A role for NCAM in the age old story of sarcopenia

muscle;NCAM;sarcopenia

Gillon, Ashley Penman ; Sheard, Philip

University of Otago

关键词: muscle;    NCAM;    sarcopenia;   

Others  :  https://ourarchive.otago.ac.nz/bitstream/10523/5723/3/GillonAshleyP2015MSc.pdf

美国|英语

来源: Otago University Research Archive

【 摘 要 】

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 pathogenesis of this condition is essential if we are to delay its onset and reduce its significance to our society. The current hypotheses suggest age-associated loss of muscle follows the permanent loss of motoneuron synaptic contact (denervation). The failure of neighbouring intact neurons to compensate (re-innervation) results in death or atrophy of the fibre. I propose that the loss of re-innervative ability is the result of age-related down regulation of a neurite attracting factor (NAF) released from muscle fibres upon denervation. Neural cell adhesion molecule (NCAM) is a prime candidate protein for this proposed NAF as it is an essential mediator of nerve growth and synaptic contact during development. More recently NCAM cell adhesion and intracellular signalling roles have both been identified based on the post-translational addition of polysialic acid (PSA) to NCAM. Therefore, the following investigation aimed to first replicate previous work showing that young muscle fibres produce high levels of NCAM in response to denervation. Second, I aimed to determine if an age-related decline in NCAM up-regulation exists in response to denervation in elderly muscle. Young animals responded to denervation with significantly increased NCAM present at extra-junctional locations in the muscle fibre. There were significant extra-junctional increases in un-polysialylated NCAM (unNCAM) (14.1 - 20.5 relative protein level), while polysialylated NCAM (PSA-NCAM) showed significant cytoplasmic increases (19.9 - 31.7 relative protein level). By contrast, elderly animals showed 8.7% less extra-junctional unNCAM and 22.5% less cytoplasmic PSA-NCAM than young animals. These observations suggest that an age-related decline in the production of NCAM in response to denervation may be a key regulator of the inability of muscle fibres to attract a neuronal sprout. Therefore, I believe that reduced ability to respond to denervation by up-regulation of NCAM production may be a primary contributor to the problem of long-term denervation among elderly muscle fibres. Further investigation needs to focus on what specific NCAM regulatory signalling pathways are impaired in elderly muscles so that in future we may develop a strategy to keep or restore neuronal input to elderly muscle fibres, thereby preventing much of the age-related muscle atrophy.