Aging Brain Circuits May Drive Muscle Weakness, Mouse Study Finds

Muscle weakness is one of the most universal hallmarks of aging, and it is far more dangerous than it first appears. Large population studies have shown that age-related weakness is strongly associated with mortality, including deaths from cardiovascular events, cancer, and dementia. With the global population aged 65 and older projected to exceed 20 percent of the world’s population by 2050, the burden that declining strength places on healthcare systems and on individual independence is set to grow dramatically. Yet the biological mechanisms behind this weakness remain incompletely understood, and no approved therapies currently exist to prevent or reverse it.

For decades, the dominant explanation was simple: muscles shrink with age, a condition known as sarcopenia, and smaller muscles produce less force. But population data have long revealed a puzzle. Strength declines at a substantially faster rate than muscle mass itself, which means that atrophy alone cannot account for the full loss of power. This discrepancy has pushed researchers to look beyond the muscle and toward the nervous system, which is required to generate and sustain muscular force. Most of that work has focused on the spinal cord and the periphery, where scientists have well characterized changes in spinal circuit excitability, motor neuron intrinsic properties, synaptic balance, and the transmission and remodeling of the neuromuscular junction, the synapse where nerves talk to muscle fibers.

Far less attention has been paid to the motor cortex, the region of the brain’s outer layer that serves as the cortical source of voluntary movement. Human studies have pointed to decreased voluntary activation of limb muscles in older adults, along with altered cortical output to muscle and imbalances between excitatory and inhibitory circuits in the motor cortex. But human imaging and stimulation techniques lack the resolution to identify which specific cortical circuits, neuronal populations, or molecular mechanisms change with aging, or to tie those changes directly to motor dysfunction. A new study in aged mice, published in the journal Aging Cell, set out to close that gap by measuring brain, nerve, and muscle function in the very same animals.

The research team, based at the University of Missouri, built on their own earlier discovery that layer V pyramidal neurons of the primary motor cortex become hyperexcitable in aged mice. These neurons are a heterogeneous population of deep-layer projection cells that includes the neurons responsible for transmitting and shaping cortical motor commands to the spinal cord. The finding was striking because cortical hyperexcitability mirrors what is seen in neurodegenerative diseases such as amyotrophic lateral sclerosis, where it has been implicated in motor decline, and Alzheimer’s disease, where it has been linked to cognitive deterioration. The question was whether this hyperexcitability in aging is merely a curiosity or is genuinely coupled to weakness.

To answer it, the researchers ran an unusually comprehensive battery of tests on young mice aged three months and aged mice aged 24 months, with equal numbers of males and females in each group. Behavioral testing showed that aged mice were dramatically weaker: grip strength, rotarod coordination, and a demanding weighted cart pull task were all significantly reduced. In vivo electrophysiology revealed 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 greater transmission failure at the neuromuscular junction. Direct measurements of muscle contractility confirmed that both twitch and tetanic plantar flexion torque were substantially reduced in the aged animals.

The most provocative result 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 enhanced cortical output. In contrast, stimulation at the cervical spinal cord produced smaller responses in aged animals, indicating reduced spinal output. In other words, the aged nervous system showed a paradoxical signature: a weakening spinal and neuromuscular apparatus accompanied by a louder signal coming down from the cortex. This pattern suggested that the hyperexcitable cortical neurons the team had identified previously might be actively reshaping the motor system rather than passively 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 vigorously at every depolarizing current step tested, from 50 to 300 picoamperes, roughly doubling their firing frequency at both low and high stimulation. Their membranes were also more resistive and had longer time constants, properties that reduce the current needed to reach the threshold for an action potential. Single-cell molecular analysis using digital PCR revealed that aged neurons carried elevated transcript levels of Nav1.6 and Nav1.1, sodium channel subunits that carry the persistent inward current, a powerful amplifier of repetitive firing, as well as increased levels of the serotonin receptor 5-HT2C, a known modulator of that current. These transcriptional changes provide candidate molecular markers of the hyperexcitable phenotype.

Synaptic recordings added another layer of mechanism. When the researchers stimulated layer II/III of the motor cortex, the canonical source of feedforward drive onto layer V neurons, they found that excitatory inputs onto aged neurons showed an increased paired-pulse ratio, indicating reduced initial release probability but a capacity to sustain transmission during high-frequency activity. Inhibitory inputs showed the opposite pattern: smaller evoked responses and a decreased paired-pulse ratio, suggesting that inhibitory synapses release strongly on the first pulse but deplete rapidly during repeated activation. This combination could allow excitatory drive to dominate during the sustained, high-frequency firing that characterizes voluntary movement, potentially feeding and maintaining the hyperexcitable state.

The statistical centerpiece of the study came from correlating all of these measurements within individual animals. Across 250 pairwise relationships between cortical variables and neuromuscular or behavioral outcomes, 109 were statistically significant after correction for multiple comparisons, and the large majority were negative, meaning that animals with higher cortical excitability tended to have worse motor outcomes. Firing frequency at 50 picoamperes emerged as the single strongest cortical correlate of a composite neuromuscular dysfunction index, explaining 90 percent of its variance. A mediation analysis then showed 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 swapped, accounted for a smaller 42.2 percent, underscoring that observational data of this kind cannot establish causal direction.

The authors are careful on this point: the mediation models represent a statistical decomposition of variance, not proof that cortical hyperexcitability causes weakness. It remains possible that the brain’s overactive output is a compensatory response to a failing periphery, or that both phenomena flow from a common aging process. Still, recent evidence that chemogenetically inducing layer V hyperexcitability in the motor cortex reduces muscular force and coordination in mice raises the possibility that the phenotype is maladaptive. The parallels with ALS, where cortical hyperexcitability is a well-established feature associated with downstream motor deficits, suggest it may be a shared mechanism across distinct contexts of motor dysfunction. If future experiments show that dampening layer V hyperexcitability in aged animals restores strength, the motor cortex could emerge as a genuine therapeutic target for one of aging’s most burdensome consequences, transforming weakness from an inevitable 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

DOI: 10.1111/acel.70731

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