal cancer undergoing chemoradiotherapy: results of a randomized, controlled, multicenter trial.
      ]
      Hossain 20200.1 (2.4)8.80%Colorectal cancer3000 mg EPALow[
      • Hossain T.
      • Phillips B.E.
      • Doleman B.
      • Lund J.N.
      • Williams J.P.
      A double-blind randomized controlled trial of the effects of eicosapentaenoic acid supplementation on muscle inflammation and physical function in patients undergoing colorectal cancer resection.
      ]
      Hutchins-Wiese 2013−6.1 (2.8)2.8 (1.0)8.55%Healthy1200 mg EPA + DHALow[
      • Hutchins-Wiese H.L.
      • Kleppinger A.
      • Annis K.
      • Liva E.
      • Lammi-Keefe C.J.
      • Durham H.A.
      • et al.
      The impact of supplemental n-3 long chain polyunsaturated fatty acids and dietary antioxidants on physical performance in postmenopausal women.
      ]
      Krzymińska-Siemaszko 2015−0.17 (7.2)0.84 (7.6)8.60%Healthy660 mg EPA, 440 mg DHA + 200 mg other omega-3 fatty acidsHigh[
      • Krzyminska-Siemaszko R.
      • Czepulis N.
      • Lewandowicz M.
      • Zasadzka E.
      • Suwalska A.
      • Witowski J.
      • et al.
      The effect of a 12-week omega-3 supplementation on body composition, muscle strength and physical performance in elderly individuals with decreased muscle mass.
      ]
      Logan 20151.6 (3.1)−0.3 (2.4)8.44%Healthy2000 mg EPA, 1000 mg DHAHigh[
      • Logan S.L.
      • Spriet L.L.
      Omega-3 fatty acid supplementation for 12 weeks increases resting and exercise metabolic rate in healthy community-dwelling older females.
      ]
      Nilsson 20203 (2.3)2.3 (1.6)8.59%Healthy1510 mg EPA, 950 mg DHALow[
      • Nilsson M.I.
      • 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.
      ]
      Rolland 2019 (only placebo and omega-3 subjects included)−3.5 (−0.35)−3.9 (−0.34)9.03%Healthy225 mg EPA, 800 mg DHALow[
      • Rolland Y.
      • Barreto P.S.
      • 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).
      ]
      Smith 20151 (0.4)0.5 (0.2)8.36%Healthy, elderly1860 mg EPA, 1500 mg DHALow[
      • Smith G.I.
      • Julliand S.
      • Reeds D.N.
      • Sinacore D.R.
      • Klein S.
      • Mittendorfer B.
      Fish oil-derived n-3 PUFA therapy increases muscle mass and function in healthy older adults.
      ]
      van der Meij 20121.8 (0.15)5.04%Lung cancer2020 mg EPA, 920 mg DHA
      This study used a branded Oral Nutrition Supplement known to contain 440 mg DHA in addition to 990 mg EPA per serving [67].
      Low[
      • van der Meij B.S.
      • Langius J.A.
      • Spreeuwenberg M.D.
      • Slootmaker S.M.
      • Paul M.A.
      • Smit E.F.
      • et al.
      Oral nutritional supplements containing n-3 polyunsaturated fatty acids affect quality of life and functional status in lung cancer patients during multimodality treatment: an RCT.
      ]
      Wu 20152.3 (0.74)8.31%Heart failure6500 mg fish oilLow[
      • Wu C.
      • Kato T.S.
      • Ji R.
      • Zizola C.
      • Brunjes D.L.
      • Deng Y.
      • et al.
      Supplementation of l-Alanyl-l-Glutamine and fish oil improves body composition and quality of life in patients with chronic heart failure.
      ]
      a This study used a branded Oral Nutrition Supplement known to contain 440 mg DHA in addition to 990 mg EPA per serving [
      Abbott Laboratories
      Prosure datasheet version 7.
      ].
      The Forest plot summarizing the random-effects meta-analysis of omega-3 LC PUFAs on handgrip strength is presented in Fig. 5. There was no statistically significant relationship found between omega-3 LC PUFA supplementation and handgrip strength (effect size: 0.91, 95% CI: −1.13 to 2.96, p = 0.326). The results did not appreciably change when healthy/diseased or adult/elderly subgroups were separately analyzed. Two studies were outliers on the funnel plot [
      • Hutchins-Wiese H.L.
      • Kleppinger A.
      • Annis K.
      • Liva E.
      • Lammi-Keefe C.J.
      • Durham H.A.
      • et al.
      The impact of supplemental n-3 long chain polyunsaturated fatty acids and dietary antioxidants on physical performance in postmenopausal women.
      ,
      • van der Meij B.S.
      • Langius J.A.
      • Spreeuwenberg M.D.
      • Slootmaker S.M.
      • Paul M.A.
      • Smit E.F.
      • et al.
      Oral nutritional supplements containing n-3 polyunsaturated fatty acids affect quality of life and functional status in lung cancer patients during multimodality treatment: an RCT.
      ]. When these two studies were excluded, meta-analysis favored a significant effect of omega-3 LC PUFAs on handgrip strength (mean effect size: 0.83, 95% CI 0.19 to 1.47, p = 0.003). There was considerable heterogeneity (I2 = 97%, p < 0.001), although asymmetry was not found (Egger regression p = 0.65).
      Fig. 5
      Fig. 5Forest plot of random-effects meta-analysis on effect of LC omega-3 PUFA supplementation on handgrip strength.

