Why Do We Lose Strength as We Age?
Many people notice that as they get older, walking becomes slower, carrying things gets harder, and even standing up from a chair may require using their hands. This may not just be a simple part of "getting old" — it could be a condition called sarcopenia. Sarcopenia refers to the age-related decline in muscle strength and function, affecting nearly half of adults older than 80.
Scientists have spent decades trying to understand the true cause of sarcopenia. Much of that research has focused on changes inside the muscles themselves, particularly the gradual loss of muscle mass. Other studies have examined the disappearance of neurons that send the signals needed to activate muscles. However, a new discovery from the University of Missouri reveals a critical overlooked reason.
Communication Breakdown Between Nerves and Muscles
W. David Arnold, executive director of the NextGen Precision Health initiative at the University of Missouri, and his collaborators found that communication between nerves and muscles becomes less reliable as people age. This breakdown appears to contribute to sarcopenia.
Arnold has studied the neuromuscular junction — the specialized point where a nerve sends a signal to a muscle and tells it to contract — for more than 10 years. Under normal conditions, this system works with remarkable reliability, allowing electrical signals from nerves to repeatedly activate muscle fibers. But the new research suggests that reliability declines with age.
The researchers linked the problem to lower levels of a protein known as NaV1.4, which helps muscle fibers respond to signals from nerves.
"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."
A Potentially Reversible Failure Point
Finding the source of this communication problem also revealed a possible strategy for restoring some lost muscle function.
"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."
Rather than replacing lost muscle or neurons, the approach is aimed at making existing muscle fibers more responsive to the messages they receive. In the animal model, partially blocking ClC-1 improved the ability of aging muscles to react to nerve signals and increased muscle strength.
Turning Discoveries Into Treatments
There is already clinical evidence that targeting ClC-1 can improve some measures of muscle strength and function in people with neuromuscular disorders, although those studies have involved conditions other than sarcopenia.
Arnold participated as an investigator in a multicenter clinical trial of ignaseclant, an experimental drug from NMD Pharma that partially inhibits ClC-1. The trial involved patients with Charcot-Marie-Tooth disease, the most common inherited neuromuscular disorder. Researchers reported improvements across several measures of muscle strength and physical function. Arnold presented the topline findings at the 2026 Muscular Dystrophy Association Clinical & Scientific Conference.
He is optimistic that ignaseclant could ultimately be investigated as a treatment for older adults with sarcopenia.
"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."
An International Effort to Understand Aging Muscles
The research brings together scientists and clinicians from several countries. Arnold leads an international team with collaborators from Denmark, Scotland, Saudi Arabia and India.
At Mizzou, he has also recruited specialists to the Roy Blunt NextGen Precision Health building. Among them is Hiroshi Nishimune, an internationally recognized expert on the neuromuscular junction and a co-author of the new study.
"When he came to Mizzou from Tokyo to join our lab, his specialized imaging expertise helped us start to answer questions that previously seemed out of reach," Arnold said. "He's really one of the top experts in the world when it comes to the neuromuscular junction, and it definitely gives us an edge here at Mizzou for pioneering innovative work in this field."
The study, "Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition," was published in The Journal of Clinical Investigation.
Maintaining Muscle Health: Start with Daily Monitoring
While this research brings hope for future treatments for sarcopenia, maintaining muscle health still starts with daily habits. A balanced diet, regular exercise (especially strength training), adequate sleep, and healthy lifestyle choices can all help slow muscle loss.
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