https://orcid.org/0009-0005-5420-8653
Figures
Abstract
Aim
To comprehensively investigate the effects of antioxidant nutrients on muscle mass, strength and function in chronic obstructive pulmonary disease (COPD) patients.
Methods
PubMed, Embase, Cochrane Library, and Web of Science were comprehensively searched from the inception to January 3, 2024. The quality of randomized controlled trials (RCTs) was measured using the Jadad scale. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were used as the effect size for measurement data. Further, subgroup analysis was conducted based on whether patients participated in lung rehabilitation plans while receiving nutritional interventions. Sensitivity analysis was performed on all outcomes.
Results
A total of 12 studies involving 595 patients with COPD were included, with 11 studies had high quality, and one study had low quality. For muscle mass, patients receiving antioxidant nutrients had a significantly increased lean body mass index compared with those not receiving antioxidant nutrients (pooled WMD: 0.903, 95% CI: 0.264, 1.541, P = 0.006). For patients who did not participate in lung rehabilitation plan while receiving nutritional interventions, antioxidant nutrients brought about a significantly higher lean body mass index (pooled WMD: 1.360, 95% CI: 0.560, 2.160, P = 0.001). For muscle strength, patients in the antioxidant nutrient intervention group had significantly higher hand grip strength (HGS) than those in the non-antioxidant nutrient intervention group (pooled WMD: 1.976, 95% CI: 1.337, 2.615, P < 0.001). Patients receiving antioxidant nutrients had significantly greater inspiratory muscle strength (MIP) than those not receiving antioxidant nutrients (pooled WMD: 8.127, 95% CI: 2.677, 13.577, P = 0.003).
Citation: He Q, Yang P, Wang Y, Xu W, Feng Y, Xie F, et al. (2025) Effects of antioxidant nutrients on muscle mass, strength and function in COPD patients: A meta-analysis of randomized controlled trials. PLoS ONE 20(1): e0316842. https://doi.org/10.1371/journal.pone.0316842
Editor: Giulia Squillacioti, University of Turin: Universita degli Studi di Torino, ITALY
Received: April 2, 2024; Accepted: December 17, 2024; Published: January 17, 2025
Copyright: © 2025 He et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disorder feature by persistent respiratory symptoms and progressive airflow obstruction [1]. It is a primary cause of morbidity, mortality, and health-care use globally [2]. Malnutrition, a common problem in COPD, is a consequence of reduced nutritional intake and muscle loss, further exacerbated by systemic inflammation [3, 4], with a prevalence of around 25% in patients with COPD [5]. Malnourished individuals with COPD can have cachexia, sarcopenia and weight loss, poor exercise ability, muscle function and lung function as well as increased exacerbations, mortality and cost [6, 7]. Hence, providing nutritional support is necessary for COPD patients with malnutrition.
Nutritional support can improve energy and protein imbalances, leading to enhanced nutritional status and functional capacity [4, 8]. Several nutrients have been suggested to protect against airway destruction via antioxidant activity [9], and antioxidant nutrients are related to better lung function [10]. Antioxidant supplementation refers to the therapeutic approach of administering exogenous antioxidants to counteract oxidative stress, a state characterized by an imbalance between the production of reactive oxygen species (ROS) and the ability of the body to detoxify these reactive molecules [11]. Antioxidants, including but not limited to vitamins C and E, selenium, and beta-carotene, are substances that can delay or prevent cell damage caused by ROS [12]. Recently, whey beverage fortified with magnesium and vitamin C was shown to improve skeletal muscle mass and muscle strength, and further elevate health-related quality of life in patients with moderate-to-severe COPD [13]. Intravenous ferric carboxymaltose provided improvements in exercise capacity and functional restriction due to breathlessness in COPD [14]. In another randomized controlled trial (RCT), COPD patients exhibited significant improvements of muscle strength and other training-refractory outcomes after nutritional antioxidant supplementation [15]. At present, a meta-analysis by Collins et al. [16] found that nutritional support (food strategies, dietary advice, etc.), mainly in the form of oral nutritional supplements, improves total intake, anthropometric measures and grip strength in subjects with COPD. Ferreira et al. [17] showed in their review that nutritional supplementation (oral, enteral or parenteral nutritional support) increased expiratory muscle strength (MEP) and inspiratory muscle strength (MIP) among malnourished patients with COPD. As regards the role of antioxidant nutrients in COPD, few studies have been conducted. Lei et al. [18] demonstrated that vitamin C supplementation, a single antioxidant nutrient, could increase the levels of antioxidation in serum and improve lung function. However, the influences of comprehensive antioxidant nutrients in individuals with COPD remain unknown.
