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Insight into why our muscles weaken with age revealed by Wellcome Sanger Institute researchers

Our muscles progressively weaken as we age, affecting our ability to perform everyday tasks such as standing up to walking, but the mechanisms behind this have been poorly understood.

Now researchers have created the first comprehensive map of ageing human muscles, giving us insight at the cellular and molecular level that could ultimately help us develop new interventions and therapies.

Staying active and eating healthily can help with muscle strength as we age
Staying active and eating healthily can help with muscle strength as we age

The muscle atlas, made by researchers at the Wellcome Sanger Institute and their collaborators at Sun Yat-sen University in China, forms part of the enormous Human Cell Atlas project, mapping every cell type in the human body to help us better understand health and disease.

They used single-cell and single-nucleus sequencing techniques, along with advanced imaging, to analyse and compare human skeletal muscle samples from 17 people aged 20 to 75, helping to unravel the many complex processes behind age-related muscle changes.

New cell populations that may explain why some muscle fibres age faster than others were found, while compensatory mechanisms the muscles employ to combat ageing were identified.

Muscle loss can worsen for some people as they age, leading to falls, immobility, a loss of autonomy and a condition known as sarcopenia, which affects about 25 per cent of older people and is associated with frailty. Those with it have low muscle mass, low physical function and low muscle strength, but there are no approved medications for it. Remaining physically active and eating healthily are the best ways to prevent it developing.

In their research, the team genes controlling ribosomes, which are responsible for producing proteins, were less active in muscle stem cells from aged samples, impairing the cells’ ability to repair and regenerate muscle fibres as we age.

Non-muscle cell populations in these skeletal muscle samples produced more CCL2, a pro-inflammatory molecule that attracts immune cells to the muscle and exacerbates age-related muscle deterioration.

Our muscles contain different types of fibres - some are known as ‘slow-twitch’ and are for endurance activities, while ‘fast-twitch’ fibres are used in powerful, explosive movements. The researchers found a subtype of fast-twitch muscle fibres, called type IIx, is progressively lost with ageing.

But they also found for the first time several compensatory mechanisms from the muscles that appear to make up for the loss, including a shift in slow-twitch muscle fibres to express genes characteristic of the lost fast-twitch subtype, and increased regeneration of remaining fast-twitch fibre subtypes.

Muscles progressively weaken with age
Muscles progressively weaken with age

Specialised nuclei populations within the muscle fibres were also found to help rebuild the connections between nerves and muscles that decline with age.

Use ‘knockout experiments’ in lab-grown human muscle cells, the researchers confirmed the importance of these nuclei in maintaining muscle function.

Veronika Kedlian, first author of the study from the Wellcome Sanger Institute, said: “Our unbiased, multifaceted approach to studying muscle ageing, combining different types of sequencing, imaging and investigation reveals previously unknown cellular mechanisms of ageing and highlights areas for further study.”

Prof Hongbo Zhang, senior author of the study from Sun Yat-sen University, Guangzhou, China, added: “In China, the UK and other countries, we have ageing populations, but our understanding of the ageing process itself is limited. We now have a detailed view into how muscles strive to maintain function for as long as possible, despite the effects of ageing.”

Dr Sarah Teichmann, senior author of the study from the Wellcome Sanger Institute, and co-founder of the Human Cell Atlas, said: “Through the Human Cell Atlas, we are learning about the body in unprecedented detail, from the earliest stages of human development through to old age. With these new insights into healthy skeletal muscle ageing, researchers all over the world can now explore ways to combat inflammation, boost muscle regeneration, preserve nerve connectivity, and more.

“Discoveries from research like this have huge potential for developing therapeutic strategies that promote healthier ageing for future generations.”

The atlas was published on Monday (15 April) in Nature Ageing.

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