      3.5 Quadriceps maximal voluntary capacity

      We identified studies that measured quadriceps maximal voluntary capacity (MVC) or knee extensor MVC; as several measured MVC after a fatiguing exercise bout, we only used endpoints taken from before the exercise bout (post-supplementation) compared with baseline (pre-supplementation). We found 11 articles reporting the results of intervention studies with omega-3 LC PUFAs with endpoints that included quadriceps or knee extensor MVC; one study was excluded as there was no comparison of pre-supplementation and post-supplementation values [
      • Morishima T.
      • Tsuchiya Y.
      • Ueda H.
      • Ochi E.
      Muscular endurance and muscle metabolic responses to 8 weeks of omega-3 polyunsaturated fatty acids supplementation.
      ]. The 10 included studies used for the meta-analysis are listed in Table 6, reporting results for 329 participants overall. The studies were all performed in either healthy subjects or patients with COPD, and covered a wide range of doses from 102 mg to 5000 mg omega-3 LC PUFAs per day. One study compared three different doses with placebo [
      • VanDusseldorp T.A.
      • Escobar K.A.
      • Johnson K.E.
      • Stratton M.T.
      • Moriarty T.
      • Kerksick C.M.
      • et al.
      Impact of varying dosages of fish oil on recovery and soreness following eccentric exercise.
      ]. The weighting of each study in the meta-analysis was similar because most were small with 10–20 subjects per treatment arm. Two studies had a high risk of bias. Due to the low number of included studies, we did not perform analyses using sub-groups.
      Table 6Included studies of quadriceps maximal voluntary capacity (MVC).
      Study first author and yearIntervention: Change in quadriceps/knee MVC, mean (SE)Control: Change in quadriceps/knee MVC, mean (SE)Weighting in the meta-analysisSubgroup studiedReported omega-3 PUFA dose (mg/day)Bias riskRef.
      Broekhuizen 20059 (21)12 (24)10.9%COPD400 mg STA, 760 mg GLA, 1200 mg ALA, 700 mg EPA, 340 mg DHALow[
      • Broekhuizen R.
      • Wouters E.F.
      • Creutzberg E.C.
      • Weling-Scheepers C.A.
      • Schols A.M.
      Polyunsaturated fatty acids improve exercise capacity in chronic obstructive pulmonary disease.
      ]
      Hingley 2017−4 (17)−22 (19)8.2%Healthy140 mg EPA, 560 mg DHAHigh[
      • Hingley L.
      • Macartney M.J.
      • Brown M.A.
      • McLennan P.L.
      • Peoples G.E.
      DHA-rich fish oil increases the omega-3 index and lowers the oxygen cost of physiologically stressful cycling in trained individuals.
