A failure of neuroprotective redox signalling from skeletal muscle to motor neurons leads to loss of motor units with ageing

Lead Research Organisation: University of Liverpool
Department Name: Clinical Sciences

Abstract

The loss of skeletal muscle mass that occurs as we age leads to a significant decline in muscle strength and this is a major factor leading to the physical frailty seen in the elderly. Frailty is a major contributor to many health care problems and poor quality of life and results in increased risk of falls, hypothermia, incontinence and lack of independence. The bulk of our muscle declines by ~40% between the ages of 50 and 70 years regardless of the amount of exercise that is undertaken. Most current approaches to preserve muscle function during ageing try to improve the function of the muscle that remains in the elderly and are based on exercise training regimens, but the loss of muscle cells is associated with a loss of the motor nerves that stimulate the muscle to contract and there is no evidence that these can be replaced by exercise training. Thus exercise-based approaches can optimise the remaining muscle in the elderly, but cannot replace the motor nerves that are already lost. It is currently unknown whether the loss of the motor nerves precedes and leads to loss of the muscle or whether the reverse occurs. It appears that damage to tissues by highly reactive substances called free radicals or reactive oxygen species (ROS) may play an important role in the processes of ageing. Skeletal muscle cells have sophisticated systems that allow them to increase their protection against ROS during exercise, but this process appears to fail during ageing and contributes to the age-related loss of muscle cells. It is not known whether similar protective systems exist in the motor nerves, but some data indicate that muscle cells release substances that stimulate an increased protection against ROS in the motor nerves and hence helps to maintain their vaibility. Interventions to support these system might therefore help maintain the function of motor nerves during ageing. This possibility will be tested in a project that will use a combination of cell culture and mouse models. Muscle cells and motor nerve cells will be co-cultured to determine whether contracting muscle cells release substances that act on motor neurons to upregulate their defences against ROS and then the effect of ageing on this process will be examined in young and old mice. Our group has previously shown that aged mice with a genetic modification to improve their muscle defences against ROS show an improvement in muscle function. This project will determine whether this same genetic modification also improves the function of motor nerves. Finally the project will identify the substances that mediate these protective effects since they may be potential targets for future intervention studies to maintain motor nerve and muscle function in ageing.

Technical Summary

Age-related loss of skeletal muscle mass and function is a major factor leading to the physical frailty seen in the elderly. The age-related decline in skeletal muscle mass is due to loss of muscle fibres and weakness of the remaining fibres. This is associated with loss of the motor nerves (neurons) that normally innervate those fibres. It is currently unknown whether the loss of the motor neurons precedes, and leads to, loss of the muscle fibres or whether the reverse occurs. Damage to tissues by highly reactive free radicals or reactive oxygen species (ROS) appears to contribute to the age-related loss of muscle fibres and is in part due to an age-related failure of homeostatic mechanisms that regulate ROS activities. Exercise or contractile activity of muscle upregulates protective systems in the muscle that help maintain ROS homeostasis, but it is unclear whether similar processes occur in the motor neurons. This project will use a combination of cell culture and mouse models to determine: (i) whether contracting skeletal muscles release substances that act on motor neurons to upregulate defences against ROS and other cytoprotective proteins, (ii) whether ageing leads to a decline in this cytoprotective signalling process potentially leading to an increased susceptibility of the motor neuron to damage during ageing, (iii) whether interventions known to improve the ability of skeletal muscle to generate ROS that signal adaptations prevent the age-related loss of motor neurons, and (iv) whether substances released from muscle oxidise proteins in the peripheral nerve axons and whether these oxidised proteins signal the upregulation of defences against ROS and other cytoprotective proteins in the motor neuron cell body. If sucessful this project may indicate novel approaches to maintaining motor neuron numbers in the ageing neuromuscular system.

