Skeletal muscle is one of the first tissues to decline as we age. This decline can lead to muscle weakness, scarring, fat accumulation inside the muscles, and loss of fast-twitch muscle fibers, which are important for quick, powerful movements.
A research team led by Professor Ryuichi Tatsumi of Kyushu University’s Faculty of Agriculture has identified a molecule that may help protect and even strengthen one of the body’s key muscle repair signals. The results of this investigation were announced on July 24, 2026. scientific report.
This study focuses on hepatocyte growth factor (HGF), which acts like an arousal signal in skeletal muscle. In healthy muscle, HGF resides quietly within the supporting network that surrounds muscle fibers. When a muscle is injured or subjected to mechanical stimulation, HGF is released and binds to c-met receptors on satellite cells, stem cells resident in skeletal muscle, awakening the muscle from a dormant state and allowing it to contribute to proliferation, differentiation, and muscle fiber repair.
However, aging can interfere with this process. The research team’s previous work showed that HGF undergoes a chemical change called nitration. This change adds nitro groups to two specific sites on the protein, Y198 and Y250. This site is exactly the one used by HGF to bind c-met. Once nitrated, HGF loses its ability to dock with receptors, like a rusty key that no longer fits. This is thought to be the root cause of age-related muscle wasting and impaired regeneration.
HGF is not necessarily lost with age. Rather, it can be chemically changed after manufacturing. This led us to wonder if compounds with strong antioxidant capacity could protect HGF by preventing nitration or by compensating for the loss of function that nitration causes. ”
Ryuichi Tatsumi, Professor, Faculty of Agriculture, Kyushu University
The research team focused on two sulfur-based compounds known for their powerful antioxidant properties: glutathione trisulfide (GSSSG) and lipoic acid trisulfide (LASSS). Both belong to a class of molecules called trisulfides, which have three sulfur atoms bonded in series. Its unusual sulfur chemistry and redox properties have recently attracted attention in drug development.
In initial experiments, both GSSSG and LASSS inhibited HGF nitration at Y198 and Y250. However, receptor binding activity was not fully restored, so the researchers increased the molar ratio of HGF to trisulfide from 1:4,000 to 1:8,000.
The surprises continued. At this higher ratio, the binding affinity of HGF for c-met was increased more than two-fold compared to untreated HGF, with concomitant resistance to nitration-induced dysfunction, especially at Y198. This enhancement occurred only in LASSS. GSSSG showed no such effect.
“This exceeded our expectations,” comments Tatsumi. “We knew that trisulfides have diverse biological functions, but we never expected that simply mixing HGF and LASSS would have such a pronounced effect.
“This suggests that LASSS does more than simply neutralize reactive molecules. It may interact directly with HGF and induce subtle conformational changes, creating an enhanced ‘super-HGF’ form that binds c-met more tightly and resists nitration.”
To test whether this effect persists in living tissue, the researchers used a mouse model of muscle atrophy induced by tail suspension. Mice pretreated with LASSS showed a significant reduction in nitration compared to untreated mice, whereas GSSSG again showed no protective effect, confirming that the protective effect of LASSS was carried over from the laboratory. Further studies in older animals are needed to confirm the efficacy and safety of LASSS. alive.
This discovery could open new avenues for strategies to maintain muscle repair during aging, long-term bed rest, or other conditions that involve muscle disuse. The research team believes that the effects of LASSS on HGF can be broadly applied to humans and companion animals such as cats and dogs, ultimately helping to maintain independence, quality of life, and a healthy lifespan later in life.
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Reference magazines:
Zushi, K.et al. (2026). Enhanced HGF with improved receptor affinity and nitration dysfunction resistance through interaction with lipoic acid trisulfide. scientific report. DOI: 10.1038/s41598-026-60835-w. https://www.nature.com/articles/s41598-026-60835-w
