Muscles do not weaken with age simply because they get smaller. New research suggests that part of the problem may lie in the electrical signals that tell them when to contract.
Scientists at the University of Missouri found that communication between nerves and muscle fibers becomes less reliable with age. The failure appears to occur at the neuromuscular junction, where nerves transmit signals that activate muscles.
The finding could help explain part of sarcopenia, the age-related loss of muscle mass, strength, and physical function that affects nearly half of adults over age 80.
Looking Beyond Muscle Loss to the Neuromuscular Junction
“While the human lifespan has increased in recent decades, our ultimate goal at Mizzou is to ensure a person’s health span remains as high as possible for as long as possible,” said W. David Arnold, executive director of the NextGen Precision Health initiative and a professor in the School of Medicine.
Scientists have long focused on muscle loss and the decline of motor neurons as major causes of age-related weakness. Arnold and his colleagues instead examined what happens where nerve signals actually reach muscle. Arnold has studied the neuromuscular junction for more than a decade. His team’s findings challenge a long-held assumption.
“A long-held assumption in the field was that the neuromuscular junction remains reliable during aging, and some even suggested it may get better with aging,” Arnold said. “The significance of this new study is we are showing, in both humans and in animal models, that the neuromuscular junction is failing with aging.”
The Protein Behind the Signal: Lower NaV1.4 Makes Muscle Less Responsive
The researchers linked part of the decline to lower levels of NaV1.4, a sodium channel that helps skeletal muscle generate the electrical activity needed for contraction.
Lower levels of NaV1.4 may make muscle fibers less responsive to signals arriving from nerves, giving researchers a possible explanation for why aging muscles do not activate as effectively, even when the nerve signal arrives.
This suggests weakness in older adults is not just a matter of having fewer muscle fibers, but also having fibers that fail to fire reliably.
Making Aging Muscle More Responsive: Targeting ClC-1
The team also investigated ClC-1, a chloride channel involved in regulating electrical activity in skeletal muscle. Working with Danish biotechnology company NMD Pharma, the researchers found that partially inhibiting ClC-1 made aging muscles more responsive to nerve signals and improved strength in an animal model.
“We identified an important point of failure at the final step in communication between nerves and muscles,” Arnold said. “And what is perhaps even more exciting is that we showed this failure is potentially reversible. In collaboration with NMD Pharma, a biotechnology company in Denmark, we applied an approach they developed that targets a protein called ClC-1. By partially inhibiting ClC-1, we were able to make aging muscles more responsive to nerve signals and improve muscle strength in an animal model. That gives us a potential path toward eventually testing this approach in older adults.”
A Drug Already Being Studied: Ignaseclant
NMD Pharma has developed ignaseclant, an experimental drug that partially inhibits ClC-1. The drug has already been studied in people with neuromuscular disease, although not specifically for sarcopenia. Arnold was an investigator in a multicenter clinical trial involving people with Charcot-Marie-Tooth disease, the most common inherited neuromuscular disorder. The study reported improvements across several measures of muscle strength and function. Arnold presented the topline findings at the 2026 Muscular Dystrophy Association Clinical & Scientific Conference.
Arnold believes understanding the biology behind sarcopenia is a critical step toward developing treatments.
“I realized that in order to make a drug widely available to treat sarcopenia, the first step is better understanding what is causing sarcopenia in the first place,” Arnold said. “That curiosity sparked my interest in becoming a researcher.”
Analysis: Why This Changes the Sarcopenia Story
1. Paradigm shift: The field assumed the neuromuscular junction remained reliable or even improved with age. Mizzou data in humans and animal models shows it fails, adding a third mechanism alongside muscle atrophy and motor neuron loss.
2. Targetable mechanism: NaV1.4 decline explains reduced excitability, while ClC-1 inhibition offers a pharmacologically tractable way to restore responsiveness without building new muscle.
3. Translational path: Because ignaseclant has already been tested in Charcot-Marie-Tooth disease with strength improvements, repurposing for age-related weakness could be faster than starting from scratch, though sarcopenia trials are not yet done.
4. Health span focus: With nearly 50% of adults over 80 affected by sarcopenia, restoring nerve-muscle communication could impact fall risk, independence, and quality of life, not just muscle size.
Q&A
Q: Why do muscles get weaker with age according to new research?
A: University of Missouri researchers found the neuromuscular junction, where nerves signal muscles, becomes less reliable with age, partly due to lower levels of NaV1.4 sodium channels.
Q: What is sarcopenia?
A: Sarcopenia is age-related loss of muscle mass, strength, and physical function, affecting nearly half of adults over 80.
Q: Can age-related muscle weakness be reversed?
A: In an animal model, partially inhibiting the ClC-1 chloride channel with an NMD Pharma approach made aging muscles more responsive to nerve signals and improved strength, but human sarcopenia trials are still needed.
Q: What is ignaseclant?
A: Ignaseclant is an experimental drug from NMD Pharma that partially inhibits ClC-1. It has been studied in neuromuscular disease like Charcot-Marie-Tooth disease, not yet specifically for sarcopenia.
FAQ
1. What is the neuromuscular junction?
The specialized connection where a motor nerve ending transmits an electrical signal to a muscle fiber to trigger contraction.
2. What does NaV1.4 do?
NaV1.4 is a sodium channel critical for generating electrical activity in skeletal muscle needed for contraction. Lower levels reduce responsiveness.
3. What does ClC-1 do?
ClC-1 is a chloride channel that regulates muscle electrical activity. Partial inhibition can increase muscle excitability.
4. Who led the study?
W. David Arnold, executive director of NextGen Precision Health and professor at University of Missouri School of Medicine, with collaboration from NMD Pharma in Denmark.
5. Is there a treatment for sarcopenia now?
No approved drug specifically reverses neuromuscular junction failure in sarcopenia yet. Exercise and nutrition remain standard, while ClC-1 inhibition is experimental.
Disclaimer: This article is for general news and educational purposes. It does not provide medical advice, diagnosis, or treatment recommendations.
