Published July 2022
Summary
Despite affecting most people over the age of 50, we don’t really know why age-related muscle loss happens. Dr Katarzyna Goljanek-Whysall, now Senior Lecturer at the National University of Ireland, Galway but who led the work when at the University of Liverpool, thinks that oxidised microRNAs could be an important clue to unlocking better treatments for declining muscle function as we get older.
We wanted to find out whether oxidised microRNAs appear in ageing muscle tissue and, if so, are they negatively affecting muscle function
Dr Katarzyna Goljanek-Whysall
As we age, it’s normal to lose muscle strength, with people over 50 losing around 1-2% of their skeletal muscle each year. However, age-related muscle loss – known as sarcopenia – can result in reduced strength, frailty and affect people’s quality of life if they are no longer able to do everyday activities and the things they enjoy.
Current management strategies for sarcopenia, such as regular exercise and a better diet, aren’t very effective at slowing the rate of decline. But right now, the search for better treatments is hampered by our lack of understanding of the underlying molecular changes that happen in ageing muscle cells.
An important clue to why muscles age
Our research is focusing on microRNAs – hundreds of tiny molecular messages that play an important role in keeping cells healthy by controlling patterns of gene activity and protein production.
Muscle is a very active tissue, using a lot of oxygen to generate movement. Over time, this leads to a build-up of damage known as oxidative stress. Some initial data suggests that microRNAs can become oxidised in the heart but we don’t know if this happens in muscles. We wanted to find out whether oxidised microRNAs appear in ageing muscle tissue and, if so, are they negatively affecting muscle function.
We predict that blocking wayward oxidised microRNAs in human muscle will help slow down decline or even restore muscle mass in our older years.
Piecing together the role of microRNA in ageing muscle
Using muscle samples from 20 volunteers ranging from 18 to over 65, we identified the microRNAs, oxidised microRNAs and proteins found in muscle and how these change with age.
By combining this data, we were able to uncover previously unknown molecular changes happening in ageing muscle. For example, we saw certain proteins becoming more or less prevalent as muscle cells age and could match them to the microRNA linked with this change.
Not only did we find that microRNAs can be oxidised in ageing human muscle, but also that oxidised microRNAs can no longer bind to and regulate the same genes as the non-oxidised version. In turn, these disrupted patterns of gene activity could have a negative impact on the health and function of the muscle.
Investigating one of these microRNAs further, microRNA-378, we saw that when there’s lots of it, muscle cells get bigger. But the oxidised version causes muscle cells to get smaller, potentially explaining one way muscle mass is lost as we get older.
Designing drugs to prevent muscle loss
Thanks to this new understanding, we predict that blocking these wayward oxidised microRNAs in human muscle will help slow down decline or even restore muscle mass in our older years.
We tested this idea by designing an inhibitor to block oxidised microRNA-378, which improved muscle strength when injected into older mice. Our research is still at an early stage, but this approach could form the basis of future treatments for age-related sarcopenia.
What’s next?
It’s been amazing having Dunhill as a funder. Despite delays from COVID, their proactive support has allowed us to complete all the data analysis and publish our results, but there’s still much more work to be done. We’re recruiting more volunteers, especially women, to check that our findings about the role of oxidised microRNAs in ageing muscle hold up across more people.
We’re also working with people who have sarcopenia to better understand the challenges they face and how our research into the underlying biology can help to solve the issues that are most important to them.
Eventually, I’d like to see therapeutics based on microRNA developed for sarcopenia. To achieve this, we need to keep investigating what happens to microRNAs in muscle in different situations and stages of life, such as during exercise, in younger and older people, and in women compared with men. With this knowledge, we could better tailor existing exercise and nutrition programmes alongside finding new drugs to slow down muscle loss in ageing.
