Site-specific failure of redox homeostasis as a cause of age-related loss of skeletal muscle mass and function

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

Abstract

As we age, our muscles become smaller and weaker, are more susceptible to damage following exercise and recovery from damage is severely impaired. Loss of muscle leads to a severe reduction in quality of life for the elderly due to increased need for assistance and residential care and increased risk of hypothermia and incontinence. We plan to investigate in mice how this age-related loss of muscle occurs as a means of eventually developing ways of preventing these changes in later life in people. A number of studies have indicated that highly reactive substances called free radicals are involved in causing ageing-related changes in many tissues, but the way that they lead to loss of muscle is unclear. We will investigate the possibility that these free radicals react with some key proteins in the muscle that regulate the way that muscle adapts to everyday tasks to prevent damage to the muscle. Our investigations will characterise the processes that occur during ageing and identify potential ways in which we might modify the muscles of old mice (and potentially those of old people) to help restore the ability to respond to everyday use and hence maintain their muscle mass.

Technical Summary

Age-related loss of muscle mass and function is a major cause of frailty and loss of independence in the elderly. The mechanisms underlying the loss of muscle function during ageing are not understood although increased oxidation of cellular components by reactive oxygen species (ROS) and a failure of skeletal muscle from old organisms to adapt to increased ROS both appear to play important roles in the pathophysiology of age-related loss of muscle. Cellular thiols are readily oxidised by ROS and play a role in protection of cells against oxidative damage, but this oxidation also leads to a change in the thiol/disulphide ratios which are important in regulation of the activity of some key transcription factors (such as NFkB and AP-1) within the muscle fibre. ROS generated as part of normal physiological processes such as contractile activity in muscle appear to oxidise cytosolic thiols and stimulate adaptive responses. It is hypothesised that ageing is associated with abberant ROS generation at specific sub-cellular sites, excessive site-specific thiol oxidation and a failure of adaptations to physiological processes in skeletal muscle. This project will test this hypothesis by using new analytical approaches that permit analyses of specific ROS (superoxide, hydrogen peroxide, NO) in mitochondria and cytosol of isolated single mature skeletal muscle fibres and analyses of reduced and oxidised thioredoxin (TRx) 1 in nuclei and cytosol and reduced and oxidised Trx2 in mitochondria of skeletal muscle fibres. Specific interventions to attempt to correct sub-cellular deficit(s) in thiol homeostasis by overexpression of TRx1 or TRx2 or by enhancement of cellular thiols (by lipoic acid supplementation) will then be used to restore redox signalling processes and overcome the inability to adapt to physiological stressors that normally characterises the muscle fibres from old mice. It is anticipated that these studies will indicate novel approaches to preservation of muscle function and mass during ageing with potential influences on quality of life of the elderly.

Publications

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Gomez-Cabrera MC (2010) Effect of xanthine oxidase-generated extracellular superoxide on skeletal muscle force generation. in American journal of physiology. Regulatory, integrative and comparative physiology

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Jackson MJ (2009) Strategies for reducing oxidative damage in ageing skeletal muscle. in Advanced drug delivery reviews

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Jackson MJ (2011) Control of reactive oxygen species production in contracting skeletal muscle. in Antioxidants & redox signaling

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Jackson MJ (2009) Skeletal muscle aging: role of reactive oxygen species. in Critical care medicine

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Jackson MJ (2009) Redox regulation of adaptive responses in skeletal muscle to contractile activity. in Free radical biology & medicine

 
Description Arthritis Rheumatism Council
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description BBSRC Healthy Organism Strategy Panel
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description BBSRC PhD studentships
Amount £183,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2011 
End 09/2015
 
Description BBSRC Project grant
Amount £370,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2011 
End 03/2014
 
Description BBSRC project grant
Amount £441,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 06/2011 
End 12/2014
 
Description MRC project grant
Amount £434,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2011 
End 08/2013
 
Description MRC-Arthritis Research UK Centre grant
Amount £2,500,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2012 
End 05/2017
 
Description Post-doctoral Fellowship
Amount £192,000 (GBP)
Organisation Age UK 
Department Research into Ageing Fund (RiAF)
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 12/2012
 
Description New Collaboration with the University of Valencia, spain 
Organisation University of Valencia
Country Spain 
Sector Academic/University 
PI Contribution Joint research studies
Collaborator Contribution Joint experiments into the role of xanthine oxidase in muscle
Impact Publication in 2010 (Gomez-cabrera et al,
Start Year 2008
 
Description New collaborative link with the University of Michigan 
Organisation Michigan Medicine
Department Geriatrics Center and Institute of Gerontology
Country United States 
Sector Hospitals 
PI Contribution Expertise in fluoresecent probes and approaches to monitor ROS
Collaborator Contribution Joint development of new techniques to study single muscle fibres and very small muscle preparationsJoint research in reactive oxygen species in single muscle fibres
Impact Joint application for funding to NIH (pending)
Start Year 2008
 
Description New collaborative link with the University of Michigan 
Organisation University of Michigan
Country United States 
Sector Academic/University 
PI Contribution Expertise in fluoresecent probes and approaches to monitor ROS
Collaborator Contribution Joint development of new techniques to study single muscle fibres and very small muscle preparationsJoint research in reactive oxygen species in single muscle fibres
Impact Joint application for funding to NIH (pending)
Start Year 2008
 
Description New collaborative link with the University of Washington, Seattle 
Organisation University of Washington
Department Division of Medical Genetics
Country United States 
Sector Academic/University 
PI Contribution Joint design of viral vectors and probes for transfection
Collaborator Contribution Provision of viral vectors for transfection of skeletal muscle Development and production of viral vectors
Impact New probes for fluoresecence measurements of reactive oxygen species etc.
Start Year 2008
 
Description New collaborative link with the University of Washington, Seattle 
Organisation University of Washington
Country United States 
Sector Academic/University 
PI Contribution Joint design of viral vectors and probes for transfection
Collaborator Contribution Provision of viral vectors for transfection of skeletal muscle Development and production of viral vectors
Impact New probes for fluoresecence measurements of reactive oxygen species etc.
Start Year 2008
 
Description Help the Aged - Manchester 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Presentation to the Charity supporters aboput the work of our research group.

Personal discussion/information exchange with member of the public.
Year(s) Of Engagement Activity 2008
 
Description Presentation to lay audience 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact 10 supporters of a research charity

Visit of lay supporters to the laboratory
Year(s) Of Engagement Activity 2009
 
Description Radio Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Interview broadcast on radio merseyside as part of series of programmes on ageing

Lay interest in our research
Year(s) Of Engagement Activity 2010