An experimental compound could slow muscle loss in ageing

The gradual loss of muscle mass and strength is one of the most common consequences of ageing, with direct effects on mobility, independence, and the onset of physical frailty in older people. For this reason, researchers continue to seek a better understanding of the biological mechanisms behind muscle regeneration, in order to discover methods that could slow this decline.

A team of researchers from Japan, at the Faculty of Agriculture of Kyushu University, has identified an experimental compound that appears capable of protecting and even enhancing the action of a biological signal essential for muscle repair. The discovery was made through laboratory experiments and a preclinical mouse model, meaning the efficacy and safety of the method must be confirmed through further research.

How muscle regeneration works and what changes with ageing

Skeletal muscles repair themselves after injury with the help of satellite cells, a type of stem cell that remains dormant until it receives an activation signal. One of the most important such signals is hepatocyte growth factor (HGF), a protein that activates satellite cells and triggers the regeneration process.

For HGF to function, it must bind to the c-Met receptor, located on the surface of satellite cells. Activation of this receptor stimulates the proliferation and maturation of muscle stem cells, which contribute to the repair of muscle fibres.

Previous studies by the same team showed that, with ageing, HGF undergoes a chemical modification known as nitration, whereby nitro groups are added at two essential positions within the protein. As a result, HGF can no longer bind efficiently to the c-Met receptor and loses its ability to activate muscle regeneration.

Testing two antioxidant substances

Building on this observation, the researchers examined whether two substances with antioxidant properties could protect HGF from nitration: glutathione trisulphide (GSSSG) and lipoic acid trisulphide (LASSS). Both belong to the class of trisulphides — compounds with three sulphur atoms bonded together — which are being studied for potential pharmaceutical applications.

In the initial experiments, both substances reduced nitration of the HGF protein, but the protection was insufficient to fully restore its function.

When the researchers increased the amount of LASSS used relative to HGF, they observed an unexpected effect: HGF's affinity for the c-Met receptor doubled compared to the untreated protein, and HGF became more resistant to the loss of function caused by nitration. This effect was seen only with LASSS, not with GSSSG.

The authors named this modified form "Super HGF". According to them, LASSS not only reduces oxidative stress but also produces a subtle change in the protein's structure, allowing it to bind more effectively to the receptor and retain its function even under conditions that favour nitration.

"HGF does not disappear with ageing. The problem is that the protein can be chemically modified after it is produced. That is why we asked ourselves whether a compound with strong antioxidant properties might be able to protect HGF or compensate for the loss of its function," explained Professor Ryuichi Tatsumi, the lead researcher.

Confirmation in animal models

To verify whether the results could be reproduced in a living organism, the researchers used a mouse model of muscle atrophy induced by hindlimb suspension. Animals pre-treated with LASSS showed significantly lower levels of HGF nitration compared to untreated animals. GSSSG did not provide a similar protective effect.

The authors note that further studies in aged animals are needed to evaluate the efficacy and safety of this approach before any potential clinical application.

Should the results be confirmed, the research could contribute in the future to the development of therapies that support the muscles' capacity to regenerate both during ageing and in other situations associated with muscle mass loss, such as prolonged bed rest.

The study was published on Friday in the journal Scientific Reports.