A collaboration of researchers at Kyushu University has published a study in Scientific Reports that flips an old assumption about aging muscle on its head. The familiar story goes like this: as we age, key signaling proteins dwindle, muscles lose their regenerative spark, and the slow slide into sarcopenia begins. The new work, led by Ryuichi Tatsumi and involving 18 co-authors across several Japanese institutions and the University of Manitoba, suggests the reality is more insidious, and more surprising.
The problem, they report, is not that the signaling protein hepatocyte growth factor (HGF) disappears with age. It is that the same protein gets chemically corrupted by a normal metabolic byproduct. And in what the team calls an unexpected finding, a molecule made from three linked sulfur atoms does not just prevent that corruption: it appears to remodel HGF into a form with more than double its original receptor binding affinity, producing what might be called a Super HGF.
The findings, published July 24 under the title Enhanced HGF with increased receptor affinity and nitration-dysfunction resistance through interaction with lipoic acid trisulfide, carry implications for age-related sarcopenia, cancer-related cachexia, prolonged bed rest, and disuse atrophy in humans and potentially companion animals.
A Key That No Longer Fits Its Lock
Muscle satellite cells sit sandwiched between the basal lamina and the sarcolemma of muscle fibers. These adult stem cells are essential for muscle repair and growth. Their activation depends on HGF binding to a receptor called c-met on the satellite cell surface: a precise molecular handshake that signals the cell to wake up, divide, and rebuild muscle tissue.
In earlier work published in 2024, the Tatsumi group demonstrated that in 20-month-old rats: roughly the equivalent of late middle age in humans, this handshake breaks down. The HGF protein itself remained at normal quantities, but it had undergone a subtle chemical change: nitration at specific tyrosine amino acid residues, predominantly at positions 198 and 250 on the protein chain. The nitration was concentrated on fast-twitch IIa and IIx muscle fibers, the type most prone to age-related atrophy.
The agent responsible is peroxynitrite (ONOO-), a highly reactive molecule formed when nitric oxide and superoxide: both normal byproducts of cellular metabolism, collide. Peroxynitrite modifies tyrosine residues in proteins, and when those tyrosines happen to sit in the binding interface of HGF, the result is functionally devastating: the nitrated HGF loses its ability to bind c-met.
The team describes the situation as a key that has rusted and no longer fits its lock. The key is still there; the lock is still there. But the rust: biochemical nitration, prevents engagement.
A Molecule With Three Sulfur Atoms
The researchers tested two trisulfide compounds: molecules featuring three consecutive sulfur atoms in a chain, against this nitration problem: glutathione trisulfide (GSSSG) and lipoic acid trisulfide (LASSS, R-enantiomer, formula weight 238.39). Both are highly reactive by design, with a labile central sulfur that can participate in unusual redox and exchange chemistry unavailable to the more common disulfide form.
In controlled in vitro experiments, the team exposed HGF to peroxynitrite in the presence of each compound at molar ratios of 1:4000 and 1:8000 relative to HGF, along with companion controls using ordinary glutathione, ordinary lipoic acid (LASS, without the third sulfur), and no treatment at all.
The results were unambiguous and, in one respect, startling.
The Surprise: More Than Double the Affinity
Glutathione trisulfide and plain lipoic acid showed minimal activity. But LASSS at the 1:8000 molar ratio did something the authors describe as unexpected: after incubation with the compound followed by ultra-filtration to wash away any free LASSS, the treated HGF showed a c-met binding affinity more than two times higher than untreated, non-nitrated HGF.
This was not mere protection. The HGF molecule had not simply been shielded from peroxynitrite damage: it had been structurally enhanced.
The same treatment also conferred resistance to nitration at both Y198 and Y250, with stronger protection at the Y198 site. The mechanism, the authors argue, is independent of any general antioxidant function. Neither GSSSG nor plain lipoic acid produced this effect. Something about the specific structure of LASSS: its lipoic acid backbone combined with the trisulfide group, enabled a direct chemical interaction with HGF that remodeled it into a state both resistant to nitration and hyperactive toward its receptor.
How LASSS Might Work
The paper proposes that LASSS modifies specific disulfide bridges within the HGF protein itself. Two cysteine pairs: Cys149-Cys189 and Cys177-Cys201, are identified as potential targets for remodeling into trisulfide bonds. This would represent a genuine structural modification of the protein, not a pharmacological shielding effect. The third sulfur atom inserted into a disulfide bridge could alter the local geometry and electronic environment of the binding region, rendering critical tyrosine residues less accessible to peroxynitrite attack while simultaneously improving the fit between HGF and c-met.
If confirmed by structural biology techniques such as X-ray crystallography or mass spectrometry, this would represent a novel category of protein modification: a small molecule that deliberately remodels a specific disulfide bond into a trisulfide to improve a therapeutic protein’s function.
Evidence in Living Animals
The team then moved to an in vivo model. Mice received LASSS in their drinking water for five days before undergoing hind-limb unloading via tail suspension: a standard model for simulating disuse atrophy. The results paralleled the in vitro findings: pre-administration of LASSS prevented disuse-induced HGF nitration in the unloaded muscles. Glutathione trisulfide, tested in parallel, did not protect.
The researchers caution, however, that this was a disuse model, not a true aging model. The mice were young males, and the study did not measure actual muscle atrophy prevention: only the reduction of HGF nitration as a biochemical endpoint. The paper explicitly notes that sex was not considered as a biological variable; only male animals were used.
What This Means for Age-Related Muscle Decline
The broader implication of the study is a conceptual shift. Age-related decline in muscle regenerative capacity has often been framed as a problem of depletion: satellite cells dying off, growth factors dwindling, the system running out of parts. The Kyushu work suggests an alternative: the parts are present, but they have been chemically corrupted by the normal byproducts of metabolism, and that corruption is reversible.
If HGF nitration represents a “rusted key” problem, LASSS appears to function as both a rust remover and a key sharpener. The compound does not need to be present continuously or at high concentrations; a brief exposure at a precise molar ratio, followed by removal of the free compound, produces a lasting structural change.
Limitations and Next Steps
The authors are direct about the study’s limitations. The in vivo experiments used only young male mice, not aged animals, so direct evidence that LASSS reverses age-related nitration in old muscle has not yet been produced. The study measured biochemical nitration levels, not functional outcomes such as muscle mass, fiber diameter, or grip strength. Long-term safety data for LASSS administration do not exist. And because only male subjects were tested, potential sex differences in HGF nitration or LASSS response remain unknown.
The next step, the team indicates, is to repeat the experiments in aged animals and to measure actual changes in muscle structure and function alongside the biochemical markers. Cross-species conservation of HGF: the protein sequence is highly similar across mammals, suggests the mechanism should translate to humans and companion animals, but that remains to be tested directly.
A New Path Forward
For all its caveats, the study opens a genuinely new direction in the biology of aging muscle. The discovery that a small trisulfide molecule can structurally remodel a growth factor to resist nitration and enhance receptor binding is, as the authors note, an unprecedented finding. If subsequent work confirms it in aged animals and demonstrates functional muscle protection, LASSS or a derivative could form the basis for interventions against sarcopenia, cachexia, disuse atrophy from hospitalization or spaceflight, and other conditions where the satellite cell activation cascade stalls.
The rusted key, it turns out, may be reparable after all.
Scientific Reports 16, 22053 (2026)
DOI: 10.1038/s41598-026-60835-w