Mitochondrial reactive oxygen species as a target for prevention of age-related loss of muscle mass and function

Lead Research Organisation: University of Liverpool
Department Name: Institute of Ageing and Chronic Disease

Abstract

As we age, we lose skeletal muscle and this has a major effect on our ability to undertake everyday tasks and, although this can be partly reduced by regular exercise, the mechanisms underlying the loss of muscle remain unknown. One strong possibility is that, as we age, mitochondria (the highly specialised organelle in our muscles that generates the energy we need for movement) start to release increased amounts of highly reactive molecules called free radicals or reactive oxygen species (ROS). These species can damage parts of the muscle cell and prevent them from working properly. We plan to study this possibility on small muscle biopsies taken from the upper thigh muscles under local anaesthetic from volunteers of different ages. Previous techniques have required substantial amounts of tissue to allow isolation of the mitochondria, but we will use an alternative approach in which the muscle biopsies will be split into several small bundles of muscle fibres in which the mitochondria remain in place. These can be studied using techniques that will allow us to assess the amount of ROS released and compare this to the maximum force that the muscle can exert and to the amount of damage that has occurred in the muscle. These studies should allow us to determine the likelihood that increased release of ROS from mitochondria leads to the age-related loss of muscle mass and function. The study will also examine potential therapeutic approaches to reduce the release of ROS from mitochondria by testing the effects of 2 novel compounds that are targeted to the mitochondria. Finally if either of these compounds are found to be promising in their effects, we will undertake a preliminary intervention study in aged mice to determine whether chronic consumption of the drug can prevent the age-related loss of muscle mass and function normally seen in old mice. This is a necessary first step to a potential future intervention study in the elderly.

Technical Summary

Loss of skeletal muscle mass and function has a profound effect on the quality of life in the elderly, but the mechanisms underlying this process remains obscure. An increase in reactive oxygen species (ROS) generation by mitochondria has been implicated in this process but much of the published data derives from studies of experimental models and there remains considerable doubt about whether an increase in mitochondrial ROS generation actually occurs in muscles of elderly humans. In addition recent publications have also cast doubt on the validity of data obtained from the standard technique for examination of ROS generation in mitochondria that requires isolation of mitochondria from skeletal muscle. The proposed studies will therefore examine hydrogen peroxide release and superoxide activities in mitochondria within muscle biopsies from groups of elderly, middle-aged and young individuals using an alternative technique (permeablised fibres) in which the organelle remains in situ within the cytoskeletal environment of the muscle fibre. In addition studies will examine whether changes in mitochondrial ROS generation are important in the age-related degeneration of muscle by determining whether the rates of ROS generation are related to maximum force generation by the permeablised fibres, to measures of oxidative damage to muscle proteins (3-nitrotyrosine and carbonyl content) and to the muscle fibre type composition. Previous work has determined that the loss of muscle mass during ageing in rodent models is associated with a failure of redox-regulated pathways that signal adaptations to contractile activity and therefore we will also determine whether increased rates of mitochondrial ROS generation are associated with chronic activation of redox-regulated pathways in the human biopsy samples. In order to explore the potential for pharmacological intervention to reduce mitochondrial ROS generation, the effect of ex vivo additions of mitochondria-targeted antioxidants (SS-31 or MitoQ) on mitochondrial ROS generation in permeablised fibres from human subjects will be studied. Finally a pre-clinical intervention study will be undertaken with any mitochondria-targeted antioxidant found to be effective in reducing mitochondrial ROS release ex vivo. This will determine whether 16 week treatment of mice prevents the age-related loss of muscle mass and function normally seen in 26 month old mice. Thus these studies will provide the first clear description of whether mitochondrial ROS generation is abnormal in muscle of aged individuals and provide a guide to approaches to normalise any defect and whether such interventions might prevent age-related loss of skeletal muscle mass and function.

Publications

10 25 50
 
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 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