Summary: Age-related loss of skeletal muscle innervation by motor neurons leads to impaired neuromuscular function and is a well-established clinical phenomenon. However, the underlying pathogenesis remains unclear. Studying mice, we find that the number of motor units (MUs) can be maintained by counteracting neurotoxic microglia in the aged spinal cord. We observe that marked innervation changes, detected by motor unit number estimation (MUNE), occur prior to loss of muscle function in aged mice. This coincides with gene expression changes indicative of neuronal remodeling and microglial activation in aged spinal cord. Voluntary exercise prevents loss of MUs and reverses microglia activation. Depleting microglia by CSF1R inhibition also prevents the age-related decline in MUNE and neuromuscular junction disruption, implying a causal link. Our results suggest that age-related changes in spinal cord microglia contribute to neuromuscular decline in aged mice and demonstrate that removal of aged neurotoxic microglia can prevent or reverse MU loss. : Aging is characterized by progressive loss of functional motor units. Giorgetti et al. report that age-related defects at the neuromuscular junction are associated with a switch in microglia to an activated phenotype. Exercise or CSF1R inhibition prevents loss of innervation in aged mice through modulation of microglia. Keywords: aging, motor unit, exercise, microglia, CSF1R inhibition, neuroinflammation, innervation, neuromuscular system, neuromuscular junction, spinal cord
