Role of reactive oxygen species in age‐related neuromuscular deficits

Although it is now clear that reactive oxygen species (ROS) are not the key determinants of longevity, a number of studies have highlighted the key role that these species play in age‐related diseases and more generally in determining individual health span. Age‐related loss of skeletal muscle mass and function is a key contributor to physical frailty in older individuals and our current understanding of the key areas in which ROS contribute to age‐related deficits in muscle is through defective redox signalling and key roles in maintenance of neuromuscular integrity. This topical review will describe how ROS stimulate adaptations to contractile activity in muscle that include up‐regulation of short‐term stress responses, an increase in mitochondrial biogenesis and an increase in some catabolic processes. These adaptations occur through stimulation of redox‐regulated processes that lead to the activation of transcription factors such as NF‐κB, AP‐1 and HSF1 which mediate changes in gene expression. They are attenuated during ageing and this appears to occur through an age‐related increase in mitochondrial hydrogen peroxide production. The potential for redox‐mediated cross‐talk between motor neurons and muscle is also described to illustrate how ROS released from muscle fibres during exercise may help maintain the integrity of axons and how the degenerative changes in neuromuscular structure that occur with ageing may contribute to mitochondrial ROS generation in skeletal muscle fibres. Schematic illustration of the process of redox signalling of responses to contractile activity and their modification during ageing. In muscle from young and adult subjects, contractile activity leads to activation of muscle NADPH oxidase(s) with generation of superoxide that is rapidly converted to hydrogen peroxide with local oxidation of redox‐active thiols and activation of specific redox‐sensitive transcriptional pathways. This mediates multiple adaptations to the contractile activity including stress responses and mitochondrial biogenesis. In old subjects, this process is attenuated by over‐production of hydrogen peroxide by mitochondria which at the level of individual fibres may be related to the partially or full fibre denervation.