Motor Cortex Hyperexcitability Is Coupled to Neuromuscular Dysfunction in Aged Mice.

Age-related weakness is strongly associated with disability and mortality in older adults. While muscle atrophy contributes to weakness, strength declines at a faster rate than muscle mass, implicating neural mechanisms such as changes at the spinal cord and neuromuscular junction. Yet, the role of the motor cortex in age-related weakness remains largely unexplored. We previously identified layer V pyramidal neurons (LVPNs) of the primary motor cortex as hyperexcitable in aged mice, but whether this phenotype was coupled to neuromuscular dysfunction was unknown. Here, we show that aged mice exhibit impaired strength, coordination, and neuromuscular excitability. However, cortical motor output to muscle measured in vivo was enhanced, with patch-clamp recordings from the same aged animals confirming LVPN hyperexcitability. This was accompanied by altered excitatory and inhibitory synaptic responses evoked by layer II/III stimulation, and by transcriptional changes in excitability-related genes of aged LVPNs. Statistical analysis across 250 cortical-neuromuscular/behavioral pairwise relationships revealed that greater cortical excitability is broadly and consistently correlated with worse whole-animal neuromuscular and behavioral outcomes. Most strikingly, LVPN firing frequency emerged as the single strongest correlate of neuromuscular dysfunction and statistically accounted for 75% of the age effect on neuromuscular function, while the reverse analysis showed that neuromuscular dysfunction accounted for 42.2% of the age effect on LVPN firing frequency. These findings identify the motor cortex as a potential contributor to age-related weakness-a finding with broader significance given that hyperexcitability of LVPNs is a shared feature of motor dysfunction across neurodegenerative disease contexts.