*Exercise-Induced Formation of Reactive Oxygen Species and Select Antioxidant Defense Mechanisms*

ROS generation from exercise has a significant role in triggering and sustaining the healthy cellular, tissue, and organ level adaptations that help improve and maintain cardiometabolic health. Acute ROS generation from exercise occurs via electron transport oxygen catabolism in the skeletal muscle. This is triggered by a substantial increase in mitochondrial oxygen uptake into the skeletal muscle cell, increasing ROS production [34]. Exercise-induced ROS production can also produce muscle injury, which sends inflammatory signals that attract polymorphonuclear neutrophils and macrophages and produce additional ROS in its defense mechanism of oxidative burst [35]. If there is a chronic imbalance of more ROS production than antioxidant activity, chronic oxidative stress may lead to apoptotic pathways in tissues [36]. A skeletal muscle oxidative stress imbalance is commonly seen in untrained individuals who begin a strenuous training program or "weekend-warriors" who perform a single bout of infrequent strenuous exercise (Figure 2). Although exercise is known to increase the abundance of ROS, progressive exercise training allows time for the upregulation of defense mechanisms that help protect the body from oxidative damage. This is known as redox balance (Figure 3), where free radicals are balanced by the adaptive antioxidants produced [37]. Exercise may stimulate the generation of antioxidants by triggering significant cell adaptations and upregulating antioxidantproducing enzymes [38]. Those who are exercise-trained and perform a single bout of exercise can leverage the benefits of endogenous antioxidant upregulation, along with mitochondrial expansion, cryoprotection, and insulin sensitivity [35]. The importance of ROS is highlighted in experimental models treated with allopurinol. This compound inhibits ROS production and protects muscle tissue from oxidative stress. However, because exercise-induced ROS was not produced, the important adaptive signaling pathways for oxidative protection were blunted. Thus, the formation of ROS in exercise can help activate these intrinsic protective pathways. Notwithstanding, allopurinol is a competitive inhibitor for xanthine oxidase that produces H2O2. H2O2 is a kind of ROS; thus, xanthine oxidase is an intrinsic prooxidant. This adaptive signaling response is an important body regulation, and if extrinsic, pharmaceutical dose antioxidants are administered, the body's natural adaptive ability to produce in trinsic antioxidants may be thwarted [38].

**Figure 2.** Relationship of HO-1 and ROS in habitually trained versus untrained subjects. Individuals who have performed a single bout of exercise (non-trained) versus individuals with exercise training experience (trained).

**Figure 3.** Redox Balance of ROS and Antioxidants. Exercise potentiates the release of reactive oxygen species due to increased oxidative exposure. However, exercise training also induces an adaptive response with the upregulation of antioxidant defense mechanisms that will help restore redox balance. The downregulation of endogenous antioxidant systems or the increased production of reactive oxygen species can precipitate an imbalance in redox balance and potentiate chronic oxidative damage.

Ultimately, exercise-related ROS adaptations improve oxygen transport and delivery that translate into better aerobic fitness that help explain many of the health benefits of exercise. Furthermore, upregulation of endogenous antioxidant systems can work in concert with exogenous dietary antioxidants to mitigate ROS-related tissue damage and support normal metabolic function and healthy aging. Conversely, the accumulation of ROS and inadequate ROS defense responses has been implicated as a key mechanism leading to significant atrophy in muscle tissue. Muscle atrophy due to chronic excessive ROS exposure progresses slowly as part of the normal aging process but is more pronounced and accelerated in severe underlying pathological processes such as in cancer wasting (cancer cachexia) [39], neurodegenerative diseases (Parkinson's, Alzheimer's), and immobilization (musculoskeletal injury) [40].
