Blocking stress‑hormone pathway protects against age‑related muscle loss

New research led by scientists at the University of Birmingham has identified a promising biological pathway that could be targeted to prevent muscle wastage, known clinically as sarcopenia, caused by ageing. The findings from a study looking at sarcopenia in chronic kidney disease could lead to potential new treatment options for older adults.

Published in the European Journal of Endocrinology and delivered through the National Institute for Health and Care Research (NIHR) Biomedical Research Centre: Birmingham, the study shows that blocking a specific enzyme in skeletal muscle can protect against age‑related muscle wasting, rather than muscle loss driven by chronic kidney disease.

Muscle wasting, known clinically as sarcopenia, is common in older adults and is associated with poorer survival and reduced quality of life. In people with chronic kidney disease, sarcopenia is particularly severe and can lead to increased risk of falls, fractures and poorer long‑term outcomes. However, the biological drivers behind this process have remained unclear.

The Birmingham research team set out to investigate whether a pathway involving the enzyme 11β‑hydroxysteroid dehydrogenase type 1 (11β‑HSD1), which regulates activity of the stress hormone cortisol within tissues, was contributing to muscle loss in these patients.

A surprising finding

In an observational clinical study of patients with chronic kidney disease, the team discovered that activity of the 11β‑HSD1 pathway in muscle increased primarily with ageing, rather than being driven by kidney disease itself.

To explore this further, the researchers conducted intervention studies in mouse models of both age‑related muscle wasting, and muscle wasting caused by chronic kidney disease.

The results revealed a clear distinction between the two conditions:

• Blocking 11β‑HSD1 in skeletal muscle prevented muscle loss associated with ageing

• The same intervention did not prevent muscle wasting driven by chronic kidney disease

Dr Rowan Hardy, study author and Associate Professor in Steroid Metabolism and Signalling at the University of Birmingham, said: “We wanted to understand whether the 11β‑HSD1 pathway was driving the muscle wasting process in kidney disease patients and, importantly, whether it could be targeted.

“The results were not what we initially expected. But they showed very clearly that this pathway plays a key role in muscle loss caused by ageing, rather than kidney disease specifically.”

What happens next?

With this work building on a previous clinical trial by the group which demonstrated that drugs acting on the 11β‑HSD1 pathway could increase muscle mass in another patient population, the research team now plans to work with industry partners to examine whether existing, safe and approved drugs targeting this pathway could be repurposed for use in older adults with muscle wasting.

Dr Michael Sagmeister, corresponding author of the study, Clinical Lecturer in Renal Medicine at the University of Birmingham and Deputy Theme Lead for Sarcopenia and Multimorbidity at the NIHR Biomedical Research Centre: Birmingham, said: “This study provides important insight into the biological mechanisms that drive muscle loss as we age. Identifying a pathway that can be safely targeted opens up real opportunities to develop treatments that help people stay stronger for longer and reduce the risk of falls and fractures.

“By building on existing drugs and working closely with industry, we have the potential to accelerate translation of this research into meaningful benefits for patients.”

The work was carried out in collaboration with researchers from Nottingham Trent University and Queen Mary University of London and funded by the Medical Research Council (MRC).