Life expectancy continues to extend, although frailty caused by loss of skeletal muscle mass continues unimpeded. Muscle atrophy caused by withdrawal of motor nerves is a feature of old age, as it is in amyotrophic lateral sclerosis (ALS) in which skeletal muscle denervation results from motoneuron death. In ALS, direct links have been established between motoneuron death and altered nucleocytoplasmic transport, so we ask whether similar defects accompany motoneuron death in normal ageing. We used immunohistochemistry on mouse tissues to explore potential links between neuromuscular junction (NMJ) degeneration, motoneuron death and nucleocytoplasmic transport regulatory proteins. Old age brought neuromuscular degeneration, motoneuron loss and reductions in immunodetectable levels of key nucleocytoplasmic transport proteins in lumbar motoneurons. We then asked whether exercise inhibited these changes and found that active elderly mice experienced less motoneuron death, improved neuromuscular junction morphology and retention of key nucleocytoplasmic transport proteins in lumbar motoneurons. Our results suggest that emergent defects in nucleocytoplasmic transport may contribute to motoneuron death and age-related loss of skeletal muscle mass, and that these defects may be reduced by exercise.

Sarcopenia is the loss of skeletal muscle mass with age, the precise cause of which remains unclear. Several studies have shown that sarcopenia is at least partly driven by denervation which, in turn, is related to loss of motor nerve cells. Recent data suggests degradation of the nucleocytoplasmic barrier and nuclear envelope transport process are contributors to nerve loss in a number of neurodegenerative diseases. Having recently shown that important components of the nuclear barrier are lost with advancing age, we now ask whether these emergent defects accompany increased nuclear permeability, chromatin disorganization and lower motoneuron loss in normal ageing, and if so, whether exercise attenuates these changes. Immunohistochemistry was used on young adult, old and exercised mouse tissues to examine nucleocytoplasmic transport regulatory proteins and chromatin organization. We used a nuclear permeability assay to investigate the patency of the nuclear barrier on extracts of the spinal cord from each group. We found increased permeability in nuclei isolated from spinal cords of old animals that correlated with both mislocalization of essential nuclear transport proteins and chromatin disorganization, and also found that in each case, exercise attenuated the age-associated changes. Findings suggest that the loss of nuclear barrier integrity in combination with previously described defects in nucleocytoplasmic transport may drive increased nuclear permeability and contribute to age-related motoneuron death. These events may be significant indirect drivers of skeletal muscle loss.