Summary: A new study shows that lipoic acid trisulfide (LASSS) prevents age-related chemical modification of hepatocyte growth factor (HGF) and can convert it into a more potent form. In aged tissue, HGF is nitrated on tyrosine residues Y198 and Y250, preventing it from binding the c‑met receptor on muscle satellite cells and impairing muscle repair. Treatment with LASSS not only reduces this inhibitory nitration but also appears to induce a structural change in HGF that doubles its binding affinity for c‑met, producing an enhanced “Super HGF” with greater resistance to nitration.
In mouse experiments using a tail‑suspension model of disuse atrophy, pretreatment with LASSS markedly lowered HGF nitration and preserved regenerative signaling, suggesting a potential therapeutic approach for sarcopenia, disuse-induced muscle loss, and other conditions that impair muscle regeneration.
Key Facts
- Molecular cause of regeneration loss: In aged skeletal muscle, HGF becomes nitrated at tyrosine residues Y198 and Y250. This chemical modification blocks HGF from docking with c‑met receptors on satellite cells, preventing activation of muscle stem cells that drive repair.
- Formation of a “Super HGF”: When HGF is exposed to lipoic acid trisulfide (LASSS) at a 1:8000 molar ratio and free LASSS is removed, HGF’s affinity for c‑met increases more than two‑fold compared with native, unnitrated HGF, while gaining resistance to nitration.
- Trisulfide specificity: Of the trisulfides tested, LASSS produced the enhanced receptor binding and nitration resistance. Glutathione trisulfide (GSSSG), despite antioxidant activity, did not restore receptor binding or protect tissue in the same in vivo model.
- In vivo protection: LASSS pretreatment significantly reduced HGF nitration in a tail‑suspension mouse model of disuse muscle atrophy, supporting translation from biochemical experiments to living tissue.
- Broad relevance: Because HGF–c‑met signaling is conserved across mammals, LASSS‑mediated protection of HGF may have relevance for age‑related muscle loss in humans and companion animals.
Source: Kyushu University
Skeletal muscle declines early during aging. This decline leads to weakness, scarring, infiltration of fat into muscle, and loss of fast‑twitch fibers that support rapid, powerful movements. Preserving the molecular signals that activate muscle stem cells is therefore key to maintaining strength and mobility with age.
Researchers led by Professor Ryuichi Tatsumi at Kyushu University’s Faculty of Agriculture investigated how a specific trisulfide compound affects HGF, the primary signal that awakens satellite cells and initiates muscle repair. Their results were published in Scientific Reports on July 24, 2026.
HGF sits in the extracellular matrix around muscle fibers and is released to bind c‑met on satellite cells when muscle is injured or mechanically stimulated. Binding triggers satellite cells to exit quiescence, proliferate, and contribute to fiber repair. Previous work from the team showed that peroxynitrite‑driven nitration of HGF at Y198 and Y250—sites critical for c‑met interaction—blocks receptor binding and undermines satellite cell activation.
Because nitration is an oxidative modification that accumulates with age, the researchers tested whether trisulfide compounds with strong redox activity could prevent nitration or restore HGF function. They compared two trisulfides: glutathione trisulfide (GSSSG) and lipoic acid trisulfide (LASSS).
Both compounds reduced nitration at Y198 and Y250 in initial biochemical assays. However, only LASSS produced a striking, unexpected result when used at a higher molar ratio (HGF:LASSS of 1:8000): after removing unreacted LASSS, treated HGF bound c‑met with more than double the affinity of untreated HGF and showed increased resistance to nitration, particularly at Y198. GSSSG did not induce this enhancement, indicating a specific interaction between LASSS and HGF that goes beyond simple antioxidant activity.
Professor Tatsumi and colleagues interpret these findings to mean LASSS may interact directly with HGF and induce a subtle conformational change that both strengthens receptor binding and shields the binding region from nitrative damage, producing what they term a “Super HGF.”
To confirm physiological relevance, the team tested LASSS in a mouse model of disuse muscle atrophy induced by tail suspension. Mice pretreated with LASSS showed significantly less HGF nitration compared with untreated controls, while GSSSG again provided no protection. These in vivo results support the biochemical data and motivate further studies in aging animals to evaluate long‑term safety and efficacy.
The discovery suggests a new strategy to preserve muscle repair signaling: protecting HGF from oxidative nitration or enhancing its receptor affinity using specific trisulfide chemistry. If validated in further preclinical and clinical studies, LASSS or related approaches could help prevent or treat sarcopenia, disuse atrophy, and impaired regeneration leading to fibrosis and fat infiltration.
Key Questions Answered:
A: HGF is the primary activation signal for muscle satellite cells. Stored in the extracellular matrix, it is released after injury or mechanical stress to bind c‑met receptors on satellite cells, triggering proliferation and muscle fiber repair.
A: HGF is present but becomes chemically modified by nitration at specific tyrosine residues (Y198, Y250). This modification distorts the receptor‑binding region and prevents effective docking to c‑met, impairing satellite cell activation.
A: LASSS prevents nitration and appears to induce a structural change in HGF that both increases c‑met binding affinity and protects the key binding residues from nitrative damage, producing an enhanced HGF form with greater functional resilience.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by editorial staff.
- Additional contextual information was added by staff editors.
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 et al., 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
HGF, the myogenic stem cell activator, is susceptible to nitration of tyrosine residues Y198 and Y250—especially on fast‑twitch fibers—when peroxynitrite is generated during aging, which reduces its binding affinity for c‑met. The study demonstrates that interaction with lipoic acid trisulfide (LASSS) under physiological conditions produces an HGF form with increased c‑met affinity and resistance to nitration. After treatment at a 1:8000 molar ratio and removal of free LASSS, c‑met binding affinity rose more than twofold compared with native HGF, with greater protection observed at Y198 than Y250. Control treatments with glutathione trisulfide (GSSSG) or lipoic acid did not reproduce these effects. In vivo, LASSS pre‑administration prevented disuse‑induced HGF nitration in a tail‑suspension mouse model, while GSSSG did not. These findings point to a potential strategy for protecting HGF signaling to maintain muscle regeneration and counteract age‑related atrophy and impaired repair.