Summary: A new study demonstrates how a specific trisulfide molecule, lipoic acid trisulfide (LASSS), prevents the age-related chemical alteration of HGF. In aging tissue, HGF undergoes nitration at residues Y198 and Y250, blocking it from binding its c-met receptor on muscle satellite cells. LASSS not only suppresses this inhibitory nitration but structural modifications transform the protein into a “Super HGF” state with double the normal binding affinity for c-met.
In vivo experiments in tail-suspended mouse models confirmed that LASSS treatment significantly reduces HGF nitration and preserves muscle repair signals, offering a promising therapeutic target for sarcopenia, age-related atrophy, and prolonged disuse.
Key Facts
- Molecular Cause of Regeneration Loss: In aged muscle, HGF is chemically modified by nitration at tyrosine sites Y198 and Y250, preventing it from docking to c-met receptors on resident satellite cells to trigger muscle repair.
- Creation of “Super HGF”: When HGF is treated with lipoic acid trisulfide (LASSS) at an 1:8000 molar ratio, its binding affinity for c-met increases more than two-fold compared to unnitrated, native HGF while remaining highly resistant to nitration.
- Trisulfide Specificity: Out of the two sulfur-based trisulfides tested, LASSS induced structural protection and enhanced c-met binding, whereas glutathione trisulfide (GSSSG) failed to restore receptor binding or protect tissue in mouse models.
- In Vivo Protection: Pretreatment with LASSS significantly reduced HGF nitration in a tail-suspension mouse model of disuse muscle atrophy.
- Cross-Species Application: Because HGF signaling is highly conserved across mammals, this trisulfide intervention could potentially apply to age-related muscle loss in humans as well as companion animals like dogs and cats.
Source: Kyushu University
Skeletal muscle is one of the first tissues to decline with age. This decline can lead to weakness, scarring, fat accumulation inside muscle, and the loss of fast-twitch muscle fibers that are important for quick and powerful movements.
A research team led by Professor Ryuichi Tatsumi at Kyushu University’s Faculty of Agriculture has now identified a molecule that may help protect and even strengthen one of the body’s key muscle-repair signals.
The findings were published on July 24, 2026, in Scientific Reports.
The study centers on hepatocyte growth factor, or HGF, which acts like a wake-up signal in skeletal muscle. In healthy muscle, HGF sits quietly in the supportive network surrounding muscle fibers. When muscle is injured or mechanically stimulated, HGF is released and binds to c-met receptors on satellite cells—the resident stem cells of skeletal muscle—awakening them from a resting state, enabling them to proliferate, differentiate, and contribute to muscle fiber repair.
However, aging can interfere with this process. The team’s earlier work showed that HGF undergoes a chemical change called nitration, in which a nitro group is added to two specific sites on the protein, Y198 and Y250—the very region HGF uses to bind c-met. Once nitrated, HGF loses its ability to dock with the receptor, like a rusted key that no longer fits its lock. This is thought to be a root cause of age-related muscle wasting and impaired regeneration.
“HGF is not necessarily missing as we age,” explains Tatsumi. “Rather, it can be chemically altered after it is made. That led us to wonder whether a compound with strong antioxidant capacity might protect HGF, either by preventing nitration or by compensating for the functional loss it causes.”
The team turned to two sulfur-based compounds known for strong antioxidant activity: glutathione trisulfide (GSSSG) and lipoic acid trisulfide (LASSS). Both belong to a class of molecules called trisulfides, which carry three consecutively linked sulfur atoms. Their unusual sulfur chemistry and redox properties have recently attracted attention for pharmaceutical development.
In initial experiments, both GSSSG and LASSS suppressed nitration of HGF at Y198 and Y250. But receptor-binding activity was not fully restored, so the team raised the molar ratio of HGF to trisulfide, from 1:4000 up to 1:8000.
A surprise followed. At this higher ratio, HGF’s binding affinity for c-met increased more than two-fold compared with untreated HGF, while also becoming more resistant to nitration-induced dysfunction, especially at Y198. This enhancement appeared with LASSS alone; GSSSG showed no such effect.
“This exceeded our expectations,” comments Tatsumi. “We knew trisulfides had diverse biological functions, but we never expected that simply mixing HGF with LASSS would produce such a striking effect.