To fill this research gap, this meta-analysis of randomized controlled trials intended to comprehensively investigate the effects of antioxidant nutrients on muscle mass, strength and function in COPD patients, in order to provide a clinical reference for COPD management.
Methods
This systematic review and meta-analysis was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [19]. The study was prospectively registered with the PROSPERO International Prospective Register of Systematic Reviews. The registration ID is CRD42024528396.
Search strategy
PubMed, Embase, Cochrane Library, and Web of Science were comprehensively searched from the inception to January 3, 2024. Two investigators (QMH and PY) conducted the search independently. English search terms included the following: “Antioxidants” OR “Anti-Oxidants” OR “Anti Oxidants” OR “Antioxidant” OR “Anti-Oxidant” OR “Anti Oxidant” OR “Endogenous Antioxidants” OR “Antioxidants, Endogenous” OR “Endogenous Antioxidant” OR “Antioxidant, Endogenous” OR “Antioxidant Activity” OR “Activity, Antioxidant” OR “Antioxidant Effect” OR “Anti-Oxidant Effect” OR “Anti Oxidant Effect” OR “Anti-Oxidant Effects” OR “Anti Oxidant Effects” OR “Antioxidant Effects” OR “Whey Proteins” OR “Protein, Whey” OR “Proteins, Whey” OR “Whey Protein” AND “Pulmonary Disease, Chronic Obstructive” OR “Chronic Obstructive Lung Disease” OR “Chronic Obstructive Pulmonary Diseases” OR “COAD” OR “COPD” OR “Chronic Obstructive Airway Disease” OR “Chronic Obstructive Pulmonary Disease” OR “Airflow Obstruction, Chronic” OR “Airflow Obstructions, Chronic” OR “Chronic Airflow Obstructions” OR “Chronic Airflow Obstruction” OR “Bronchitis, Chronic” OR “Chronic Bronchitis” OR “Pulmonary Emphysema” OR “Emphysemas, Pulmonary” OR “Pulmonary Emphysemas” OR “Emphysema, Pulmonary” OR “Focal Emphysema” OR “Emphysema, Focal” OR “Emphysemas, Focal” OR “Focal Emphysemas” OR “Panacinar Emphysema” OR “Emphysema, Panacinar” OR “Emphysemas, Panacinar” OR “Panacinar Emphysemas” OR “Panlobular Emphysema” OR “Emphysema, Panlobular” OR “Emphysemas, Panlobular” OR “Panlobular Emphysemas” OR “Centriacinar Emphysema” OR “Centriacinar Emphysemas” OR “Emphysema, Centriacinar” OR “Emphysemas, Centriacinar” OR “Centrilobular Emphysema” OR “Centrilobular Emphysemas” OR “Emphysema, Centrilobular” OR “Emphysemas, Centrilobular”. The PubMed search strategy is shown in S1 File. The retrieved studies underwent a preliminary screening based on titles and abstracts, followed by screening through full text reading.
Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) studies on patients with COPD; (2) studies on patients receiving antioxidant nutrient intervention versus placebo or other therapies without antioxidant nutrient intervention, such as dietary recommendations and routine care; (3) studies on differences in muscle mass, strength, and function indicators (endpoint value minus baseline value); (4) RCTs; (5) English literature.
The exclusion criteria were as follows: (1) animal experiments; (2) retracted studies; (3) conference summaries, case reports, meta-analyses, reviews, editorial materials, letters, annotations, trial protocols, trial registration records; (4) studies without matched themes.
