Mouse Study Links Aging Motor Circuits to Declining Muscle Strength

Muscle weakness is one of the most common signs of aging, and it may be more serious than it first seems. Large population studies have found that age-related loss of strength is closely tied to higher mortality, including deaths related to cardiovascular disease, cancer, and dementia. As the global population age 65 and older is expected to rise to more than 20 percent of the world’s total by 2050, the strain that shrinking strength places on healthcare systems and personal independence is likely to increase sharply. Even so, the biological basis of this weakness is still not fully understood, and there are no approved treatments to prevent or reverse it.

For many years, the main explanation was straightforward: muscles get smaller with age, a process called sarcopenia, and smaller muscles generate less force. But long-running population data have shown a puzzle. Strength drops much faster than muscle mass does, suggesting that muscle loss alone cannot explain the full decline in power. That has led scientists to look beyond the muscle and toward the nervous system, which must generate and sustain force. Most of that research has focused on the spinal cord and the body’s periphery, where changes in spinal circuit excitability, motor neuron properties, synaptic balance, and neuromuscular junction signaling have been well documented.

Much less attention has been given to the motor cortex, the outer brain region that serves as the source of voluntary movement. Human studies have suggested that older adults have reduced voluntary activation of limb muscles, altered cortical drive to muscle, and an imbalance between excitatory and inhibitory circuits in the motor cortex. But imaging and stimulation methods in people do not have the precision needed to identify which specific circuits, cell types, or molecular pathways change with age, or to connect those changes directly to impaired movement. A new study in aged mice, published in Aging Cell, was designed to fill that gap by measuring brain, nerve, and muscle function in the same animals.

The team, based at the University of Missouri, built on an earlier finding from their lab that layer V pyramidal neurons in the primary motor cortex become hyperexcitable in aged mice. These deep-layer projection neurons include the cells that shape and carry cortical motor commands to the spinal cord. The result was notable because cortical hyperexcitability resembles what is seen in neurodegenerative diseases such as amyotrophic lateral sclerosis, where it has been linked to motor decline, and Alzheimer’s disease, where it has been associated with cognitive decline. The key question was whether the aging-related hyperexcitability was just an interesting observation or whether it was truly connected to weakness.

To test that, the researchers carried out a wide set of experiments in young mice, aged three months, and older mice, aged 24 months, with equal numbers of males and females in each group. Behavioral tests showed that the aged mice were much weaker: grip strength, rotarod performance, and a demanding weighted cart pull task were all significantly reduced. In vivo electrophysiology showed that the compound muscle action potential, a measure of overall neuromuscular excitability, was smaller in aged animals, as was the estimated number of functioning motor units, while individual motor units were larger and repetitive nerve stimulation revealed more transmission failure at the neuromuscular junction. Direct muscle measurements confirmed that both twitch and tetanic plantar flexion torque were markedly reduced in the aged mice.

The most striking finding came from motor evoked potential recordings, which measure the brain’s output to muscle. When the researchers stimulated across the motor cortex, the evoked response in the gastrocnemius muscle was larger in aged mice, indicating stronger cortical output. By contrast, stimulation at the cervical spinal cord produced smaller responses in aged animals, indicating weaker spinal output. In other words, the aged nervous system showed a paradoxical pattern: a failing spinal and neuromuscular system paired with a louder signal from the cortex. That suggested the hyperexcitable cortical neurons identified earlier might be actively reshaping the motor system rather than simply reflecting its decline.

Patch-clamp recordings from 160 individual layer V pyramidal neurons across the same animals confirmed the intrinsic hyperexcitability. Aged neurons fired more strongly at every depolarizing current step tested, from 50 to 300 picoamperes, roughly doubling their firing rate at both low and high stimulation. Their membranes were also more resistive and had longer time constants, properties that lower the amount of current needed to reach action potential threshold. Single-cell molecular analysis using digital PCR showed that aged neurons had higher transcript levels of Nav1.6 and Nav1.1, sodium channel subunits that contribute to persistent inward current, a powerful enhancer of repetitive firing, along with increased levels of the serotonin receptor 5-HT2C, a known regulator of that current. These transcriptional shifts offer candidate molecular markers of the hyperexcitable state.