      ]
      Lewis 201527 (158)6 (131)8.9%Healthy375 mg EPA, 230 mg DPA, 510 mg DHALow[
      • Lewis E.J.
      • Radonic P.W.
      • Wolever T.M.
      • Wells G.D.
      21 days of mammalian omega-3 fatty acid supplementation improves aspects of neuromuscular function and performance in male athletes compared to olive oil placebo.
      ]
      McGlory 2019−33 (34)−69 (35)7.4%Healthy2970 mg EPA, 2030 mg DHALow[
      • McGlory C.
      • Gorissen S.H.M.
      • Kamal M.
      • Bahniwal R.
      • Hector A.J.
      • Baker S.K.
      • et al.
      Omega-3 fatty acid supplementation attenuates skeletal muscle disuse atrophy during two weeks of unilateral leg immobilization in healthy young women.
      ]
      Mickleborough 20159.3 (19.7)6.7 (20.9)9.1%Healthy58 mg EPA, 44 mg DHALow[
      • Mickleborough T.D.
      • Sinex J.A.
      • Platt D.
      • Chapman R.F.
      • Hirt M.
      The effects PCSO-524(R), a patented marine oil lipid and omega-3 PUFA blend derived from the New Zealand green lipped mussel (Perna canaliculus), on indirect markers of muscle damage and inflammation after muscle damaging exercise in untrained men: a randomized, placebo controlled trial.
      ]
      Nilsson 20209 (9.7)7.9 (12.7)9.1%Healthy1510 mg EPA, 950 mg DHALow[
      • Nilsson M.I.
      • 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.
      ]
      Ramos-Campo 20202.74 (13)0.57 (16)8.9%Healthy240 mg EPA, 2100 mg DHALow[
      • Ramos-Campo D.J.
      • Avila-Gandia V.
      • Lopez-Roman F.J.
      • Minarro J.
      • Contreras C.
      • Soto-Mendez F.
      • et al.
      Supplementation of Re-esteri fi ed docosahexaenoic and eicosapentaenoic acids reduce inflammatory and muscle damage markers after exercise in endurance athletes: a randomized, controlled crossover trial.
      ]
      Rodacki 201435.5 (7)17 (7)7.0%Healthy400 mg EPA, 300 mg DHAHigh[
      • Rodacki C.L.
      • Rodacki A.L.
      • Pereira G.
      • Naliwaiko K.
      • Coelho I.
      • Pequito D.
      • et al.
      Fish-oil supplementation enhances the effects of strength training in elderly women.
      ]
      Sugawara 20105 (1.4)−0.6 (9.8)8.8%COPD1200 mg PUFAsHigh[
      • Sugawara K.
      • Takahashi H.
      • Kasai C.
      • Kiyokawa N.
      • Watanabe T.
      • Fujii S.
      • et al.
      Effects of nutritional supplementation combined with low-intensity exercise in malnourished patients with COPD.
      ]
      VanDusseldorp 2020
      Three doses are reported for this study, 2G used 2 g fish oil, 4G used 4 g fish oil, 6G used 6 g fish oil.
      2G: −8.33 (63)

      4G: −16.0 (52)

