Abstract
Acute exercise increases reactive oxygen and nitrogen species generation. This phenomenon is associated with two major outcomes: (1) redox signaling and (2) macromolecule damage. Mechanistic knowledge of how exercise-induced redox signaling and macromolecule damage are interlinked is limited. This review focuses on the interplay between exercise-induced redox signaling and DNA damage, using hydroxyl radical (·OH) and hydrogen peroxide (H2O2) as exemplars. It is postulated that the biological fate of H2O2 links the two processes and thus represents a bifurcation point between redox signaling and damage. Indeed, H2O2 can participate in two electron signaling reactions but its diffusion and chemical properties permit DNA oxidation following reaction with transition metals and ·OH generation. It is also considered that the sensing of DNA oxidation by repair proteins constitutes a non-canonical redox signaling mechanism. Further layers of interaction are provided by the redox regulation of DNA repair proteins and their capacity to modulate intracellular H2O2 levels. Overall, exercise-induced redox signaling and DNA damage may be interlinked to a greater extent than was previously thought but this requires further investigation.
Highlights
Acute exercise disrupts homeostasis, imposing a transient stress that inducts beneficial cyto-protective responses and adaptations with repeated bouts (Cobley et al, 2012; Egan and Zierath, 2013; Hawley et al, 2014)
This paradigm is well-established in many settings and likely occurs with the nanomolar (∼10–100 nM; Levonen et al, 2014) H2O2 fluxes that define growth factor signaling in the resting state (Rhee, 2006)
Exercise-induced quantal H2O2 yields are likely in the micromolar range (∼1 μM; Palomero et al, 2008) and in this situation DNA damage and redox signaling are unlikely to be mutually exclusive
Summary
Acute exercise disrupts homeostasis, imposing a transient stress that inducts beneficial cyto-protective responses and adaptations with repeated bouts (Cobley et al, 2012; Egan and Zierath, 2013; Hawley et al, 2014). A resultant mechanistic requirement exists for ·OH to be generated proximal to DNA and existence of conditions that promote reactions 1 and 2 (e.g., nuclear H2O2 diffusion) for exercise-induced ·OH mediated DNA damage to occur. Exercise-induced ·OH mediated DNA damage proceeds in a random and indiscriminate chemical manner, exemplified by a myriad of guanine oxidation products (Radak et al, 2011b).
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