Increased nuclear permeability is a driver for age-related motoneuron loss

Abstract

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.

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Correspondence to Ashley Gillon.

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figure8

Permeability controls. A series of control experiments was conducted to validate the technique used in the current investigation (Fig. S1). First, both brain tissue homogenate and clear microspheres (impermeable) were incubated in 70 kDa dextran, and the infiltration measured. Second, nuclear fraction isolated from spinal cord homogenate was incubated in large fluorescent microspheres (0.24 μm, much larger than the nuclear pore) to determine whether nuclei retained any barrier. (PNG 222 kb)

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Gillon, A., Steel, C., Cornwall, J. et al. Increased nuclear permeability is a driver for age-related motoneuron loss. GeroScience 42, 833–847 (2020). https://doi.org/10.1007/s11357-020-00155-7

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Keywords

  • Ageing
  • Sarcopenia
  • Nucleocytoplasmic transport
  • Nuclear permeability
  • Motoneuron death
  • Neurodegeneration