      6G: 0.54 (68)
      −19.5 (69)2G: 7.21%

      4G: 7.22%

      6G: 7.19%
      Healthy2G: 800 mg EPA, 600 mg DHA

      4G: 1600 mg EPA, 1200 mg DHA

      6G: 2400 mg EPA, 1800 mg DHA
      Low[
      • VanDusseldorp T.A.
      • Escobar K.A.
      • Johnson K.E.
      • Stratton M.T.
      • Moriarty T.
      • Kerksick C.M.
      • et al.
      Impact of varying dosages of fish oil on recovery and soreness following eccentric exercise.
      ]
      a Three doses are reported for this study, 2G used 2 g fish oil, 4G used 4 g fish oil, 6G used 6 g fish oil.
      The Forest plot summarizing the results of the meta-analysis of omega-3 LC PUFAs on quadriceps MVC is presented in Fig. 6. There was a statistically significant increase in quadriceps/knee MVC with omega-3 LC PUFAs (mean difference 0.47, 95% CI 0.02 to 0.93, p = 0.022). No significant omega-3 LC PUFA dose effect was found, although the number of studies was small. There was significant heterogeneity (I2 = 67.5%, p < 0.001). The Egger regression statistic indicated that asymmetry may be present (p = 0.09). When the article from Rodacki and co-workers [
      • Rodacki C.L.
      • Rodacki A.L.
      • Pereira G.
      • Naliwaiko K.
      • Coelho I.
      • Pequito D.
      • et al.
      Fish-oil supplementation enhances the effects of strength training in elderly women.
      ], identified as an outlier in the funnel plot, was excluded, the Hedge's g for the meta-analysis decreased to 0.27 (95% CI 0 to 0.53) and remained statistically significant (p = 0.025).
      Fig. 6
      Fig. 6Forest plot of random-effects meta-analysis on effect of omega-3 LC PUFA supplementation on quadriceps maximal voluntary contraction.

      3.6 1-Repetition maximum chest press

      We found 5 articles reporting the results of intervention studies with omega-3 LC PUFAs on 1-repeat maximum (1RM) chest press results. For two studies, the 1RM chest press results were only reported as part of a composite score and not individually; therefore the results were not included in the meta-analysis [
      • Snijders T.
      • Bell K.E.
      • Nederveen J.P.
      • Saddler N.I.
      • Mazara N.
      • Kumbhare D.A.
      • et al.
      Ingestion of a multi-ingredient supplement does not alter exercise-induced satellite cell responses in older men.
      ,
      • Smith G.I.
      • Julliand S.
      • Reeds D.N.
      • Sinacore D.R.
      • Klein S.
      • Mittendorfer B.
      Fish oil-derived n-3 PUFA therapy increases muscle mass and function in healthy older adults.
      ]. One study reported results separately for men and women [
      • Cornish S.M.
      • Chilibeck P.D.
      Alpha-linolenic acid supplementation and resistance training in older adults.
      ]; this study used flaxseed oil (a source of ALA) as an intervention. The included studies are listed in Table 7. The small number of studies meant that we did not perform a sub-group analysis nor investigate the effect of dose on the study outcomes.
      Table 7Included studies of 1-repetition maximum (1RM) chest press.
      Study first author and yearIntervention: Change in 1RM chest press, mean (SE)Control: Change in 1RM chest press, mean (SE)Weighting in the meta-analysisReported omega-3 PUFA dose (/day)Bias riskRef.
      Cornish 201815.815.425.1%1980 mg EPA, 990 mg DHALow[
      • Cornish S.M.
      • Myrie S.B.
      • Bugera E.M.
      • Chase J.E.
      • Turczyn D.
      • Pinder M.
      Omega-3 supplementation with resistance training does not improve body composition or lower biomarkers of inflammation more so than resistance training alone in older men.
      ]
      Cornish 2009 (male)23.520.825.8%14,000 mg ALALow[
      • Cornish S.M.
      • Chilibeck P.D.
      Alpha-linolenic acid supplementation and resistance training in older adults.
      ]
      Cornish 2009 (female)14.615.425.1%
      Hayward 20163.333.8024.1%540 mg EPA, 360 mg DHAHigh[
      • Hayward S.
      • Wilborn C.D.
      • Taylor L.W.
      • Urbina S.L.
      • Outlaw J.J.
      • Foster C.A.
      • et al.
      Effects of a high protein and omega-3-enriched diet with or without creatine supplementation on markers of soreness and inflammation during 5 consecutive days of high volume resistance exercise in females.
      ]
      The Forest plot summarizing the results of the meta-analysis of omega-3 LC PUFA supplementation on 1RM chest press is presented in Fig. 7. A negative, non-significant effect of omega-3 LC PUFAs was seen on 1RM maximum chest press measurements (effect size −0.29, 95% CI -1.76 to 1.18). Substantial heterogeneity was present (I2 = 78.2%, p < 0.001) but there was no evidence of asymmetry (Egger regression p = 0.8), with the results of Hayward et al., 2016 [
      • Hayward S.
      • Wilborn C.D.
      • Taylor L.W.
      • Urbina S.L.
      • Outlaw J.J.
      • Foster C.A.
      • et al.
      Effects of a high protein and omega-3-enriched diet with or without creatine supplementation on markers of soreness and inflammation during 5 consecutive days of high volume resistance exercise in females.
      ] producing an outlier in the funnel plot.
      Fig. 7
      Fig. 7Forest plot of random-effects meta-analysis on effect of omega-3 LC PUFA supplementation ation on 1-repetition maximum chest press.

