Role of reactive oxygen species in age-related neuromuscular deficits

Abstract

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.

Figure 1. Schematic representation of the two potential pathways of redox signalling to account for activation of key transcription factors following contractile activity in skeletal muscle

Contractions initially lead to activation of NADPH oxidase (probably Nox2) within muscle. This occurs through rapid translocation of the regulatory sub‐units of NADPH oxidase to a muscle membrane and assembly of the catalytic enzyme. It is currently unknown how contractile activity leads to activation of this enzyme. The NADPH oxidase generates superoxide that is rapidly converted to H₂O₂. Some evidence suggests that the major NADPH oxidases predominantly generate superoxide on the outside of the muscle fibre with some H₂O₂ generated rapidly diffusing into the fibre although this is not firmly established. The process by which the increased H₂O₂ leads to activation of transcriptional responses is the subject of debate, but the conventional view is that local concentrations of H₂O₂ are sufficiently high for it to diffuse through the cytoplasm and interact with redox‐sensitive components of pathways activating various transcription factors (shown as a dashed line in the scheme). Note that the cytoplasm contains various enzymes that can degrade H₂O₂ and compounds (e.g. glutathione) with which it can react. The alternative pathway involves the reaction of low levels of H₂O₂ with a highly reactive protein (e.g. Prx or Trx) that is closely associated with the NADPH oxidase with subsequent formation of disulphides and disulphide exchange with partner proteins thus transferring oxidising equivalents from H₂O₂ to proteins with which it would not react at low concentrations. Subsequent activation of the TF occurring through disulphide exchange with a key signalling protein. This pathway has not yet been shown to occur in skeletal muscle. Ageing appears to influence the overall scheme leading to an inability of contractile activity to further activate these transcription factors, but it is currently unknown how this occurs. GPx, glutathione peroxidase; CAT, catalase; Prx, peroxiredoxin; IKK, I kappa B kinase; TF, transcription factor.

Figure 2. Schematic representation of putative redox cross‐talk from muscle to neurons

A shows the situation in innervated muscle fibres from young/adult where contractile activity leads to generation of NADPH oxidase‐derived H₂O₂ in the extracellular space that interacts with adjacent neurons inducing up‐regulation of cytoprotective proteins in the axons. During ageing, this process is likely to be modified since skeletal muscle from old mice does not release equivalent amounts of ROS to the extracellular space (Vasilaki et al. 2006 b) and hence this cytoprotective cross‐talk will not occur. B shows the effect of denervation in young/adult organisms and may also reflect the situation in some fibres from old organisms. Denervation of a fibre induces the fibre mitochondria to release very large amounts of H₂O₂ (and other ROS) that can diffuse out of the fibre to interact with neurons and other adjacent fibres or tissues. These changes may initially represent an initial attempt to stimulate adaptations/axonal sprouting, but if sustained must inevitably lead to degeneration of the muscle fibre and potentially other local tissues. NTF, neurotrophic factors.