Antioxidant nutrients and outcome measures
Our study incorporated a range of antioxidants supplements, including eicosapentaenoic acid (EPA)-enriched oral nutritional supplements, partially hydrolyzed whey protein, an oral mixture of essential amino acids, whey protein supplements, beverages fortified with magnesium and Vitamin C, omega-3 fatty acids, Vitamin D, Vitamin E, Vitamin C, zinc gluconate, selenium, and intravenous iron.
The outcome measures included muscle mass, strength, and function indicators. Muscle mass was evaluated by lean body mass, fat-free mass, lean body mass index, fat-free mass index, and skeletal muscle mass index. Muscle strength was assessed by hand grip strength (HGS), isometric maximal quadriceps strength (IMS Quad), MEP, and MIP. Muscle function was measured by six-minute walk distance (6MWD).
Data extraction
Two investigators (QMH and PY) collected relevant data from the included studies, including author, year of publication, country, study design, group, way of treatment, sample size (N), male/female, age, body mass index (BMI), smoking, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages, pulmonary function, Jadad score, and outcomes.
Quality assessment and risk of bias assessment
The quality of RCTs were measured using the Cochrane’s Risk of Bias tool [20], which comprises seven specified domains. Then, RCTs were classified into three categories: low risk, high risk, and having some concerns (S1A and S1B Fig).
Quality of evidence assessment
The evidence quality underpinning each estimate was evaluated in accordance with the guidelines established by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group [21]. This framework assesses the confidence in the evidence by considering elements such as methodological limitations of the studies, the degree of precision in the effect estimates, the presence of heterogeneity, the relevance of the evidence to the research question, and the potential for bias in the published literature, with a focus on the primary outcomes. The evidence is then classified into one of four quality levels: high, moderate, low, or very low (S2 File).
Statistical analysis
All statistical analyses were performed with Stata 15.1 (Stata Corporation, College Station, TX, USA). Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were used as the effect size for measurement data. The effect size of each outcome was tested for heterogeneity. If the heterogeneity statistic I2 ≥ 50%, the random-effects model was adopted for analysis; on the contrary, fixed-effects model was adopted. Further, subgroup analysis was conducted based on whether patients participated in lung rehabilitation plans while receiving nutritional interventions. Sensitivity analysis was performed on all outcomes. Publication biases were assessed via visual inspection of funnel plots for outcomes with 10 or more studies [22]. The difference was statistically significant if P<0.05.
Results
Characteristics of the included studies
From the four databases, 12353 studies were retrieved. After duplicate removal, 7140 studies were left for screening based on titles and abstracts, and further on full texts. Finally, a total of 12 studies [13–15, 23–31] involving 595 patients with COPD were included in this analysis, with 296 patients in the antioxidant nutrient intervention group and 299 in the non-antioxidant nutrient intervention group. The selection process of eligible studies is shown in Fig 1. The year of publication ranged from 2007 to 2021. For the quality of the included studies, 11 studies had high quality, and one study had low quality. Table 1 illustrates the characteristics of the included studies.
Muscle mass
Lean body mass.
The results of meta-analysis are shown in Table 2. Four studies with four sets of data assessed lean body mass. No significant difference was found in lean body mass between the antioxidant nutrient intervention and non-antioxidant nutrient intervention groups (pooled WMD: 0.404, 95% CI: -0.192, 1.000, P = 0.184). Regardless of whether patients participated in lung rehabilitation plans while receiving nutritional interventions, no significant association was observed between antioxidant nutrients and lean body mass (both P > 0.05) (Fig 2A).
2a, lean body mass; 2b, fat-free mass; 2c, lean body mass index; 2d, fat-free mass index; 2e, skeletal muscle mass index. WMD, weighted mean difference; CI, confidence interval.
Fat-free mass. Fat-free mass was measured by three studies with three sets of data. The antioxidant nutrient intervention group had comparable fat-free mass to the non-antioxidant nutrient intervention group (pooled WMD: 1.647, 95% CI: -0.882, 4.176, P = 0.202) (Fig 2B).
Lean body mass index.
