Do age-related changes in microRNA expression in muscle mediate sarcopenia?

Sarcopenia is an age-related loss of skeletal muscle mass and strength. It is characterised by muscle fibre atrophy (decreased muscle fibre size) and reduced muscle function linked to increase of the presence of non-muscle cells, like fat, within the muscle and disrupted muscle repair. Sarcopenia leads to poor balance, falls and fractures and increased morbidity and mortality in our ageing population. As the ageing population increases, it is important to identify the mechanisms responsible for this age-related muscle loss. The molecular factors responsible for sarcopenia are not fully understood, however changes in the expression of genes have been implicated in sarcopenia.
MicroRNAs (miRNAs, miRs) are small RNA molecules that regulate gene expression. Each microRNA is predicted to regulate the expression of up to several hundred genes. Expression of numerous microRNAs and their target genes changes with age or in diseases. This makes microRNAs very strong candidates for therapeutic targets for sarcopenia and other age-related disorders, for example by controlling their levels by using molecules that mimic their behaviour.
In preliminary data the applicant has shown that that the levels of microRNAs, important for muscle function, change in muscle with age. This new research proposes that the age-related changes in microRNA abundance are a major contributing factor to the muscle loss process. Using cell culture and model organism systems, the levels of these small molecules (microRNAs) will be manipulated in muscle cells and tissues and the effects on muscle wasting will be examined. Concurrently, the potential of miRNA-based intervention to prevent, delay or treat sarcopenia will be established.
The first objective will determine the set of muscle-specific microRNAs that are changed in the muscle tissue of old mice compared with adult mice. The second objective will confirm important microRNA target genes in muscle and characterise the details of the interactions of microRNAs and the specific genes they regulate in the context of loss of muscle mass and function. The final aim of the project will examine the potential of microRNA mimics and antagomiRs (small molecules that increase or decrease of the microRNA levels, respectively) in preventing age-related loss of muscle using a mouse model organism.
This project is important to strengthen our knowledge about the molecular basis of sarcopenia and is likely to lead to the design of novel therapeutic approaches to prevent, delay or treat age-related skeletal muscle wasting.

Skeletal muscle homeostasis depends on a balance between muscle regeneration, hypertrophy and atrophy. This balance is disturbed as we age. A common characteristic of ageing is sarcopenia related to myofibre atrophy and decreased muscle mass and function. Sarcopenia leads to poor balance, falls and fractures and a decreased quality of life in our ageing population. There are currently few studies showing the involvement of miRNAs in skeletal muscle ageing, although miRNAs are likely to be involved in the ageing process and particularly in sarcopenia.
microRNAs (miRNAs; miRs) are novel regulators of gene expression. miRNAs control myogenesis, regeneration and cellular programming. Each miRNA is predicted to target several hundred genes and expression of numerous miRNAs is conserved between species and disrupted with age. This makes miRNA-based interventions a promising therapeutic strategy against sarcopenia.
This project will test the hypothesis that changes in miRNA activity act as effectors of age-related changes in the myofibres and surrounding environment by directly contributing to muscle fibre atrophy, fibrosis and impaired regeneration. This hypothesis is built upon the applicant's preliminary data showing disrupted expression of muscle-specific miRNAs and their putative targets in muscles of old mice and their involvement in myoblast apoptosis, proliferation, differentiation and myofibre atrophy, processes related to muscle ageing. Among miRNA putative target genes are myogenesis inhibitors, chromatin remodelling factors, FGF and Wnt signalling pathway components. The findings of this project will advance our knowledge of the molecular events involved in sarcopenia and will establish the potential of miRNA-targeted interventions aiming at preventing, delaying or treating sarcopenia.

The increase in the ageing population is an important scientific, medical and social challenge. Projections from the European Commission predict that by 2060 the proportion of people aged over 60 will significantly increase in the UK and Europe. Frailty, increased risk of falls and lack of independence are the main factors related to health care problems and the quality of life for older people. Sarcopenia is a major contributor to frailty. This research aims to make a significant impact on understanding and treating sarcopenia through a comprehensive analysis of microRNA involvement in ageing.
This project will impact the following groups:
1. Staff employed on the project and researchers within and outside the NI's research field- immediate impact and impact over months and years
2. General public (society) - immediate impact through education and public engagement
3. UK industry (biotechnology or pharmaceutical companies) - impact over 3-10 years
4. Public health - impact over 5-10 years (treatment developments)
5. Government, NHS, welfare state - impact over 10-30 years.
The NI and PDRA funded on this project will undertake public engagement activities, such as taking part in outreach activities in local schools, engaging with lay audience during events like Institute Science Impact Day and providing work experience placements, that will increase awareness of science in the society. The visits to schools will include primary schools and will aim at sparking interest in science in all age groups. This impact will occur during the duration of the project and after the project ends, as the New Investigator has previously been involved in, and enjoys taking part in the outreach activities (see CV).
This project will establish the potential of miRNA-targeted therapies for sarcopenia and may therefore be commercially exploited and attractive to existing SMEs, biotechnology and pharmaceutical companies. The NI and PDRA will meet with a relevant industrial organisation to discuss the potential of the project's findings in the year 3. Two miRNA-targeted therapeutic molecules are currently undergoing clinical trials in humans proving the potential of miRNA-based therapies. Researchers from other fields will also benefit from the outcomes of this research, as miRNA-associated age-related changes in muscle may be common to other tissues. The PDRA employed on the project will be trained in relevant molecular biology techniques, as well as working with rodent models of ageing, and will gain transferable skills, such as scientific writing, project management and presentation. This will result in an individual with a skill set attractive to UK public or private sector employers. These impacts will occur over a period of months and years with presentations of findings at conferences and in scientific literature.
The societal impact of this project's findings will be through understanding the mechanisms underlying sarcopenia and helping to design effective interventions, ultimately leading to improved health and lifestyle of older people. Novel and effective treatments may also lead to decreased care costs within the NHS. As a result of improved health of individuals, the UK economy will benefit strongly from savings in disability and mobility benefit payments and the employers from reduced sickness pay and lost working hours. This is an important and timely impact considering the latest trends in the UK economy. These societal impacts are likely to be long-term (years or decades).
Timescales for these impacts vary from several months for public engagement, to several years for academic beneficiaries and public and private sector employers, to decades for societal, health care impact. The potential of the findings to be translated into an "anti-ageing" therapy and affect welfare on a potentially international scale may be measured in decades.