**1. Introduction**

Many athletes have utilized ergogenic aids to maintain fitness, improve recovery, and physiological adaptations in long-term exercise programs. Therefore, the effects of ergogenic aids have always attracted a lot of attention, and many researchers have tried to combine exercise programs and ergogenic aids to enhance the benefits of exercise [1,2].

One of the favorite ergogenic supplements among athletes (at all levels) is creatine. Studies have shown that creatine supplementation combined with resistance training had a higher effectiveness in training and increased muscle strength and lean mass [1,2]. As a popular creatine supplement in the sports and fitness industry, it is believed that creatine supplementation helps maintain high-energy phosphate stores during exercise. Moreover, specific mechanisms of creatine supplementation have been identified in improving athletic performance [3,4]; there are ambiguities about its effects on oxidative stress and its mechanism of action. The antioxidant effects of creatine may be due to various functional mechanisms, such as indirect mechanisms involved in the cell membrane stabilization and improvement of cellular energy capacity [5] and its direct antioxidant properties [6]. Oxidative stress reduces strength and performance [7]; mechanically, reactive oxygen

**Citation:** Arazi, H.; Eghbali, E.; Suzuki, K. Creatine Supplementation, Physical Exercise and Oxidative Stress Markers: A Review of the Mechanisms and Effectiveness. *Nutrients* **2021**, *13*, 869. https:// doi.org/10.3390/nu13030869

Academic Editor: David C. Nieman

Received: 31 January 2021 Accepted: 27 February 2021 Published: 6 March 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

species (ROS) can speed up skeletal muscle fatigue by reducing calcium sensitivity [8] and can decrease maximal calcium-activated force [9]. ROS are free radical molecules that can oxidatively alter cellular compounds such as lipids, proteins, and DNA, and damage cells [10]. They are also associated with several diseases such as cancer, cardiovascular disease, Parkinson's, Alzheimer's, etc. [11]. Increased ROS production due to certain diseases or exercise can exceed the capacity of the antioxidant system, which can lead to oxidative stress and dysfunction. However, its predominant impact on the human health and function is still controversial [12].

One of the common physiological conditions associated with the enhancement of oxidative stress is exercise [13,14]. Exercise can have positive and negative effects on oxidative stress [15]. High-intensity exercise can lead to a temporary imbalance between the active oxygen/nitrogen species production and removal, which can lead to oxidative stress. Although exercise-induced ROS is required for the production of natural force in the muscles, high levels of ROS appear to cause contractile dysfunction [16]. Exercise-induced ROS production is important for exercise-induced mitochondrial biogenesis [17], because ROS are used as signaling molecules to activate redox-sensitive signaling pathways [16]. Evidence suggests that exercise intensity and duration are associated with oxidative stress in humans, and has been confirmed by several studies [18,19]. Intense exercise or exercise in untrained people is associated with a greater increase in oxidative stress compared to moderate and regular aerobic exercise [20]. In addition, long-term regular training may improve some antioxidant defense mechanisms, and thus may limit mitochondrial oxidative damage [21,22].

Using antioxidant supplements along with physical activity can reduce the harmful effects of oxidative stress caused by exercise, increase the antioxidant defense system associated with exercise and increase the positive effects of physical activity. Creatine is one of the most popular supplements for athletes; it can act as a cellular energy buffer, increase creatine phosphate (CrP) and adenosine triphosphate (ATP) regeneration [23]; additionally, creatine compounds can have different effects. It seems that creatine has significant antioxidant effects. In general, the purpose of this study was to investigate the available information on the effects of endurance, resistance, and combination exercise along with the creatine supplementation on oxidative stress and their mechanism of action. Therefore, the present study tried to summarize the available information and research on the effects of creatine supplement consumption and physical exercise on oxidative stress and how it works, together with the mechanisms of action.
