Correction: Impact of creatine supplementation on inflammation: evidence from a systematic review and meta-analysis of randomized double-blind placebo trials

Inflammation plays a pivotal role in both physiological adaptation and pathological processes. Inflammation is the response of living vascularized tissue to injury and can be triggered by microbial infections, physical agents, chemical substances, necrotic tissue, or immunological reactions. The goal of inflammation is to contain and isolate the injury, destroy invading microorganisms, and inactivate toxins, as well as prepare the tissue for healing and repair (1).Conversely, chronic low-grade inflammation is defined as a two to four-fold elevation in circulating pro-inflammatory markers, including C-reactive protein (CRP), tumor necrosis factor-a (TNFa), and interleukin-6 (IL-6). This persistent inflammatory state is strongly associated with the aging process and contributes mechanistically to sarcopenia-the age-related reduction in muscle mass and strength (2). Beyond aging, inflammation drives the progression of several chronic diseases: elevated CRP and TNF-a concentrations are associated with increased total knee pain in osteoarthritis, and chronic inflammation can lead to metabolic disorders such as Type 2 Diabetes Mellitus and cardiovascular diseases. However, the increase in IL-6 following exercise may play a beneficial role by mobilizing substrates for energy and enhancing insulin sensitivity, potentially protecting against disorders like Type 2 Diabetes Mellitus by inhibiting TNF-a production (3). The clinical and performance implications of managing inflammation are critical, as exercise-induced muscle trauma results in pain, delayed onset muscle soreness (DOMS), reduced range of motion, and prolonged muscle strength loss, negatively impacting subsequent athletic performance (4,5). With this in mind, pharmacological and nonpharmacological interventions have gained attention for improving quality of life by enhancing cardiovascular, metabolic, and inflammatory parameters (6)(7)(8)(9).In this context, creatine is a widely popular dietary supplement utilized as an ergogenic aid. Its well-established performanceenhancing effects are rooted in its fundamental role as a temporal and spatial energy buffer. Supplementation reliably increases total muscle creatine concentration, enhancing phosphocreatine (PCr) availability to facilitate ATP resynthesis during high-intensity exercise (10). When combined with resistance training, creatine reliably promotes strength and fat-free mass gains in diverse populations, including older adults (11). While creatine is widely recognized for its performance-enhancing properties, recent studies suggest it may also modulate inflammatory responses, especially following intense physical activity. Creatine is reported to be anti-inflammatory in nature, helping to maintain muscle integrity and attenuating inflammatory markers after strenuous exercise sessions (4,12).The precise mechanisms underlying creatine's antiinflammatory and cytoprotective effects remain to be definitively determined. However, several mechanisms have been proposed. One theory involves osmotic effects and cellular swelling; creatine increases intracellular water content (13).Current evidence regarding creatine's potential antiinflammatory properties remains inconsistent, highlighting significant knowledge gaps across different populations and protocols. Positive effects in athletes subject to high physiological stress have been frequently reported. For instance, creatine supplementation for five days prior to a half-ironman competition significantly reduced the exercise-induced increase in plasma levels of pro-inflammatory cytokines, including TNF-a, interferon-alpha (IFN-a), and interleukin-beta (IL-1b), as well as Prostaglandin E2 (PGE2), 24 and 48 hours post-competition (4,12). Similarly, creatine supplementation attenuated the post-race increase in plasma TNF-a (by 33.7%) and PGE2 (by 60.9%), and abolished the increase in lactate dehydrogenase (LDH) activity following a strenuous 30 km race in marathon runners (4,12). However, null findings have limited the generalization of these effects to other populations or exercise types. In studies focused on chronic, low-grade inflammation, 12 weeks of creatine supplementation yielded no effect on inflammatory biomarkers (CRP, IL-1b, IL-6, TNF-a) in patients with mild to moderate knee osteoarthritis (14). Moreover, combining creatine supplementation (5 g/day for 12 weeks) with resistance training in community-dwelling older adults failed to provide additional benefits on systemic inflammation markers such as IL-6, interleukin 10 (IL-10), and CRP, compared to training with placebo (15). Creatine also failed to reduce muscle damage (assessed via strength, range of motion, soreness, and elevated creatine kinase activity) or enhance recovery following a resistance exercise challenge designed to be hypoxic in trained men (5). Several methodological limitations contribute to these discrepancies, as many studies are small-scale; for example, the study investigating creatine in osteoarthritis included only 18 participants (14) and the half-ironman study included only 11 triathletes (4,5). Furthermore, the inflammatory markers assessed vary widely across trials, ranging from cytokines (IL-6, TNF-a, IL-1b, IFN-a) and pain mediators (PGE2) to muscle damage proxies (creatine kinase-CK, lactate dehydrogenase-LDH, CRP). Despite growing interest, current evidence on creatine's impact on inflammation remains fragmented, with no consensus across populations or protocols.The inconsistencies observed between trials that investigated acute exercise-induced inflammation (4,12) and those addressing chronic inflammation (14,15) highlight a critical need for synthesizing the accumulated data (14). A systematic synthesis and meta-analysis is therefore warranted to rigorously aggregate findings from randomized controlled trials. Such an approach will permit a detailed evaluation of acute versus chronic creatine effects across different physiological states and population subsets (5). Crucially, this effort must focus on objective inflammatory markers measured in human participants to clarify the clinical and physiological relevance of creatine's purported antiinflammatory effects. A systematic review with meta-analysis is warranted to clarify whether creatine exerts clinically meaningful anti-inflammatory effects in humans, particularly in the context of exercise-induced and chronic inflammation.Therefore, the present study aimed to systematically review and meta-analyze randomized controlled trials investigating the effects of creatine supplementation on inflammatory biomarkers in humans. 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