      4. Discussion

      We found that lean body mass, skeletal muscle mass and quadriceps MVC all increased after omega-3 LC PUFA supplementation. These results indicate that omega-3 LC PUFAs could be useful in increasing skeletal muscle mass or strength, particularly in populations at risk of sarcopenia. The quadriceps is required for locomotion and may be more susceptible to wasting in the elderly [
      • Samuel D.
      • Wilson K.
      • Martin H.J.
      • Allen R.
      • Sayer A.A.
      • Stokes M.
      Age-associated changes in hand grip and quadriceps muscle strength ratios in healthy adults.
      ]. A reduction in muscle mass would parallel decreases in muscle strength of the quadriceps. Hence the effects of omega-3 LC PUFAs on muscle mass and quadriceps MVC are likely to be linked. Most trials used EPA and DHA and the trial that used a high intake of ALA [
      • Cornish S.M.
      • Chilibeck P.D.
      Alpha-linolenic acid supplementation and resistance training in older adults.
      ] did not see effects on any outcome.
      Although it might be anticipated that there would be a dose response effect of increased intake of omega-3 LC PUFAs, we did not find evidence for such dose effect on these outcomes. This may suggest that the threshold for an effect is reached by many studies, although it is more likely that the lack of a clear dose response effect reflects the heterogeneity between studies, the small number of studies reporting on any particular outcome, their varying duration, and the variations in relative amounts of EPA and DHA used particularly in the low-to-medium dose range. Many people do not meet omega-3 LC PUFA intake recommendations [
      • Micha R.
      • Khatibzadeh S.
      • Shi P.
      • Fahimi S.
      • Lim S.
      • Andrews K.G.
      • et al.
      Global, regional, and national consumption levels of dietary fats and oils in 1990 and 2010: a systematic analysis including 266 country-specific nutrition surveys.
      ], and have low red blood cell omega-3 LC PUFA levels [
      • Stark K.D.
      • Van Elswyk M.E.
      • Higgins M.R.
      • Weatherford C.A.
      • Salem N.
      Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults.
      ]. The doses used in most studies were generally much higher than amounts recommended for cardiovascular disease prevention; however, the lack of clear dose effect may indicate that a low-dose supplement is sufficient to improve lean body mass. Future trials should carefully assess the effect of different doses of omega-3 LC PUFAs in appropriately designed studies of ample sample size.
      The meta-analyses did not identify an effect of omega-3 LC PUFAs on MAMC, handgrip strength, or 1RM chest press. The low number of subjects and studies hampered the ability to draw definitive conclusions about the effect of these relationships.
      A systematic review and meta-analysis by Abdelhamid et al. published in 2019 on RCTs supplementing omega-3 or omega-6 PUFAs for at least 26 weeks did not find an effect of omega-3 LC PUFAs on muscle mass and functional outcomes such as handgrip strength [
      • Abdelhamid A.
      • Hooper L.
      • Sivakaran R.
      • Hayhoe R.P.G.
      • Welch A.
      The relationship between omega-3, omega-6 and total polyunsaturated fat and musculoskeletal health and functional status in adults: a systematic review and meta-analysis of RCTs.
      ]. Our finding of a lack of effect on handgrip strength agrees with this earlier analysis, but our finding of an effect on muscle mass differs. Nevertheless, once two outliers were removed, we found a positive effect for handgrip strength as well. The Abdelhamid meta-analysis included a much smaller number of studies for each endpoint than ours due to the inclusion requirement of a 26-week intervention, and the number of studies that met the inclusion criteria was low. We did not exclude studies according to length of supplementation, and therefore we were able to include a larger number of studies for each endpoint, increasing statistical power to find a significant association if one exists.
      With higher intakes, EPA and DHA increase in plasma over the course of days to weeks [
      • Yurko-Mauro K.
      • Kralovec J.
      • Bailey-Hall E.
      • Smeberg V.
      • Stark J.G.
      • Salem Jr., N.
      Similar eicosapentaenoic acid and docosahexaenoic acid plasma levels achieved with fish oil or krill oil in a randomized double-blind four-week bioavailability study.
