Muscle loss in liver disease varies by underlying cause

Different types of liver disease are leading to distinct signatures of muscle loss, according to a new study which could help pave the way for more personalised treatments for sarcopenia in people with end‑stage liver disease.

The research was led by scientists at the University of Birmingham, published in the Journal of Cachexia, Sarcopenia and Muscle and delivered through the National Institute for Health and Care Research (NIHR) Biomedical Research Centre (BRC): Birmingham. The study reveals for the first time that the underlying cause of liver disease shapes how muscle loss develops and how it may respond to treatment.

Sarcopenia, the loss of skeletal muscle mass and strength, affects around one in three people who develop end‑stage liver disease. It is linked to a higher risk of falls, serious complications such as infections, and a two‑fold increase in mortality. Despite its impact, there are currently no approved pharmacological treatments to prevent or reverse muscle loss in this patient group.

In the study, researchers analysed muscle tissue taken directly from patients with end‑stage liver disease and compared it with tissue from healthy individuals. Using a technique known as transcriptomics, which provides a detailed picture of which genes are switched on or off, they identified more than 600 genes that behaved differently in diseased muscle.

“different liver diseases leave different signatures in muscle.”

Professor Simon Jones, senior author, University of Birmingham

These changes affected key biological processes, including cellular ageing, energy production and protein breakdown. When patients were grouped by the underlying cause of their liver disease such as alcohol‑related liver disease, metabolic liver disease or immune‑associated liver disease, each group showed a distinct molecular pattern in their muscle tissue.

This finding suggests that sarcopenia in liver disease is not a single condition, but a collection of related disorders driven by different biological mechanisms.

Professor Simon Jones, senior author of the study and lead for the NIHR Biomedical Research Centre: Birmingham’s Sarcopenia and Multimorbidity research theme, said:

“By mapping molecular changes directly in patient muscle tissue, we’ve been able to show that different liver diseases leave different signatures in muscle. That’s a crucial step towards moving away from one‑size‑fits‑all approaches and towards treatments tailored to the patient’s underlying disease.”

Signals in the blood linked to muscle loss

To understand what might be driving these muscle changes, the team also measured the levels of 60 different proteins in patients’ blood, including inflammatory and growth factor hormone signals – and exposed human muscle cells in the laboratory to blood plasma from patients with liver disease.

The plasma triggered changes in muscle cells that closely mirrored those seen in patient muscle tissue, including increased protein breakdown. Three proteins – IL‑1α, GDF‑15 and HGF – emerged as potential drivers of muscle loss.

The study found that GDF-15, a stress-related protein, was elevated across all disease subtypes, while IL-1α was specifically elevated in patients with immune-associated liver disease and HGF in those with metabolic and alcohol-related liver disease – reinforcing the idea that different forms of liver disease promote muscle loss through different pathways.

Personalised treatments for sarcopenia in future

When human muscle cells were treated with the three proteins at levels similar to those seen in patients, the cells became thinner, showed impaired growth, and had disrupted energy metabolism – all hallmarks of muscle wasting.

Some of these proteins are already being targeted by drugs used, or in development, for other conditions. This raises the possibility that existing treatments could be repurposed, potentially alongside exercise and nutritional support, to better protect muscle health in people with liver disease.

Thomas Nicholson, first author of the study and a doctoral researcher at the University of Birmingham, said:

“End‑stage liver disease isn’t one single condition – it includes very different diseases with different underlying biology. Our findings show that this diversity is reflected in how muscle loss develops, and that identifying what is driving sarcopenia in an individual patient may be key to developing treatments that actually work for them.”

Delivered through the NIHR Biomedical Research Centre: Birmingham, this study reflects a wider programme of research focused on improving outcomes for people living with complex, overlapping long‑term conditions.