Planned Impact

Who will benefit from the work? In the longer term the elderly are anticipated to be the main beneficiaries of this work. The need to find ways of improving the health and quality of life of ageing populations in the UK and most other countries is a major scientific and social challenge. Projections from the Office for National Statistics & Government Actuary Department indicate that by 2050 the proportion of people over 60 in Britain will rise from 21% to almost 40%. Frailty is a major contributor to many health care problems and poor quality of life in the elderly leading to increased risk of falls, hypothermia, incontinence and lack of independence. Muscle mass declines by ~40% between the ages of 50 and 70 years regardless of the amount of exercise undertaken by subjects and this reduction in muscle mass and increasing weakness is a major contributor to frailty. Understanding the mechanisms by which loss of muscle mass occurs with increasing age is also relevant in agriculture and animal husbandry, since meat yields decline in older farm animal species. A third group that may benefit from this research are the pharmaceutical and personal care products sectors of UK industry, for whom the data generated may provide a resource to guide identification of pharmaceutical or non-pharmaceutical interventions to reduce age-related loss of muscle mass and function. With the increasing elderly population there is increased demand for anti-ageing products. Anti-ageing products have enormous economic potential for the pharmaceutical and personal care products sector and there is therefore potential for EU and UK economic benefit and improved quality of life as a consequence of the development of anti-ageing products. How will they benefit from this research? The aim of the overall research programme is to identify interventions to maintain muscle mass and function in the elderly. Most current approaches to preserve muscle function in the elderly are based on exercise programmes that aim to optimise the mass and function of the muscle that remains, but cannot replace the motor units that are lost and even very active older adults still show an age-related decline in muscle mass and function. The current project aims to identify approaches that will maintain motor nerve function with a preservation of whole functional motor units (motor neurons, motor axons, neuromuscular junctions and muscle fibres) with ageing. This approach has great potential to minimise age-related loss of muscle mass and function although the timescale of development of appropriate interventions rom the current work may be several years. If successful, the prevention of age-related loss of skeletal muscle mass and function would lead to an improvement in quality of life of elderly individuals with an increase in mobility, independence and a reduced tendency to become frail with a major economic impact on UK healthcare costs. What will be done to ensure that they benefit from this research? In addition to the usual route of publication of the scientific data in peer-reviewed international journals and presentations at international scientific meetings, the applicant will utilise other methods for communicating his work. For example, he regularly gives lay presentations to the public and schools in association with relevant charitable organisations such as Help the Aged and provides material for relevant local and national television and radio programmes. Information about the study and results will be presented on the senescence.info website (http://www.senescence.info). This website has been maintained by Dr Joao de Magalhaes since 1997. It is dedicated to the biology of ageing and attracts roughly 7,000 unique users per month. The site serves to inform potential beneficiaries and the general public about ageing research, its impact and importance.

Publications

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Description This project examined the possibility that loss of the integrity of motor neurons and neuromuscular junctions in ageing was attributable to a failure of release of neuroprotective substances by muscle. Studies have identified that:

1. Reactive oxygen species released by contracting muscle cells in culture induce an up-regulation of protective proteins in motor neuron cells when both cells are cultured together. These proteins which are modified acting to potentially prevent the motor neuron cells from damage.
2. During ageing, nerves from old mice had an increased amount of oxidative damage compared with those from young mice and an exercise protocol induced a further increase in the activity of damaging oxidants in nerves from the old mice, but had no effect on nerves from young mice. These data suggest that interventions aimed at reduction of oxidation in nerves may be beneficial in preserving the integrity of neurons during ageing.
Exploitation Route The data are being taken forward by our research group in current MRC funded projects that are attempting to define the role of disruption of neuromuscular junctions and denervation in age-related weakness and loss of muscle.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description MRC project grant (Jackson,, Barratt-Jolley, McArdle, Vasilaki)
Amount £648,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2015 
End 01/2018
 
Description Project grant scheme
Amount £80,000 (GBP)
Organisation UK Space Agency 
Sector Public
Country United Kingdom
Start 10/2017 
End 03/2018
 
Description Dissemination event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact Invitation to present research programmes to business/industry
Year(s) Of Engagement Activity 2014,2015
 
Description Radio interview 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interviews on Radio Merseyside relating to ageing and frailty
Year(s) Of Engagement Activity 2014,2016