The lean body mass index was evaluated by three studies with three sets of data. Patients receiving antioxidant nutrients had a significantly increased lean body mass index compared with those not receiving antioxidant nutrients (pooled WMD: 0.903, 95% CI: 0.264, 1.541, P = 0.006). For patients who did not participate in lung rehabilitation plan while receiving nutritional interventions, antioxidant nutrients brought about a significantly higher lean body mass index (pooled WMD: 1.360, 95% CI: 0.560, 2.160, P = 0.001) (Fig 2C).
Fat-free mass index.
Three studies with three sets of data reported the fat-free mass index. There was no significant difference in the fat-free mass index between the antioxidant nutrient intervention and non-antioxidant nutrient intervention groups (pooled WMD: 0.499, 95% CI: -0.158, 1.157, P = 0.137). Regardless of whether patients participated in lung rehabilitation plans while receiving nutritional interventions, no significant association was found between antioxidant nutrients and the fat-free mass index (both P > 0.05) (Fig 2D).
Skeletal muscle mass index.
The SMI was explored in three studies with three sets of data. The SMI of the antioxidant nutrient intervention group was similar to that of the non-antioxidant nutrient intervention group (pooled WMD: 0.031, 95% CI: -0.001, 0.063, P = 0.057). Regardless of whether patients participated in lung rehabilitation plans while receiving nutritional interventions, no significant association existed between antioxidant nutrients and the SMI (both P > 0.05) (Fig 2E).
Muscle strength
HGS.
Three studies with four sets of data assessed HGS. Patients in the antioxidant nutrient intervention group had significantly higher HGS than those in the non-antioxidant nutrient intervention group (pooled WMD: 1.976, 95% CI: 1.337, 2.615, P < 0.001) (Fig 3A).
3a, HGS; 3b, IMS Quad; 3c, MEP; 3d, MIP. HGS, hand grip strength; IMS Quad, isometric maximal quadriceps strength; MEP, expiratory muscle strength; MIP, inspiratory muscle strength; WMD, weighted mean difference; CI, confidence interval.
IMS Quad.
IMS Quad was evaluated by one study with two sets of data. No significant difference was found in IMS Quad between the antioxidant nutrient intervention and non-antioxidant nutrient intervention groups (pooled WMD: 0.869, 95% CI: -2.659, 4.396, P = 0.629) (Fig 3B).
MEP.
Two studies with two sets of data measured MEP. There was no significant difference in MEP between the antioxidant nutrient intervention and non-antioxidant nutrient intervention groups (pooled WMD: 8.078, 95% CI: -5.251, 21.407, P = 0.235). Regardless of whether patients participated in lung rehabilitation plans while receiving nutritional interventions, no significant association was observed between antioxidant nutrients and MEP (both P > 0.05) (Fig 3C).
MIP.
Information on MIP was assessed by two studies with two sets of data. Patients receiving antioxidant nutrients had significantly greater MIP than those not receiving antioxidant nutrients (pooled WMD: 8.127, 95% CI: 2.677, 13.577, P = 0.003). For patients who participated in lung rehabilitation plan while receiving nutritional interventions, antioxidant nutrients resulted in significantly higher MIP (WMD: 11.000, 95% CI: 3.709, 18.291, P = 0.003) (Fig 3D).
Muscle function
6MWD.
Five studies with five sets of data investigated the 6MWD. There was no significant difference in the 6MWD between the antioxidant nutrient intervention and non-antioxidant nutrient intervention groups (pooled WMD: 3.489, 95% CI: -13.170, 20.149, P = 0.681). Regardless of whether patients participated in lung rehabilitation plans while receiving nutritional interventions, no significant association was found between antioxidant nutrients and the 6MWD (both P > 0.05) (Fig 4).
6MWD, six-minute walk distance; WMD, weighted mean difference; CI, confidence interval.
Sensitivity analysis
Sensitivity analysis was conducted by removing one study and synthetically analyzing the remaining studies. Its result exhibited that one-study removal did not significantly influence the overall outcomes, suggesting that the findings of this meta-analysis were stable and robust (S2–S4 Figs).