      ,
      • Browning L.M.
      • Walker C.G.
      • Mander A.P.
      • West A.L.
      • Madden J.
      • Gambell J.M.
      • et al.
      Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish.
      ], reaching a new steady state fairly quickly. Incorporation into white and red blood cells takes longer and a new steady state is not reached for many weeks to months [
      • Browning L.M.
      • Walker C.G.
      • Mander A.P.
      • West A.L.
      • Madden J.
      • Gambell J.M.
      • et al.
      Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish.
      ]. It is known that EPA and DHA are incorporated into skeletal muscle cells over a period of weeks [
      • Smith G.I.
      • Atherton P.
      • Reeds D.N.
      • Mohammed B.S.
      • Rankin D.
      • Rennie M.J.
      • et al.
      Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia-hyperaminoacidaemia in healthy young and middle-aged men and women.
      ,
      • McGlory C.
      • Galloway S.D.
      • Hamilton D.L.
      • McClintock C.
      • Breen L.
      • Dick J.R.
      • et al.
      Temporal changes in human skeletal muscle and blood lipid composition with fish oil supplementation.
      ]. Furthermore, the augmentation of muscle protein synthesis during a hyperaminoacidemic-hyperinsulinemic clamp found by Smith et al. occurred after 8 weeks of combined EPA and DHA supplementation [
      • Smith G.I.
      • Atherton P.
      • Reeds D.N.
      • Mohammed B.S.
      • Rankin D.
      • Rennie M.J.
      • et al.
      Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia-hyperaminoacidaemia in healthy young and middle-aged men and women.
      ,
      • Smith G.I.
      • Atherton P.
      • Reeds D.N.
      • Mohammed B.S.
      • Rankin D.
      • Rennie M.J.
      • et al.
      Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults: a randomized controlled trial.
      ], suggesting an anticipated shorter time frame for effects of supplemental omega-3 LC PUFAs. Therefore, it is plausible that significant effects of omega-3 LC PUFAs could be seen with a shorter supplementation time than 26 weeks, the threshold used in the previous meta-analysis. All but six studies in our analysis supplemented for more than 2 weeks, and median study supplementation duration was 56 days.
      Another meta-analysis using studies performed in elderly subjects identified that omega-3 LC PUFA supplements increased muscle mass, whereas grip strength was not affected [
      • Huang Y.H.
      • Chiu W.C.
      • Hsu Y.P.
      • Lo Y.L.
      • Wang Y.H.
      Effects of omega-3 fatty acids on muscle mass, muscle strength and muscle performance among the elderly: a meta-analysis.
      ]. Our findings using a broader set of studies, including different patient groups, agree with these earlier findings in the elderly. Also, Huang et al. [
      • Huang Y.H.
      • Chiu W.C.
      • Hsu Y.P.
      • Lo Y.L.
      • Wang Y.H.
      Effects of omega-3 fatty acids on muscle mass, muscle strength and muscle performance among the elderly: a meta-analysis.
      ] did not find an effect of omega-3 LC PUFAs on 1RM leg strength and we did not find an effect on 1RM chest press. On the other hand, we found an improvement in quadriceps MVC; this seems to contrast with the lack of effect on 1RM leg strength, since these are both strength measurements in the same area of the body. Due to our broader inclusion criteria, we included more studies in our meta-analysis: we used data from 10 studies, compared to Huang et al. with 3 studies for this endpoint [
      • Huang Y.H.
      • Chiu W.C.
      • Hsu Y.P.
      • Lo Y.L.
      • Wang Y.H.
      Effects of omega-3 fatty acids on muscle mass, muscle strength and muscle performance among the elderly: a meta-analysis.
      ]. Including data from a larger number of studies may have allowed a significant effect to be seen for this parameter.
