A surprising discovery could help aging muscles repair themselves

Now, scientists in Japan have identified a promising molecule that could help protect the body's natural muscle repair system and potentially make it more effective. In laboratory experiments, the compound strengthened an important biological signal involved in muscle regeneration, increasing its ability to connect with a key cellular receptor by more than twofold.

The discovery comes from a team led by Professor Ryuichi Tatsumi at Kyushu University's Faculty of Agriculture. Their findings, published in Scientific Reports, suggest a possible new approach to addressing 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 that repair depends on specialized stem cells known as satellite cells. These cells normally remain inactive, positioned alongside muscle fibers until they receive a signal that repair or regeneration is needed. Once activated, they can multiply and develop into muscle cells that help restore damaged tissue.

An essential 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 the stem cells responsible for muscle regeneration.

Under normal conditions, HGF is stored within the supportive material surrounding muscle fibers. When muscles experience an 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 helps awaken dormant satellite cells, allowing them to multiply, mature, and participate in repairing muscle fibers.

But this carefully coordinated system becomes less reliable with age.

A Hidden Chemical Change May Weaken Aging Muscles

The researchers' previous work revealed that HGF can undergo a chemical modification known as 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 especially important locations, Y198 and Y250. Both lie within the region involved in attaching to the c-met receptor.

When these sites undergo nitration, HGF becomes less capable of connecting with its receptor. The result is similar to a key that has become damaged and can no longer operate its intended lock.

This disruption could have important consequences for aging muscles. Even if the body continues producing HGF, chemical changes may prevent the protein from properly activating the stem cells needed for tissue repair. The researchers believe this mechanism may contribute to age-related muscle wasting and declining regenerative capacity.

"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."

Scientists Test Two Powerful Sulfur Compounds

To investigate that 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.

The two compounds belong to a chemical family called trisulfides. Their defining feature is a chain of three sulfur atoms connected to one another. This arrangement gives them unusual chemical properties, including an ability to participate in reactions involving the transfer of electrons, known as redox reactions.

Because these reactions play important roles in cellular chemistry, trisulfides have attracted growing interest as potential ingredients in new medicines.

In the first set of experiments, both compounds reduced nitration at the two vulnerable sites on HGF. However, preventing this chemical modification did not completely restore the protein's ability to attach to c-met.

The scientists therefore increased the amount of trisulfide used relative to HGF. They changed the molar ratio, which compares the number of molecules of each substance, from 1:4000 to 1:8000.

That adjustment produced an unexpected result.

An Unexpected Discovery Creates "Super HGF"

At the higher concentration, LASSS did much more than protect HGF from chemical damage. It also dramatically improved the protein's ability to bind to its receptor.

Compared with untreated HGF, the protein exposed to LASSS showed more than twice the binding affinity for c-met. In other words, it could attach to its target receptor much more strongly, potentially enhancing a critical step in the muscle repair process.

The treatment also made HGF more resistant to the loss of function caused by nitration, particularly at the Y198 site.

Notably, the effect was specific to LASSS. Although GSSSG had also reduced nitration in the earlier experiments, it did not produce the same improvement in receptor binding.

"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."

The researchers suspect that LASSS interacts with HGF in a way that slightly alters the protein's three-dimensional shape. Because a protein's shape helps determine how well it interacts with other molecules, even a small structural adjustment could substantially 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.

Importantly, stronger receptor binding does not automatically establish that muscle regeneration itself has improved. Additional experiments will be needed to determine whether this molecular enhancement translates into better muscle healing and strength.

Mouse 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 weight bearing and muscle use, this technique produces some of the changes associated with prolonged inactivity, including muscle deterioration.

Mice that received LASSS before the experiment showed significantly less HGF nitration than untreated animals. This suggested that the compound's ability to protect the muscle repair protein was not limited to controlled laboratory conditions.

Once again, GSSSG failed to produce the same protective result.

These findings provide early evidence that LASSS can influence the chemical processes affecting HGF within living animals. However, the mouse experiments demonstrated protection against nitration, not that LASSS restored lost muscle mass or improved physical strength.

The researchers emphasize that studies involving aging animals are still necessary to establish the compound's effectiveness and safety in vivo, meaning within a living organism.

A Potential New Strategy Against Age-Related Muscle Loss

The discovery could eventually contribute to treatments aimed at maintaining muscle function during aging or extended periods of inactivity.

Muscle deterioration is not limited to older adults. It can also occur during prolonged bed rest or other situations in which muscles are used less frequently. When muscle repair mechanisms become impaired, recovering lost strength and function can become especially challenging.

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, strengthening HGF activity could become one strategy for supporting muscle regeneration.

The scientists also believe that the underlying effects of LASSS on HGF may extend across species. That raises the possibility of applications not only in human medicine but also in veterinary care, particularly for aging companion animals such as dogs and cats.

For now, the findings represent an early step toward understanding how a naturally occurring muscle repair pathway might be strengthened. Whether LASSS can safely and effectively preserve muscle function during aging remains an open question.

Still, the unexpected discovery that a sulfur-based compound can both protect and enhance a critical 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 grow older.