How exercise induces oxidative eustress

Abstract Exercise induces oxidative eustress by provoking beneficial hormetic responses (e.g., upregulating endogenous antioxidant enzymes). Current knowledge regarding how exercise induces oxidative eustress is critiqued with particular reference to superoxide and lipid peroxidation-derived electrophile-mediated signaling in skeletal muscle. First, NADPH oxidase-derived superoxide seems to induce oxidative eustress by activating redox-sensitive transcription factors like nuclear factor erythroid 2-related factor 2 (Nrf-2). Second, lipid peroxidation-derived electrophiles like 4-hydroxynonenal may also activate Nrf-2 by covalently alkylating Kelch-like ECH-associated protein 1—which enables Nrf-2 to translocate to the nucleus to transcribe cytoprotective genes. Despite pharmacological evidence supporting both mechanisms, many of the underlying signaling steps remain unclear. For example, whether superoxide signals directly (e.g., by reacting with iron-sulfur proteins like aconitase) is unclear. Further, a role of redox relays in transducing redox signals is appealing, but direct evidence in an exercise setting is lacking. Disambiguating how exercise induces oxidative eustress holds promise for optimizing exercise training interventions in health and disease.