      Our research has some limitations. Firstly, we conducted a meta-analysis based on published mean values. A more sensitive approach is to obtain individual subject data. This would also allow for the effect of inflammation markers or other potential confounders such as subject age, body weight or nutritional status on the muscle parameters to be taken into account. Secondly, as this was a scoping review, we wanted to include a wide range of studies to identify potential associations across different muscle-related endpoints. This meant that we did not restrict studies based on number of subjects, patient populations, type of supplement used, dose, muscle fatigue or disuse procedures, or duration of supplementation, all of which may affect outcomes. As we excluded few studies and attempted to include as many datapoints as possible, our results are less likely to be affected by selection or publication bias. On the other hand, the broad inclusion criteria may introduce greater variability and a lower likelihood of finding a significant result due to heterogeneity in study design and patient populations. Indeed, the Egger's regression statistic indicated that heterogeneity was significant for several outcomes.
      The link between omega-3 LC PUFA supplementation and increases in muscle mass and strength is supported by mechanistic evidence [
      • Ferguson E.J.
      • Seigel J.W.
      • McGlory C.
      Omega-3 fatty acids and human skeletal muscle.
      ]. Hyperinsulinemic clamp studies in adults of different age groups found an increase in muscle protein synthesis in the hyperglycemic state after supplementation with a combination of EPA and DHA given as ethyl esters [
      • Smith G.I.
      • Atherton P.
      • Reeds D.N.
      • Mohammed B.S.
      • Rankin D.
      • Rennie M.J.
      • et al.
      Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia-hyperaminoacidaemia in healthy young and middle-aged men and women.
      ,
      • Smith G.I.
      • Atherton P.
      • Reeds D.N.
      • Mohammed B.S.
      • Rankin D.
      • Rennie M.J.
      • et al.
      Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults: a randomized controlled trial.
      ], pointing to a stimulation of muscle protein anabolism by omega-3 LC PUFAs.
      Even though we found that omega-3 LC PUFA supplementation could increase muscle mass and strength, the majority of studies were small and heterogeneity was high. There were also few studies conducted in sarcopenic patients, our population of interest, therefore the sample size would be too small. The bias assessment also indicated that many studies were at risk of bias due to a lack of blinding or randomization, or had deficits in reporting these study design elements. More conclusive results could be drawn from larger studies with rigorous control of sources of bias. Dosing ranges used across the studies were also large and an incorporation of different dosing levels into study design could also be beneficial, as discussed earlier. The use of standard procedures to assess outcomes would allow the results from different studies to be compared.
      In summary, our scoping meta-analysis found that omega-3 LC PUFA supplementation had a positive effect on lean body mass, skeletal muscle mass and quadriceps MVC. These results could have implications for sarcopenia prevention. Further research will help to determine whether omega-3 LC PUFAs could improve functional outcomes in muscle-wasting disorders such as sarcopenia and cancer cachexia.

      5. Conclusion

      This scoping review and meta-analysis shows that omega-3 LC PUFA supplementation was associated with improvements in muscle mass and function, namely lean body mass, skeletal muscle mass and quadriceps MVC. However, the heterogeneity present in the studies and a wide range of doses used limit the applicability of the findings to sarcopenia prevention. Further research conducted in free-living elderly populations that investigate functional endpoints and mechanisms of action would advance the evidence base.

      Declaration of competing interest

      PCC acts as an advisor/consultant to DSM Nutritional Products, BASF AS, Cargill, Smartfish, Fresenius-Kabi, Nutrileads, Bayer Consumer Care and GSK Consumer Healthcare. BT and IW are employed by DSM Nutritional Products. JKB is a consultant for DSM Nutritional Products.

      Acknowledgements

      None.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

      Funding statement

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Author contributions

      Julia K. Bird: data curation, formal analysis, visualization, Roles/Writing - original draft. Philip C. Calder: Conceptualization, Writing - review & editing. Barbara Troesch: Conceptualization, Writing - review & editing, Project administration. Ines Warnke: Conceptualization, Writing - review & editing.

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