Abstract 051 | Age-related disruption of redox-regulated signalling following contractile activity in skeletal muscle

Malcolm J Jackson, Robert Heaton, Samrajni Banerjee, Caroline A. Staunton, Anne McArdle | Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, UK.

Specific skeletal muscle adaptations to contractile activity appear to be modulated by redox signaling, primarily through reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂). While all early research assumed that ROS were deleterious by-products generated in muscle during exercise, subsequent studies established their roles as signaling molecules involved in a variety of key processes including mitochondrial biogenesis, stress responses, and metabolic regulation. Superoxide can potentially be generated through several pathways in contracting skeletal muscle, but most data now indicate that activation of NADPH oxidase 2 plays a key role (1, 2). Nox2-generated superoxide is rapidly converted to H₂O₂ which acts to activate a series of adaptive signalling pathways. Despite clear evidence that H₂O₂ is generated in muscle during contractions and that some key adaptations can be inhibited by high dose antioxidants, a major challenge in elucidating redox-regulated mechanisms in muscle has been the disparity between physiological intracellular H₂O₂ levels and the higher concentrations typically used in in vitro studies to activate redox-sensitive signalling pathways (3). This has led to development of the concept of redox relays, in which thiol peroxidases, particularly 2-Cys peroxiredoxins (Prdxs), act as intermediates by reacting with H₂O₂ and transferring oxidizing equivalents to downstream proteins (4). Our recent findings demonstrate that low levels of H₂O₂, or electrically-stimulated contractions rapidly oxidize Prdx1, Prdx2, and Prdx3 in mouse muscle fibres (5). Subsequent transcriptomic analysis of human skeletal muscle myotubes confirmed that Prdx2 is essential for upregulating mitochondrial genes in response to H₂O₂ or contraction (6). With ageing, skeletal muscle exhibits attenuated adaptations to exercise and impaired redox signalling with elevated mitochondrial H₂O₂ generation (7). Using an ageing mouse model, we observed diminished Prdx2 oxidation during contractile activity suggesting disruption of redox signalling (5). Thus, it appears that impaired muscle redox signalling may contribute to the poor responses to contractile activity seen during ageing that are a factor in age-related loss of muscle mass and function. Our findings emphasize the importance of redox homeostasis (not merely ROS suppression) in maintaining muscle health and the need to identify specific redox sensitive pathways and proteins affected by ageing.