Introduction
Exercise-induced oxidative (eu)stress has received considerable attention over the last four decades, with circa 900 original investigations published since 1978. Indeed, redox research per se is a contemporary feature of biomedical journals and conferences, with a plethora of exciting new information relating to health and disease being presented.
The discovery that free radicals (i.e., molecules capable of existing independently, and containing one or more unpaired electrons) exist in living biological organisms occurred in 1954 when Commoner and colleagues (Commoner et al., 1954) first used electron paramagnetic resonance (EPR) spectroscopy to detect free radicals in growing seeds. Around this time, Gerschman et al. (1954) proposed that free radicals damage cells, and second, when mice are exposed to hyperoxia, the biological injury that ensues is likely related to increased free radical production. Following the publication of this work in the mid-1950s, a series of seminal studies confirmed the biological importance (Powers et al., 2016). For example, the work of Chance and Williams (1956) demonstrated that respiring mitochondria can generate hydrogen peroxide, which can diffuse in cells. Then, McCord and Fridovich (1969) discovered the metalloenzyme superoxide dismutase (SOD), showing in the process that superoxide radicals are spontaneously degraded to hydrogen peroxide. The milestone discovery of SOD not only provided much of the basis of our current understanding of antioxidant defence systems, but it is also credited with providing the first convincing evidence that biological reactive oxygen species (ROS) exist and that they are likely salient regulators of cell biology (Powers et al., 2016).
Since these landmark discoveries, the exercise physiology and redox field have grown exponentially with prominent work enhancing our understanding of the role that free radicals (e.g., superoxide) and non-radicals (e.g., hydrogen peroxide), collectively termed ROS, play in systemic and intracellular muscle biology. It is now known, for example, that both different exercise modalities generate ROS and their production is associated with molecular biomarkers of oxidative stress. To the contrary, exercise-induced low-levels of ROS activate key signalling pathways leading to exercise-induced skeletal muscle adaptations. This chapter is designed to introduce the basic concept of oxidative (eu)stress, and in doing so, a brief overview of the key studies pertaining to exercise-induced oxidative stress and those identified as eustress regulators of skeletal muscle will be highlighted. A brief introduction to ground state molecular dioxygen and its derivatives (i.e., ROS) will also provide context to the general area of interest.
‘Oxidative stress’ is a popular term among exercise physiologists and is widely used in the literature, but rarely defined. Sies and Cadenas (1985) defined the term oxidative stress as ‘a disturbance in the prooxidant–antioxidant balance in favour of the former’. Although this definition was widely accepted for over two decades, this description of oxidative stress has undergone scrutiny (Powers et al., 2016), and subsequently, Jones and Sies revised the definition of oxidative stress to ‘an imbalance between oxidants and antioxidants in favour of the oxidants, leading to a disruption of redox signalling and control and/or molecular damage’ (Sies & Jones, 2007). On the latter, the basic premise is that, in an open metabolic system, a steady-state redox balance is maintained at a particular setpoint, providing a basal redox tone, and any deviation away from the steady-state redox balance is regarded as a stress response. This oxidative distress concept, which explains supraphysiological disruption to redox signalling and/or oxidative stress damage to biomolecules, however, only explains one end of the continuum. At the other end, the term oxidative eustress may be used to connect low levels of oxidative stress to intracellular redox signalling and regulation (Sies 2020a).
Oxygen and Its Derivatives
Arguably the most important free radicals in biological systems are radical derivatives from oxygen, and although oxygen is necessary for survival, it has the potential to become toxic when supplied at concentrations higher than normally encountered (i.e., the toxicity of molecular oxygen is primarily due to the production of ROS). Ground state molecular oxygen is, in fact, a di-radical, with two unpaired electrons located in a different antibonding orbital with the same directional spin. Consequently, oxygen can only react with non-radicals by accepting a pair of electrons that spin in an anti-parallel manner (McCord, 1979).
Free radicals in biological organisms include, but not limited to superoxide (O2.−), hydroperoxyl (HO2.), hydroxyl (OH.), carbonate (CO3.−), peroxyl (RO2.), alkoxyl (RO.) and nitric oxide (NO) radicals (Table 1.1). Hydrogen peroxide (H2O2) and hypochlorous acid (HOCL) have no unpaired electrons, and by definition they are non-radicals, but nevertheless these ROS can be powerful oxidants that are often involved in free radical reactions.
Superoxide Anion
Superoxide is a commonly known oxygen-centred free radical. The reduction of a single electron to an O2 molecule produces the superoxide anion. is relatively unreactive with non-radical species in comparison to other radical types (e.g., hydroxyl radical); however, if is generated near the site of any biochemical molecule it can be damaging. The reactivity of in aqueous solutions is more likely to occur in vivo (Halliwell and Gutteridge, 2015). In this environment, can act as a base, accepting a proton to form the hydroperoxyl radical (HO2.). The pKa for this reaction is 4.8, indicating that approximately only 1% of is in the form at physiological pH (Pryor, 1986). However, there may be more at comparatively acidic membrane nanodomains. under a normal metabolic response is dismutated by SOD, which can increase the rate of intracellular dismutation by a factor of 10−9 M−1s−1 to form hydrogen peroxide...