Fig 1. Schematic representation of the activation of the stress response in skeletal muscle
Considerable data has been presented concerning the possibility that oxidative processes play important roles in the pathogenesis of many common disorders such as coronary heart disease and some cancers, in addition to a fundamental role in the ageing process.
Several theories of ageing have been proposed, but new techniques including molecular genetics and intervention studies in model organisms strongly support a role for reactive oxygen species and the stress response in modulation of the ageing process.
The Free Radical Theory of Ageing was first described by Harman (1956), and there now is considerable evidence that an accumulation of oxidative damage to lipids, proteins and DNA occurs in tissues of aged mammals, including skeletal muscle.
Recent transgenic and pharmacological interventions, which reduce oxidant damage to cells in model systems, appear to confirm the importance of this mechanism.
Transgenic approaches with genes such as superoxide dismutase and catalase involved in detoxifying superoxide and hydrogen peroxide in the mitochondria and cytosol and pharmacological approaches using mimetics of these antioxidant enzymes have shown that the endogenous production of ROS by normal physiological processes is a major limit to lifespan.
Stress (or heat shock) proteins are an important part of the cellular responses to free radicals and overexpression of specific HSPs protects cells against free radical-mediated pathology.
Lithgow and colleagues have demonstrated that these proteins play an important role in regulation of the ageing process in the model organism, Caenorhabditis elegans.
They reported that all naturally occurring mutants that demonstrate increased longevity also showed increased resistance to stress and analysis of these C. elegans mutants indicate that a proportion have an accumulation of HSPs.
These data, therefore, suggest that factors which modify oxidative stress or the response of the cell to oxidative stress may play a major role in modulating the ageing process and hence be important in maintenance of muscle function in skeletal muscle of aged individuals.
In summary, there is now considerable evidence that an increased production of free radicals plays a major role in activation of adaptive responses in skeletal muscle.
The production of free radicals is modified somewhat in muscle from older individuals and new evidence is emerging to suggest that the ability of muscle from older individuals to respond to stress is blunted.
It may be that the balance between pro-oxidant production and ability to mount a successful adaptive response is crucial in the ability of muscles to recover from damage and the changes in redox state of the muscle cells results in a vicious circle of events which result in development of the functional deficits which occur in our muscles as we age.