Muscle strength declines with age. For a long time, the focus has been primarily on two factors: the loss of muscle mass and the decline in the number of nerve cells that control the muscles. A new study from the University of Missouri now suggests that communication between nerves and muscles may also play an important role. The findings may open up a new approach to treating age-related muscle weakness. However, this research is still in its early stages. A significant portion of the studies was conducted on animal models.
When Nerve Signals No Longer Reach the Muscle Reliably
For a muscle to move, a complex communication process must function properly. A nerve sends an electrical signal, which is transmitted to the muscle fiber at the so-called neuromuscular junction, where it triggers a contraction. Scientists led by W. David Arnold at the University of Missouri investigated precisely this interface.
Their findings suggest that communication between nerves and muscles becomes less reliable with age. The researchers found evidence of this in both humans and animal models. The protein NaV1.4 appears to play an important role in this process. It helps muscle cells respond to electrical signals from the nerves. The researchers found lower levels of this protein in aging muscles. This brings into focus a mechanism that has received less attention to date in research on age-related muscle weakness.
Sarcopenia is More Than Just the Loss of Muscle Mass
The age-related loss of muscle strength and physical performance is known as sarcopenia. The condition can limit mobility and, among other things, increase the risk of falls. According to the University of Missouri, sarcopenia affects nearly half of people over the age of 80. For those affected, the progressive loss of strength can make everyday movements—such as getting up, climbing stairs, walking for extended periods, or carrying objects—increasingly difficult.
In the search for the causes, much of the research to date has focused on changes within the muscle itself. These include, in particular, the loss of muscle mass, changes in muscle fibers, and an overall decline in muscle performance. At the same time, the nervous system also changes with age. Among other things, nerve cells responsible for controlling the muscles may be lost.
The new study from the University of Missouri now turns its attention to another possible factor. The researchers believe that it may not only be the number of nerve cells or the existing muscle mass that is decisive. Communication between nerves and muscles also appears to be impaired. Even if both structures are still present, signals from the nervous system may activate the muscles less reliably as we age.
This finding is interesting because it could provide another explanation for why muscle strength declines with age. The muscle may be weaker not only because it lacks mass, but also because it no longer responds as effectively to incoming nerve signals. This suggests that the so-called neuromuscular junction could become an important focal point for further research into sarcopenia.
Further Studies Confirm this Research Approach
Other studies also provide evidence that the connection between nerves and muscles plays an important role in age-related loss of strength. A study published in 2024 involving older adults showed that changes in neuromuscular connections can occur even before pronounced sarcopenia sets in. Among other things, the researchers observed signs of impaired signal transmission and increasing denervation of the muscles.
An experimental study from 2022 reached a similar conclusion. In that study, researchers found that the protein MFG-E8 was associated with changes in neuromuscular connections and increasing muscle weakness in older mice. When levels of the protein were reduced, certain age-related changes were less pronounced. Both studies thus support the hypothesis that not only muscle mass itself, but also communication between nerves and muscles, may be important for maintaining muscle strength in old age.
A Protein Could Offer a New Therapeutic Approach
Of particular interest is the question of whether sarcopenia can be at least partially reversed. The researchers therefore investigated another protein called ClC-1, which is involved in the electrical function of muscle cells. The scientists used an approach in which ClC-1 activity was partially inhibited. In an animal model, this treatment led to older muscles responding better to nerve signals. At the same time, muscle strength improved.
This approach thus differs from a therapy that focuses exclusively on rebuilding lost muscle mass. Instead, the goal is to improve the responsiveness of existing muscle fibers. Put simply: the muscle should once again be able to reliably receive nerve signals and convert them into a contraction.
An Active Ingredient is Already Being Studied for Another Condition
The ClC-1 mechanism is already being investigated in clinical research. The experimental drug Ignaseclant was developed by the Danish biotechnology company NMD Pharma and partially inhibits ClC-1. W. David Arnold participated in an international clinical trial in which the drug was tested in people with Charcot-Marie-Tooth disease.
Improvements were observed in patients across several measures of muscle strength and physical function. However, Charcot-Marie-Tooth disease is a different condition than sarcopenia. The results therefore cannot simply be applied to older adults with age-related muscle loss. Separate clinical trials would be necessary to explore a potential treatment for sarcopenia.
Could Muscle Strength be Specifically Improved in Older Adults?
If the current results are confirmed in further studies, this could open up a new avenue of research for the treatment of age-related muscle weakness. The key insight is this: Not every age-related decline in muscle strength is necessarily caused solely by reduced muscle mass or the loss of nerve cells. Part of the problem could also lie in the fact that the existing nerves and muscle fibers no longer communicate efficiently with one another.
A future therapy might therefore not only focus on building muscle mass. A treatment that improves the sensitivity of muscle fibers to nerve signals is also conceivable. However, there is still a long way to go before such a therapy becomes a reality. For now, the current findings provide initial clues about a possible mechanism and a potential therapeutic approach.
Scientists and clinicians from several countries participated in the research. The team led by W. David Arnold collaborates with researchers from Denmark, Scotland, Saudi Arabia, and India, among others. Among the participating scientists is Hiroshi Nishimune, a specialist in neuromuscular connections and a co-author of the study. The study was published in the Journal of Clinical Investigation.
What the Results Mean for Older Adults
For older adults, the study does not immediately offer a new, readily available treatment for sarcopenia. However, the results point to a possible mechanism that has received less attention to date: As people age, not only might muscle mass be lost, but communication between nerves and muscles may also become less reliable. As a result, existing muscle fibers may respond less effectively to signals from the nervous system. If this connection is confirmed in further studies, it could lead, in the long term, to a new approach for treating age-related muscle weakness.
Until then, further research is needed, particularly clinical trials involving people with sarcopenia. The findings from animal models to date cannot automatically be applied to older adults. Nevertheless, the discovery is interesting because it highlights an additional way to maintain muscle strength in old age: Not only could building or maintaining muscle mass play a role, but so might improving signal transmission between nerves and muscles. Such an approach could one day help people perform everyday movements—such as walking, standing up, or climbing stairs —for longer, thereby supporting physical independence in old age.
Regardless of how this line of research develops, regular exercise and targeted strength training remain important factors in maintaining muscle strength. The new study does not replace these measures but could help us better understand in the future why muscles can increasingly lose function with age despite the presence of muscle mass. This opens up another avenue for scientists to investigate the causes of sarcopenia more closely and potentially develop new treatment options.