From ROS Signaling to Redox Resistance in Exercise and Metabolic Disease

Physical exercise induces metabolic and cellular adaptations that are essential for maintaining systemic homeostasis and for preventing metabolic diseases. A growing body of evidence indicates that many of these effects are mediated by reactive oxygen species (ROS), which act as signaling molecules rather than merely as damaging byproducts. During skeletal muscle contraction, ROS are generated in a spatially and temporally controlled manner, primarily through enzymatic sources, such as NADPH oxidases, and regulate pathways involved in glucose uptake, mitochondrial biogenesis, and metabolic adaptations. In addition to skeletal muscle, exercise-induced ROS contributes to systemic adaptation through direct redox mediators and endocrine communication regulated by ROS, influencing tissues including the liver, heart, vasculature, and pancreas. Circulating factors, such as selenoprotein P (SeP), have emerged as important modulators of redox balance. As a liver-derived selenium transport protein, SeP regulates antioxidant enzyme expression and activity, and can shift the balance between ROS production and scavenging. Elevated SeP levels, as observed in metabolic diseases, may impair physiological ROS signaling and blunt exercise-induced metabolic responses. Exercise also improves pancreatic β-cell function, although the mechanisms underlying these effects remain unclear. Given the central role of ROS in skeletal muscle signaling, redox-dependent mechanisms may also contribute to β-cell responses. Herein, we propose redox resistance as an emerging conceptual framework, defined as impaired responsiveness to physiological ROS signaling . This concept may provide a unifying model to explain impaired metabolic adaptation in type 1 diabetes, obesity, and type 2 diabetes and may guide strategies to restore physiological ROS signaling and adaptive responses to exercise.