Discussion
This meta-analysis probed into the effects of antioxidant nutrients on the muscle mass, strength and function of COPD patients, based on the 12 studies involving 595 patients. It was found that antioxidant nutrient intervention significantly improved HGS, MIP and lean body mass index in COPD; for patients who did not participate in lung rehabilitation plan while receiving nutritional interventions, antioxidant nutrients resulted in a significantly higher lean body mass index. Considering these findings, antioxidant nutrients may be used in clinical practice to increase the muscle mass and function of patients with COPD.
Several meta-analyses have explored the role of nutritional support in COPD. Collins et al. [8] reported that nutritional support in COPD led to significant improvements in a number of clinically relevant functional outcomes, while it was also demonstrated by another study that nutritional support had no influence on improving anthropometric measures, lung function, or functional exercise capacity in patients with stable COPD [32]. Ferreira et al. [17] showed in their review that nutritional supplementation was shown to enhance MEP and MIP in malnourished patients with COPD. Nevertheless, as regards the role of antioxidant nutrients in COPD, vitamin C supplementation, as found by Lei et al. [18], could increase the levels of antioxidation in serum and improve lung function. In a meta-analysis by Wang et al. [33], vitamin D supplementation improved the indicators of asthma and COPD, including pulmonary function and St. George’s Respiratory Questionnaire (SGRQ) scores. To make comprehensive analysis of various antioxidant nutrients in individuals with COPD, the current study was carried out, and COPD patients intervened with antioxidant nutrients had significantly elevated HGS, MIP and lean body mass index. Dietary intake of vitamin C and vitamin E are correlated with higher relative muscle strength according to the study of Shahinfar et al. [34]. The following may explain the positive influence of antioxidant nutrients on HGS, MIP and lean body mass index: (1) COPD patients exhibit heightened oxidative stress levels, with excessive production of free radicals leading to damage of pulmonary and systemic muscle tissues, including those responsible for respiratory function like inspiratory muscles [35–37]. Supplementation with antioxidants such as vitamin C and selenium can neutralize free radicals within the body, thus reducing oxidative stress-induced damage to muscle tissue and preserving and enhancing muscle strength [38]; (2) oxidative stress can lead to increased breakdown and decreased synthesis of muscle proteins, contributing to muscle atrophy [39]. Antioxidants protect muscle cells from oxidative stress-induced protein damage, helping to maintain a healthy balance between muscle protein synthesis and breakdown, thus preserving lean body mass [40]; (3) antioxidants can inhibit pro-inflammatory responses, improving the microenvironment within muscles to facilitate repair and regeneration of damaged muscle tissue [41]. Additionally, they can stimulate the release of muscle growth factors by activating certain signaling pathways, promoting muscle growth and recovery of strength [42]; (4) COPD patients often experience malnutrition, particularly protein-energy malnutrition [43]. Supplementation with antioxidants contributes to an overall improvement in nutritional status, enhancing immune function and metabolic processes, which in turn benefits muscle function improvement and weight maintenance [44]; (5) a high antioxidant state helps improve blood oxygen-carrying capacity and enhances energy metabolism within muscle cells [45], thereby increasing exercise tolerance and functional performance, including grip strength and inspiratory muscle strength. Notably, the mechanism underlying different antioxidant nutrients in COPD patients may vary depending on patient individual differences and the types, doses and treatment duration of nutrients, which necessitates clinical trials and individualized assessments.
In addition, among patients who did not participate in lung rehabilitation plan while receiving antioxidant nutrient interventions, antioxidant nutrients brought about a significantly higher lean body mass index. This finding suggested that clinicians can consider incorporating antioxidant nutrient supplementation into the standard treatment regimens for COPD patients, particularly for those not enrolled in pulmonary rehabilitation programs, as an effective means to enhance lean body mass and prevent muscle atrophy; and for patients who cannot attend pulmonary rehabilitation promptly or are unsuitable for such programs, improving lean body mass index through antioxidant nutrient supplementation serves as a simple and relatively cost-effective intervention, allowing for better utilization and allocation of healthcare resources. However, only two studies provided information on this subpopulation, which needs more studies for validation in the future.