Synaptic recordings pointed to additional mechanisms. When the researchers stimulated layer II/III of the motor cortex, the normal feedforward source of input to layer V neurons, they found that excitatory inputs onto aged neurons had a higher paired-pulse ratio, suggesting lower initial release probability but better maintenance of transmission during rapid activity. Inhibitory inputs behaved differently: evoked responses were smaller and the paired-pulse ratio decreased, implying that inhibitory synapses release strongly at first but weaken quickly with repeated activation. Together, these changes could let excitatory drive dominate during the sustained, high-frequency firing involved in voluntary movement, helping maintain the hyperexcitable state.

The study’s statistical centerpiece was a set of correlations linking all of these measurements within individual animals. Across 250 pairwise relationships between cortical variables and neuromuscular or behavioral outcomes, 109 remained significant after correction for multiple comparisons, and most were negative, meaning that animals with higher cortical excitability tended to have worse motor performance. Firing frequency at 50 picoamperes stood out as the strongest cortical correlate of a composite neuromuscular dysfunction index, explaining 90 percent of its variance. A mediation analysis then suggested that this firing frequency statistically accounted for 75 percent of the effect of aging on neuromuscular function, although a reverse model in which the mediator and outcome were switched explained 42.2 percent, showing that observational data like these cannot establish causation.

The authors are careful about that limitation. The mediation models describe how variance can be partitioned, not proof that cortical hyperexcitability directly causes weakness. It remains possible that overactive brain output is a compensatory reaction to a failing periphery, or that both arise from a shared aging process. Still, earlier evidence that chemogenetically inducing layer V hyperexcitability in the motor cortex reduces muscle force and coordination in mice raises the possibility that the phenotype is harmful. The similarity to ALS, where cortical hyperexcitability is a recognized feature tied to downstream motor impairment, suggests a possible shared mechanism across different forms of motor dysfunction. If future studies show that reducing layer V hyperexcitability in older animals restores strength, the motor cortex could become a real therapeutic target for one of aging’s most burdensome problems, turning weakness from an unavoidable decline into a treatable disorder of brain circuitry.

Subject of Research: Motor cortex hyperexcitability and its relationship to neuromuscular dysfunction in aged mice

Article Title: Motor Cortex Hyperexcitability Is Coupled to Neuromuscular Dysfunction in Aged Mice

Article References: Viteri, J. A., Kerr, N. R., Darvishi, F. B., Dashtmian, A. R., Brennan, C. D., Ayyagari, S. N., Moore, P. J., Wang, M., Snyder, H., Yu, B., Santin, J. M., & Arnold, W. D. (2026). Motor Cortex Hyperexcitability Is Coupled to Neuromuscular Dysfunction in Aged Mice. Aging Cell, 25(10), Article e70731. https://doi.org/10.1111/acel.70731

Image Credits: AI Generated

Keywords: aging, motor cortex, muscle weakness, sarcopenia, layer V pyramidal neurons, hyperexcitability, neuromuscular junction, patch clamp, persistent inward current, ALS, synaptic transmission, electrophysiology

Cite Scienmag News

Beatrice Stafford. (October 1, 2026). Aging Brain Circuits May Drive Muscle Weakness, Mouse Study Finds. Scienmag. https://scienmag.com/aging-brain-circuits-may-drive-muscle-weakness-mouse-study-finds/

Beatrice Stafford. "Aging Brain Circuits May Drive Muscle Weakness, Mouse Study Finds." Scienmag, 1 October 2026, https://scienmag.com/aging-brain-circuits-may-drive-muscle-weakness-mouse-study-finds/. Accessed 1 October 2026.