Effects of antioxidant pretreatment on skeletal muscle damage and oxidative stress following acute high-intensity exercise: a meta-analysis

Abstract

OBJECTIVE: Current evidence indicates that exercise-induced oxidative stress involves a dual role of reactive oxygen species, which participate in exercise adaptation while potentially causing tissue damage, highlighting the necessity for precise regulation of antioxidant dosage and timing. This study employs a Meta-analytic approach to systematically evaluate the effects of antioxidant pretreatment on biomarkers of skeletal muscle oxidative stress injury following acute strenuous exercise, and to explore the moderating effects of dosage, intervention duration, and training status. METHODS: A systematic search was conducted for randomized controlled trials that investigated the effects of antioxidant pretreatment on exercise-induced oxidative stress in PubMed, Web of Science, EBSCO, CNKI, VIP and WanFang databases from inception to February 2025. Literature quality was assessed using the physiotherapy evidence database scale. Data analysis was performed using RevMan 5.4 and Stata statistical software. RESULTS: (1) This meta-analysis included 16 studies from 12 publications, comprising 264 athletes and regularly exercising individuals. (2) The physiotherapy evidence database scale scores ranged from 6-8 (7 studies) to 9 (5 studies), indicating overall high methodological quality. (3) Meta analysis results showed that antioxidant pretreatment significantly decreased post-exercise serum creatine kinase [standardized mean difference (SMD)=-0.31, 95% confidence interval (CI) (-0.63, 0.00), P=0.05], interleukin-6 [SMD=-0.66, 95%CI (-1.03, -0.29), P=0.0005], and malondialdehyde levels [SMD=-1.10, 95%CI (-1.96, -0.23), P=0.01], and increased glutathione peroxidase activity [SMD=1.33, 95%CI (0.87, 1.78), P < 0.00001] and total antioxidant capacity [MD=4.77, 95%CI (3.87, 5.67), P < 0.00001]. Subgroup analysis showed that low-dose (≤500 mg/d) short-term (≤14 d) intervention had a more significant inhibitory effect on malondialdehyde levels (SMD=-1.15), while high-dose long-term intervention may inhibit exercise adaptation. Training status significantly moderated the effect size, with general athletes showing greater reduction in malondialdehyde levels than elite athletes (P < 0.05). CONCLUSION: Antioxidant pretreatment can effectively alleviate oxidative stress damage induced by acute strenuous exercise, but its effect is influenced by dosage, intervention duration, and training status. Short-term high-dose supplementation is suitable for rapid recovery during competition periods, while long-term application requires weighing antioxidant benefits against the risk of adaptation inhibition.

1. Introduction

Oxidative stress is a pathophysiological process in which the body produces excessive free radicals and/or exceeds its own scavenging capacity when subjected to external stimuli, leading to an imbalance in the redox system [1]. Since DILLARD et al. [2] first discovered in 1978 that exercise can increase lipid peroxidation levels, numerous studies have shown that both short-duration high-intensity and prolonged endurance exercise can induce oxidative stress, resulting in skeletal muscle damage, exercise-induced fatigue, and decreased exercise performance [3-4]. During strenuous exercise, rapid skeletal muscle contraction leads to a surge in reactive oxygen species (ROS) production from the mitochondrial electron transport chain, while pathways such as xanthine oxidase and NADPH oxidase are also activated, further exacerbating ROS generation [5]. When ROS concentrations exceed the scavenging capacity of the endogenous antioxidant system, lipid peroxidation, protein carbonylation, and DNA oxidative damage occur, ultimately leading to exercise-induced oxidative stress injury [6-7].

The discordance between the physiological and pathological roles of ROS is a core contradiction in current research. Physiological levels of ROS act as signaling molecules, activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to promote antioxidant enzyme expression, thereby enhancing the body's adaptation to exercise [8-10]. However, excessive ROS disrupt calcium homeostasis, impair mitochondrial function, and exacerbate muscle fatigue by reducing sarcoplasmic reticulum Ca²⁺ release efficiency [11-12]. Studies have shown that blood markers of oxidative damage, such as creatine kinase and malondialdehyde, are significantly elevated after exercise and are positively correlated with muscle soreness and decreased strength [13-14]. Therefore, how to balance the physiological and pathological effects of ROS through exogenous antioxidant intervention has become an important topic in sports medicine.

The application strategy of antioxidants is controversial. Antioxidants are substances that have been proven to reduce the impact of reactive oxygen and nitrogen species in the human body [15], and are typically classified as exogenous or endogenous [16]. Early studies showed that classic antioxidants such as vitamin C and vitamin E can reduce post-exercise oxidative damage by scavenging free radicals [17-18]. However, recent studies have indicated that long-term high-dose antioxidant supplementation may inhibit the exercise-induced activation of the endogenous antioxidant system, interfere with the Nrf2 signaling pathway, and thereby weaken training adaptations [19-21]. This complexity of dose and timing results in high heterogeneity in the clinical efficacy of antioxidants [22]. Currently, there is no clear consensus on the moderating effects of antioxidant pretreatment dosage [17-18], intervention duration, and training status on effect sizes and their mechanisms [23-27], necessitating analysis to provide evidence-based guidance for optimizing sports nutrition supplementation strategies.