Lipoic Acid Trisulfide Creates 'Super HGF' That Doubles Muscle Repair Signaling and Resists Age-Related Damage
核心洞察
Researchers at Kyushu University identified lipoic acid trisulfide (搜索) (LASSS), which more than doubles HGF's binding affinity for the c-met (搜索) receptor while protecting against nitration-induced dysfunction.
The compound appears to induce a structural change in hepatocyte growth factor, creating an enhanced "Super HGF" form that resists the age-related chemical damage underlying muscle wasting.
In a mouse model of muscle atrophy, LASSS pretreatment significantly reduced nitration levels compared with untreated animals, while glutathione trisulfide (搜索) showed no protective effect.
A research team led by Professor Ryuichi Tatsumi at Kyushu University's Faculty of Agriculture has discovered that lipoic acid trisulfide (搜索) (LASSS), a sulfur-based antioxidant compound, can transform hepatocyte growth factor (HGF) into a "Super HGF" form that binds its receptor more than twice as strongly as the native protein while resisting the chemical damage that drives age-related muscle decline. The findings were published on July 24, 2026, in Scientific Reports.
The discovery addresses a fundamental problem in skeletal muscle aging: HGF, the key wake-up signal for muscle stem cells, becomes chemically inactivated through a process called nitration. By identifying a compound that not only protects HGF but enhances its function, the researchers have opened a potential new avenue for combating sarcopenia (搜索) and muscle wasting.
The HGF Repair Pathway and How Aging Disrupts It
In healthy skeletal muscle, HGF resides quietly in the supportive network surrounding muscle fibers. When muscle is injured or mechanically stimulated, HGF is released and binds to c-met (搜索) receptors on satellite cells—the resident stem cells of skeletal muscle—awakening them from a resting state and enabling them to proliferate, differentiate, and contribute to muscle fiber repair.
Aging disrupts this system through a specific chemical modification. The team's earlier work demonstrated that HGF undergoes nitration, in which a nitro group is added to two specific sites on the protein: Y198 and Y250. These sites are located in the very region HGF uses to connect with c-met (搜索). Once nitrated, HGF loses its ability to dock with the receptor—described by the researchers as akin to a rusted key that no longer fits its lock. This loss of function is thought to be a root cause of age-related muscle wasting and impaired regeneration.
"HGF is not necessarily missing as we age. 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," said Professor Tatsumi.
From Protection to Enhancement: LASSS Exceeds Expectations
The team investigated two trisulfide compounds known for strong antioxidant activity: glutathione trisulfide (搜索) (GSSSG) and lipoic acid trisulfide (搜索) (LASSS). Both belong to a class of molecules carrying three consecutively linked sulfur atoms, whose 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. However, receptor-binding activity was not fully restored, prompting the researchers to increase the molar ratio of HGF to trisulfide from 1:4000 to 1:8000.
The higher concentration produced a striking and unexpected result. When HGF was mixed with LASSS, its binding affinity for c-met (搜索) rose to more than twice that of untreated HGF, while also becoming more resistant to nitration-induced dysfunction, particularly at Y198. This enhancement appeared exclusively with LASSS; GSSSG showed no such effect.
"This exceeded our expectations," Tatsumi commented. "We knew trisulfides had diverse biological functions, but we never expected that simply mixing HGF with LASSS would produce such a striking effect."
The findings suggest 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 (搜索) more strongly and resists nitration," Tatsumi explained.
In Vivo Confirmation in Muscle Atrophy Model
To determine whether the protective effect translates to living tissue, the researchers employed a mouse model of muscle atrophy caused by tail suspension. Mice pretreated with LASSS showed significantly reduced nitration compared with untreated animals. Consistent with the in vitro findings, GSSSG again provided no measurable protection, confirming that LASSS's protective effect carries over from the laboratory setting.
The researchers note that further studies in aging animals will be needed to confirm LASSS's effectiveness and safety in vivo before any clinical translation can be considered.
Broader Implications for Muscle Health
The findings may support the development of new approaches for maintaining muscle repair during aging, prolonged bed rest, or other conditions involving muscle disuse. The research team believes LASSS's effects on HGF are likely to apply broadly across species, from humans to companion animals such as cats and dogs, and could ultimately help preserve independence, quality of life, and healthy lifespan in later years.
Skeletal muscle is one of the first tissues to decline with age, with deterioration leading to weakness, scarring, fat accumulation inside muscle, and the loss of fast-twitch muscle fibers critical for quick and powerful movements. A molecule capable of both protecting and enhancing the HGF signaling axis could address a central mechanism underlying this decline.