“What this tells us is that LASSS does more than simply neutralize reactive molecules. It may interact directly with HGF and induce a subtle structural change, creating an enhanced ‘Super HGF’ form that binds c-met more strongly and resists nitration.”
To test whether this effect holds up in living tissue, the researchers used a mouse model of muscle atrophy caused by tail suspension. Mice pretreated with LASSS showed significantly reduced nitration compared with untreated animals, while GSSSG again showed no protective effect, confirming that LASSS’s protective effect carries over from the lab. Further studies in aging animals will be needed to confirm LASSS’s effectiveness and safety in vivo.
The findings may open a new path toward strategies for maintaining muscle repair during aging, prolonged bed rest, or other conditions involving muscle disuse. The team believes LASSS’s effects on HGF are likely to apply broadly, from humans to companion animals such as cats and dogs, and ultimately help preserve independence, quality of life, and healthy lifespan in later years.
Key Questions Answered:
A: Hepatocyte growth factor (HGF) acts as the primary “wake-up” signal for skeletal muscle. It sits in the extracellular matrix and, upon injury or mechanical stress, binds to c-met receptors on muscle satellite cells, activating them from quiescence so they can multiply and rebuild muscle fibers.
A: HGF is not absent in older tissue, but it becomes chemically altered through nitration. The addition of nitro groups to specific tyrosine residues (Y198 and Y250) distorts the region HGF uses to dock with c-met, making it unable to activate satellite stem cells.
A: LASSS neutralizes reactive molecules to prevent nitration and appears to induce a subtle structural shift in HGF itself. This creates an enhanced “Super HGF” that binds c-met more than twice as strongly as normal HGF while remaining protected against oxidative nitration.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuroscience and aging research news
Author: Qinlin Wu
Source: Kyushu University
Contact: Qinlin Wu – Kyushu University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Enhanced HGF with increased receptor affinity and nitration-dysfunction resistance through interaction with lipoic acid trisulfide” by Kahona Zushi, Miyumi Seki, Ryota Mizuochi, Kazuki Shitamitsu, Alaa Elgaabari, Sakiho Tanaka, Junri Miyamoto, Kaoru Mizoguchi, Reina Fujimaru, Jiaxi Han, Takashi Nakashima, Shoko Sawano, Wataru Mizunoya, Takahiro Maeno, Issei Yokoyama, Takahiro Suzuki, Judy E. Anderson, Ryuichi Tatsumi. Scientific Reports
DOI:10.1038/s41598-026-60835-w
Abstract
Enhanced HGF with increased receptor affinity and nitration-dysfunction resistance through interaction with lipoic acid trisulfide
Myogenic stem cell activator HGF (hepatocyte growth factor) undergoes nitration of tyrosine residues (Y198, Y250) predominantly on fast-twitch fibers to lose its binding affinity to the signaling receptor c-met, in response to peroxynitrite (ONOO–) generation during aging.
Here we show that HGF adopts an enhanced form with dynamically increased receptor-binding affinity and nitration-dysfunction resistance through interaction with lipoic acid trisulfide (LASSS) under physiological conditions.
When evaluated after exposure to LASSS at a 1:8000 molar ratio to HGF and subsequent ultra-filtration to wash-out un-reacted free LASSS, c-met binding affinity increased more than two-fold over the original non-nitrated HGF.
The same LASSS treatment also conferred nitration resistance with a greater effect for Y198 than Y250, indicating a novel mechanism independent of an anti-oxidative function of LASSS. Neither glutathione trisulfide (GSSSG, a potent anti-oxidant) nor lipoic acid enhanced c-met binding or nitration resistance, and thus served as controls.
Importantly, pre-administration of LASSS to mice prevented the disuse-induced HGF nitration observed in a tail-suspension model for muscle atrophy, while GSSSG did not. The findings encourage the idea that LASSS may react with HGF to enhance its receptor-binding affinity and nitration resistance, which are known to strongly drive myogenic stem cell dynamics and homeostasis.
Application of this model could potentially lead to pioneering strategies to counteract or treat age-related muscle atrophy and impaired regeneration with fibrosis and fat infiltration (including sarcopenia and frailty).
