**5. The Impact of Exercise in the REDOX System**

Exercise puts pressure on body structures and organs, so blood must be delivered in quantity to the skeletal muscle, heart, lung (among others) rich in oxygen and nutrients to atone for that [162]. However, this stressor leads to an oxygen supply insufficient for the demands of the body, and then, in response to that, many tissues produce ROS [163]. Under normal and healthy conditions, with oxidative levels within a normal range, the available free radicals promote vasodilatation, production of muscle force and maintenance of its content, signal transduction and other related activities [58,164]. In the muscle, contractions during exercise also induce ROS formation, with this upregulating the activity of transcription factors such as NF-kB, activator protein 1 (AP-1) and NRF2, which leads to a more pronounced activity of antioxidants enzymes, inducing muscle adaptations and protecting it from periods of increased OS [165–167]. A study performed in old rats who performed 12 weeks of treadmill-run exercise observed an increased Nrf2 expression [168]. Moreover, a study performed in recreationally active males observed an exercise-induced Nrf2 elevation to 3 h of eccentric contractions of the knee extensors [169].

On this basis, exercise has been shown to enhance ROS detoxifying pathways by increasing the activity of SOD, Gpx, catalase and the master regulator of antioxidant defence, Nrf2 [170,171]. It is the upregulation of these detoxifying pathways that appears to be essential for the adaptive protection developed to work against detrimental effects of OS [172]. For instance, the sarcoplasmic reticulum, which releases Ca2+ necessary for muscle contraction, is highly sensitive to ROS levels, with dysregulated increments in ROS reducing myofibrils sensitivity and therefore affecting muscle contraction [173,174]. Another example that corroborates that ROS effects are dependent on their levels is observed when talking about JNK/SMAD signalling axis, responsible for muscle growth via SMAD2 phosphorylation leading to myostatin inhibition [175]. Low levels of ROS induce JNK phosphorylation, followed by SMAD2 phosphorylation and consequently muscle growth (transient activation of JNK), whereas high levels of ROS also activate JNK but deactivate phosphates, resulting in JNK persistent activation, and were associated with muscle adaptation failure [51,175]. Excess of free radicals, due to intensive exercise or not, may result in OS, putting molecules (i.e., protein, lipids and DNA) at risk for oxidative modifications [53,100]. Proteins are the most susceptible to oxidative modifications, with the more common type of oxidation modification being carbonylation, altering protein conformation leading to partial or total inactivation [176]. The direct consequence is loss of function or structural integrity having wide downstream effects leading to cell dysfunction [177]. PA appears to promote protection against protein carbonylation, which may occur due to antioxidant defence activation or increased protein carbonyls turnover [178]. Other types of oxidation modification that proteins are susceptible to are, for example, tyrosine nitration, S- glutathionylation and advanced glycation end products (AGEs) (see [179,180] for more detailed description of these processes).

Beneficial changes observed in muscle occurs in response to long-term, regular, and moderate training due to muscle adaptation, whereas acute and strenuous exercise provokes excessive free radicals, causing OS damage and fatigue and impacting the body's health and exercise capacity [181,182]. Moreover, exercise modulation through ROS towards muscle provokes different effects on structure and function; this is majorly dependent on the type of training, which leads to activation of different pathways. In general, exercise is divided into two groups: aerobic/endurance exercise and resistance exercise. In endurance (non-exhaustive) training, the source of energy is mainly from the mitochondrial biogenesis, dependent on ROS production by exercise, modulated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the principal pathway to rise oxidative capacity of the muscle [183,184]. Regarding resistance training, the produced ROS activates signalling pathways such as IGF-1 and PI3K/AKT/mTOR, and they are associated with increments in protein synthesis [185]. Additionally, in sprinting, a short-term anaerobic exercise, high levels of ROS are produced mainly by NOXs and xanthine oxidase system; in this case, ROS production by mitochondria is less noticeable [186,187]. Moreover, in general, both resistance and endurance (exhaustive) training are shown to increase ROS levels by the skeletal muscle leading to OS, an increase in cortisol levels and a transitory immunosuppression [39]. In short, together aerobic and resistance training reduces OS, increasing resistance against it, and improves antioxidant status in the long term [188–198].

Finally, it appears that the influence that exercise has on the metabolism and on the redox system may explain the already proven benefits of exercise in health and disease.
