Is sarcopenia a neurodegenerative disease?
Sarcopenia is a major contributor to the loss of independence and deteriorating quality of life in elderly individuals. It is marked by declining skeletal muscle mass and strength beyond the age of 65. Sarcopenia places significant financial and social burdens on societies, particularly those with ageing populations such as New Zealand. Therefore, research into the mechanism underlying this condition is essential if we are to delay its onset and reduce its significance to our society. The current hypothesis suggests the decline in muscle mass evident in sarcopenia is due to muscle fibre atrophy. Although the definitive cause of muscle fibre atrophy remains unclear, denervation-induced muscle atrophy is a well described feature of old age. The driver of age-related denervation remains controversial, but what is known for certain is that death of lower motoneurons within the spinal cord will result in denervation. This study therefore sought to investigate the effect of age on motoneurons within the lumbar enlargement of the spinal cord of mice. Histochemical techniques were used to identify alpha-motoneurons within the spinal cord of mice, in doing so I showed that age results in a significant decline in motoneuron number accompanied by an increase in soma size potentially conducive of motorunit expansion as compensation for motoneuron loss and denervation. Given that ageing features significant motoneuron loss I looked to other neurodegenerative conditions that feature similar symptoms. In doing so I identified that Amyotrophic Lateral Sclerosis (ALS) also features skeletal muscle atrophy and denervation resulting from motoneuron death. In ALS, recent links have been established between motoneuron death and altered nucleocytoplasmic transport, so I asked whether similar defects correlate with motoneuron loss in normal ageing. Immunohistochemistry was used on mouse tissues to explore potential links between motoneuron loss, nucleocytoplasmic transport regulatory proteins and altered nuclear permeability. Old age brought reductions in immunodetectable levels of key nucleocytoplasmic transport proteins in lumbar motoneurons along with increased nuclear permeability. The only intervention that effectively delays the effects of sarcopenia is physical exercise which has been shown to attenuate muscle denervation, prevent neuromuscular deterioration and ultimately to mitigate the muscular losses associated with age. Although exercise is shown to be beneficial often implementation of successful protocols isn’t feasible for elderly individuals, as a result understanding the mechanism of its therapeutic benefit is of particular interest, so that other ways of targeting these pathways can be developed. I therefore asked whether exercise inhibited the age-related changes in both motoneuron number and nuclear transport proteins and found that active elderly mice experienced less motoneuron death and that key nuclear transport proteins were retained better in lumbar motoneurons. My results suggest that emergent defects in nucleocytoplasmic transport may contribute to motoneuron death and that this loss of motoneurons in turn triggers age-related loss of skeletal muscle mass associated with sarcopenia. Exercise slowed or inhibited the main changes and I suggest this may be part of the mechanism by which exercise protects muscle mass in old age. Finally, to provide critical evaluation between the parallels of motoneuron disease and ageing, I also investigated the changes in key nuclear pore proteins identified in ageing animals in the SOD1 model of ALS. In doing so I identified that some of the nuclear pore proteins reduced in ageing are also lost in the SOD1 animals, however, further research in older animals (conditions is more advanced) is required to determine if the pathophysiology of SOD1 ALS is similar to that of other ALS mutations and ageing.
Advisor: Sheard, Philip; Cornwall, Jon
Degree Name: Doctor of Philosophy
Degree Discipline: Physiology
Publisher: University of Otago
Keywords: New Zealand
Research Type: Thesis