Muscles can begin to lose their strength and ability to recover surprisingly early in the aging process. Over time, muscle tissue can develop scar tissue, accumulate fat, and lose some of the specialized fibers responsible for fast, powerful movements. These changes can make daily activities more difficult and gradually reduce mobility and physical independence.
Now, Japanese scientists have identified a promising molecule that could help protect the body’s natural muscle repair system and potentially make it more efficient. In laboratory experiments, the compound boosted an important biological signal involved in muscle regeneration, increasing its ability to connect to a key cellular receptor by more than twofold.
The discovery comes from a team led by Professor Ryuichi Tatsumi of the Faculty of Agriculture at Kyushu University. Their findings, published in Scientific reportssuggest a possible new approach to combating the cellular changes that make aging muscles increasingly difficult to repair.
How Aging Disrupts the Body’s Muscle Repair System
Skeletal muscles are the muscles attached to bones that allow us to walk, lift objects, maintain posture, and perform other voluntary movements. Although these muscles experience wear and tear throughout life, they also have a remarkable ability to repair themselves.
Much of this repair depends on specialized stem cells called satellite cells. These cells normally remain inactive, positioned next to muscle fibers until they receive a signal that repair or regeneration is necessary. Once activated, they can multiply and develop into muscle cells that help restore damaged tissue.
A critical part of this process involves a protein called hepatocyte growth factor, or HGF. Despite its name, HGF plays important roles beyond the liver, including helping activate stem cells responsible for muscle regeneration.
Under normal conditions, HGF is stored in the supporting material surrounding muscle fibers. When muscles experience injury or mechanical stimulation, such as physical movement or stretching, the protein can be released.
HGF then attaches to a receptor called c-met on the surface of satellite cells. Receptors are specialized proteins that receive molecular signals and trigger responses inside cells. In this case, the interaction awakens dormant satellite cells, allowing them to multiply, mature and participate in the repair of muscle fibers.
But this carefully coordinated system becomes less reliable with age.
Hidden chemical change may weaken aging muscles
The researchers’ previous work found that HGF can undergo a chemical modification called nitration. This process attaches a chemical group called a nitro group to particular locations on a protein, potentially changing its structure and interfering with its normal activity.
For HGF, the researchers identified two particularly important locations, Y198 and Y250. Both are found in the region involved in binding to the c-met receptor.
When these sites undergo nitration, HGF becomes less able to connect to its receptor. The result is similar to a key that is damaged and can no longer operate the intended lock.
This disruption could have significant consequences on muscle aging. Even though the body continues to produce HGF, chemical changes can prevent the protein from properly activating stem cells needed for tissue repair. Researchers believe this mechanism may contribute to age-related muscle wasting and decline in regenerative capacity.
“HGF is not necessarily lacking as we age,” says Tatsumi. “Rather, it can be chemically modified after it is manufactured. This led us to wonder whether a compound with strong antioxidant capacity could protect HGF, either by preventing nitration or by compensating for the functional loss it causes.”
Scientists test two powerful sulfur compounds
To investigate this possibility, the team studied two compounds with strong antioxidant properties: glutathione trisulfide (GSSSG) and lipoic acid trisulfide (LASSS).
Antioxidants can help limit certain types of chemical damage caused by reactive molecules. Such damage can interfere with proteins and other essential components of cells, particularly when the body’s normal protective systems become less effective.
Both compounds belong to a chemical family called trisulfides. Their defining characteristic is a chain of three sulfur atoms linked together. This arrangement gives them unusual chemical properties, including the ability to participate in reactions involving electron transfer, called redox reactions.
Because these reactions play an important role in cellular chemistry, trisulfides are attracting increasing interest as potential ingredients in new drugs.
In the first set of experiments, both compounds reduced nitration at both vulnerable sites of HGF. However, preventing this chemical modification did not completely restore the protein’s ability to bind c-met.
The scientists therefore increased the amount of trisulfide used compared to HGF. They changed the molar ratio, which compares the number of molecules of each substance, from 1:4,000 to 1:8,000.
This adjustment produced an unexpected result.
Unexpected discovery creates ‘Super HGF’
At the highest concentration, LASSS did much more than protect HGF from chemical damage. This also significantly improved the protein’s ability to bind to its receptor.
Compared to untreated HGF, the LASSS-exposed protein showed more than twofold higher binding affinity for c-met. In other words, it could attach much more strongly to its target receptor, potentially improving a critical step in the muscle repair process.
The treatment also made HGF more resistant to nitration-induced loss of function, particularly at the Y198 site.
The effect was notably specific to LASSS. Although GSSSG also reduced nitration in earlier experiments, it did not produce the same improvement in receptor binding.
“It exceeded our expectations,” comments Tatsumi. “We knew that trisulfides had various biological functions, but we did not expect that simply mixing HGF with LASSS would produce such a striking effect.
“What this tells us is that LASSS does more than just neutralize reactive molecules. It can interact directly with HGF and induce a subtle structural change, creating an enhanced form of ‘Super HGF’ that binds more strongly to c-met and is resistant to nitration.”
The researchers suspect that LASSS interacts with HGF in a way that slightly changes the three-dimensional shape of the protein. Since a protein’s shape helps determine how well it interacts with other molecules, even a small structural adjustment could significantly change its activity.
The result is what the team describes as “Super HGF,” a potentially enhanced form of the body’s existing muscle repair signal.
It is important to note that stronger receptor binding does not automatically establish that muscle regeneration itself has improved. Additional experiments will be needed to determine whether this molecular improvement translates into better healing and muscle strength.
Mice experiments reveal promising protection
After observing the effects in laboratory experiments, the researchers wanted to determine whether LASSS could also protect HGF inside living muscle tissue.
They used mice subjected to tail suspension, an established experimental method for studying muscle atrophy. By reducing normal loading and muscle use, this technique produces some of the changes associated with prolonged inactivity, including muscle deterioration.
Mice given LASSS before the experiment showed significantly less HGF nitration than untreated animals. This suggests that the compound’s ability to protect the muscle repair protein is not limited to controlled laboratory conditions.
Once again, GSSSG failed to produce the same protective result.
These results provide preliminary evidence that LASSS can influence chemical processes affecting HGF in living animals. However, mouse experiments demonstrated protection against nitration, but not that LASSS restored lost muscle mass or improved physical strength.
The researchers emphasize that studies involving aging animals are still needed to establish the compound’s effectiveness and safety. in vivothat is to say within a living organism.
A potential new strategy against age-related muscle loss
This discovery could potentially contribute to treatments aimed at maintaining muscle function during aging or prolonged periods of inactivity.
Muscle deterioration is not limited to older people. It can also occur during prolonged bed rest or other situations in which the muscles are used less frequently. When muscle repair mechanisms are impaired, regaining lost strength and function can become particularly difficult.
Rather than replacing the body’s natural repair machinery, the approach explored in this study seeks to protect and enhance an existing biological signal. If the benefits can be confirmed in future studies, enhancing HGF activity could become a strategy to support muscle regeneration.
Scientists also believe that the underlying effects of LASSS on HGF may extend across species. This opens the possibility of applications not only in human medicine but also in veterinary care, particularly for aging pets such as dogs and cats.
For now, the results represent a first step toward understanding how a natural pathway for muscle repair could be enhanced. Whether LASSS can safely and effectively preserve muscle function during aging remains an open question.
Yet the unexpected finding that a sulfur-based compound can both protect and enhance an essential repair protein offers a promising direction for future research, with the long-term goal of helping people maintain mobility, independence, and a better quality of life as they age.
Gn Health
