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

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

Abstract

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.

Technical Summary

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.

Planned Impact

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.
 
Description We have validated microRNAs, regulation of which has a positive impact on skeletal muscle mass and function in mice during ageing. We are now deciphering the mechanisms of microRNA action. So far, we have deciphered the role of microRNAs in regulating mitochondrial dynamics in muscle during ageing. This mechanisms is associated with maintaining muscle mass and function. We have also described the interplay between redox homeostasis and microRNA function and shown that disruption of this mechanisms leads to loss of muscle mass and function.
Exploitation Route This study is a proof-of-principle for using microRNA-based therapeutics against sarcopenia. We will follow this study up by focusing on specific microRNAs and pre-clinical studies of the use of microRNA-based therapeutics for muscle wasting.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description BBSRC DTP
Amount £70,000 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 09/2014 
End 08/2018
 
Description Crossley Barnes PhD studentship
Amount £100,000 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 10/2015 
End 09/2018
 
Description Defining the role and mechanisms of microRNA in cartilage ageing and disease - CoI
Amount £80,000 (GBP)
Organisation North West Consortium Doctoral Training Partnership (NWCDTP) 
Sector Multiple
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description MicroRNA role in muscle during osteoarthritis
Amount £80,000 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 09/2022
 
Description Research Grant
Amount £19,722 (GBP)
Organisation The Dunhill Medical Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2017 
End 09/2020
 
Description Targeting modified microRNAs as potential therapeutic against sarcopenia
Amount £197,222 (GBP)
Funding ID R545/0217 
Organisation The Dunhill Medical Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2017 
End 07/2020
 
Description Technology Directorate Voucher
Amount £7,500 (GBP)
Organisation University of Liverpool 
Sector Academic/University
Country United Kingdom
Start 01/2016 
End 12/2016
 
Description The role of microRNA:target dysfunction in tendon function deterioration
Amount £75,000 (GBP)
Organisation Orthopaedic Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 08/2019
 
Description UK and EIRE Glaucoma Society
Amount £40,000 (GBP)
Organisation UK and Eire Glaucoma Society 
Sector Learned Society
Country United Kingdom
Start 01/2016 
End 12/2017
 
Description microRNAs as mediators of muscle wasting in offspring of dietary-restricted mothers - CoI
Amount £640,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2017 
End 04/2020
 
Title Isolation of human primary myoblasts from adult and older people. 
Description This protocol describes a robust, reproducible and simple method of isolation and culture of myoblast progenitor cells from the skeletal muscle of adult and aged people. The muscles used here include foot and leg muscles. This approach enables the isolation of an enriched population of primary myoblasts for functional studies. 
Type Of Material Biological samples 
Year Produced 2017 
Provided To Others? Yes  
Impact To be established. 
URL https://www.jove.com/video/55047/preparation-culture-myogenic-precursor-cellsprimary-myoblasts-from
 
Description APPA role in muscle homeostasis during ageing 
Organisation AKL Technologies
Country India 
Sector Private 
PI Contribution We are in the process of finalising the details of the collaboration - thew company will fund a new line of research into muscle and ageing and use of natural compounds against muscle wasting.
Collaborator Contribution N/A
Impact n/a
Start Year 2017
 
Description Omics approaches to research of muscle wasting 
Organisation National University of Ireland, Galway
Country Ireland 
Sector Academic/University 
PI Contribution This collaboration resulted in increase understanding of microRNA-regulated muscle wasting through using omics approaches (proteomics).
Collaborator Contribution Proteomics of muscle samples (controls and treated) with analyses.
Impact Manuscript in preparation: miR-181 regulates muscle strength during ageing through autophagy.
Start Year 2016
 
Description Redox regulation of microRNA function 
Organisation National University of Ireland, Galway
Country Ireland 
Sector Academic/University 
PI Contribution Characterisation of redox regulation of microRNA function in muscle during ageing - generated sequencing data of oxidised microRNAs; functional studies to follow.
Collaborator Contribution Omics analyses
Impact Conference abstracts: EMBO Epitranscriptomics 2018 and BSRA ASM 2018
Start Year 2016
 
Description microRNAs as biomarkers for muscle wasting disorders 
Organisation Texas A&M University
Country United States 
Sector Academic/University 
PI Contribution Analysis of microRNA in plasma samples from adult, older people and people affected by disorders related to muscle wasting, such as lung cancer will be performed. Additionally, we agreed on analysing muscle samples.
Collaborator Contribution Prof. Nicolaas Deutz - plasma and muscle samples from people (healthy adult, older and with lung conditions) Dr. Katarzyna Goljanek-Whysall - microRNA analysis
Impact There are no publication outcomes of this collaboration yet as the work is ongoing, however a an ERC grant was submitted as a collaborative project (PI: K. Goljanek-Whysall).
Start Year 2015
 
Description Broadcasting research outcomes using social media 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Using social media such as Twitter or Facebook is an ongoing activity - it allows for the research outcomes to be disseminated to a large number of people, it has sparked scientific discussions and conversations about possible collaborations.
Year(s) Of Engagement Activity 2014,2015,2016
 
Description KIND event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact KIND is a charity for young children from deprived background. Events are organised to engage the kids with science (widening participation).
Year(s) Of Engagement Activity 2016,2017
 
Description Live Longer Live Well 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact As a committee member of the British Society for Research into Ageing (BSRA) I took part in the "Live longer live well" event in the House of Lords. The event aimed at raising awareness about the importance of research into ageing and raising funds to support this research. Among participants were policy makers and media, as well as scientists - discussions took place about research and some donations were made to support ageing research.
Year(s) Of Engagement Activity 2015
 
Description Meet the Scientist Outreach Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Meet the Scientist is an activity organised at the World Museum in Liverpool; it involves short presentations and demonstrations to the general public; the topics are associated with ageing and biology of the human body. This event attracts a wide group of general public, from parents with children to students and general public interested in science.
Year(s) Of Engagement Activity 2015
 
Description Patient involvement panel 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Discussion with a group of patients about the project, whether it addresses their health-associated concerns, discussing research methods and potential outputs of impact.
Year(s) Of Engagement Activity 2018
 
Description Physiology Society Education and Outreach Member (PDRA) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The panel for Education and Outreach Activity organised local and international outreach events, including collaborations with schools, interactions with politicians and media, outreach events.
Year(s) Of Engagement Activity 2015,2016,2017
 
Description School visit (Liverpool) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact School visit (primary) to talk about the job of a scientists and change views about who can do science.
Year(s) Of Engagement Activity 2017
 
Description Student placement 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Our lab hosted a disabled undergraduate students to improve their employability.
Year(s) Of Engagement Activity 2015
 
Description Work experience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact We provided work experience for A-level student from widening participation background. The student felt even more motivated to continue their education at the University level.
Year(s) Of Engagement Activity 2017
 
Description miRs in science website and blog 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Blog about recent discoveries in the field of muscle ageing and microRNAs, ageing in general and epigenetics.
Year(s) Of Engagement Activity 2018