Skeletal muscle strength declines significantly during ageing and muscle of aged mammals also is more susceptible to exercise-induced damage and has an impaired ability to fully recover from damage. This leads to instability, an increased risk of falls and an inability to perform everyday tasks, reducing the quality of life of older individuals. The mechanisms underlying these age-related functional deficits are unclear. Muscles of young individuals can adapt following exercise by the increased production of heat shock proteins (HSPs) which protect the muscle during potentially damaging exercise. In contrast the induction of HSPs following exercise is attenuated in muscles of old individuals (Vasilaki et al. 2003). Previous studies using transgenic mice demonstrated a direct link between failure to produce HSPs and functional deficits in muscles of old mice whereby overexpression of HSP70 in skeletal muscle throughout life provided some protection against the development of age-related functional deficits (McArdle et al. 2004).
This study hypothesised that the development of age-related muscle weakness is due to the failure of adaptation, particularly in the HSP response following contractile activity. Maintenance of the HSP content of old muscles at rest and following contractile activity may result in significant improvement in muscle function. The study aimed to examine physiological (treadmill training) and pharmacological interventions that may preserve the ability of muscles of old mice to induce HSPs in skeletal muscle and to assess the effect of these interventions on the susceptibility and recovery of EDL muscles from damaging exercise.
Data demonstrated that 8 weeks of training with protocol of 3 sessions per week for 15 minutes per session at 15m/min was sufficient to cause adaptations in quadriceps muscles of adult mice including changes in redox homeostasis and increases in the HSP70 and HSC70 content. Once this protocol was established, adult (12 month old) mice were trained for 12 months and old (22 months) mice were trained for 10 weeks. To assess the ability of muscles to produce HSPs following exercise, hindlimb muscles of trained and control mice were subject to a 15 minute protocol of non-damaging isometric contractions. Data demonstrated that treadmill training prevented changes in resting levels of HSP70 protein and mRNA and preserved the ability of muscles of old mice to produce mRNA for HSP70 to the same level as adult mice following the non-damaging exercise. To assess the functional effect of this intervention, the maximum tetanic force of the EDL muscle was determined. The EDL muscles were subjected to 450 damaging lengthening contractions. The ability of muscles of these mice to generate force was assessed at 3 hrs and 28 days following the contractions to determine the susceptibility to and recovery from damage. Data demonstrated that treadmill training did not correct the age-related loss of force, protect against a severe protocol of damaging lengthening contractions or enhance recovery.
Pharmacological investigations demonstrated that treatment with the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) significantly increased the HSP70 content of skeletal muscle cells both in vitro and in vivo. HSP70 remained elevated in muscle of adult mice for up to 6 days following a single dose. Adult and old mice were then treated for 4 weeks with 17AAG. Data demonstrated that 17AAG significantly increased HSP70 in muscle of adult and old mice via activation of the transcription factor HSF1. This did not affect markers of oxidative stress or prevent the loss of force in muscles of old mice.
In summary, data have suggested that short- or long-term treadmill training or treatment with 17-AAG resulted in some maintenance of the ability of muscles to produce HSPs. However, the lack of protection against the development of functional defects suggests that this was insufficient to be of significant benefit to muscles of old mice.
This work was funded by Research into Ageing.