The population included in the study included patients in the acute exacerbation and stable phases, with interventions including oral and injectable interventions. The analysis was not based on the final values of each outcome indicator, but on the difference relative to baseline, which better indicated that the changes were caused by the intervention. Given the positive role of antioxidant nutrients in COPD, clinical practitioners should consider increasing food intake or supplementation rich in antioxidants such as vitamin C, vitamin E, selenium, carotenoids, etc. in the treatment plan of COPD patients, as an auxiliary means of routine treatment. During the implementation of antioxidant nutrient intervention, regular monitoring of changes in patient HGS, MIP and lean body mass index is important indicators for evaluating treatment effectiveness, and nutritional intervention plans could be adjusted accordingly. Furthermore, education and counseling services on the benefits of antioxidant nutrients could be provided to COPD patients and their families, encouraging them to prioritize consumption of foods abundant in antioxidants in their daily lives and to use supplements judiciously under professional guidance when necessary.
There were some limitations. First, we acknowledge a limitation in our analysis related to the inability to perform subgroup analyses based on the type and frequency of antioxidant supplementation. The mixed composition of some supplements and the limited number of studies reporting on specific outcomes restricted our capacity to conduct these analyses. This limitation may affect the generalizability of our findings to specific supplement types or intake frequencies. Second, studies on muscle function could only be analyzed with 6MWD, while other methods such as the incremental cycling test and incremental shuttle walking test (ISWT) are evaluated by a small number of studies and cannot be used in this analysis. Third, the number of studies included for the outcome evaluation was relatively small, which may affect the reliability of the results. Fourth, there were limited number of studies available for outcomes. Consequently, we were unable to perform a comprehensive evaluation of publication bias using funnel plots, a common method that requires a sufficient number of studies to generate reliable results. This limitation could potentially affect the generalizability of our findings, as publication bias might influence the observed effect sizes and the overall conclusions drawn from the available literature. Fifth, one of the key limitations of this meta-analysis is the inability to extract data on daily energy and protein intake from the included studies. Many of the included studies did not report these essential variables, which are important factors influencing muscle mass, strength, and function. The absence of such data may limit our ability to fully assess the impact of antioxidant nutrients on muscle outcomes in the context of nutritional status. We acknowledge this gap in the data and recommend that future studies consider reporting energy and protein intake to provide a more comprehensive understanding of how these factors interact with antioxidant supplementation in COPD patients.
Conclusion
Antioxidant nutrient intervention significantly improved HGS, MIP and lean body mass index in COPD; for patients who did not participate in lung rehabilitation plan while receiving antioxidant nutrients, antioxidant nutrients resulted in a significantly higher lean body mass index. Future studies are warranted to confirm these findings.
Supporting information
S1 Fig. Results of risk of bias.
1a, risk of bias graph; 1b, risk of bias summary.
https://doi.org/10.1371/journal.pone.0316842.s001
(TIF)
S2 Fig. Sensitivity analysis for muscle mass in the antioxidant nutrient intervention group versus non-antioxidant nutrient intervention group.
2a, lean body mass; 2b, fat-free mass; 2c, lean body mass index; 2d, fat-free mass index; 2e, skeletal muscle mass index.
https://doi.org/10.1371/journal.pone.0316842.s002
(TIF)
S3 Fig. Sensitivity analysis for muscle strength in the antioxidant nutrient intervention group versus non-antioxidant nutrient intervention group.
3a, HGS; 3b, IMS Quad; 3c, MEP; 3d, MIP.
https://doi.org/10.1371/journal.pone.0316842.s003
(TIF)
S4 Fig. Sensitivity analysis for muscle function (6MWD) in the antioxidant nutrient intervention group versus non-antioxidant nutrient intervention group.
6MWD, six-minute walk distance.
https://doi.org/10.1371/journal.pone.0316842.s004
(TIF)
S2 File. The evidence quality assessed by the Grading of Recommendations Assessment, Development and Evaluation.
https://doi.org/10.1371/journal.pone.0316842.s006
(DOCX)
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