Abstract During aging and neuromuscular diseases, there is a progressive loss of skeletal muscle volume and function in that impacts mobility and quality of life. Muscle loss is often associated with denervation and a loss of resident muscle stem cells (satellite cells or MuSCs), but the relationship between MuSCs and neural control has not been established. Herein, using a combination of single-cell transcriptomic analysis, high-resolution immunofluorescence imaging and transgenic young and aged mice as well as from mice with neuromuscular degeneration (Sod1 -/- ), a compensatory neuro-responsive function for a subset of MuSCs was identified. Genetic rescue of motor neurons in Sod1 -/- mice reduced this subset of MuSCs and restored integrity of the neuromuscular junction (NMJ) in a manner akin to young muscle. Administration of severe neuromuscular trauma induced young MuSCs to specifically engraft in a position proximal to the NMJ but in aging, this behavior was abolished. Contrasting the expression programs of young and aged MuSCs after muscle injury at the single cell level, we observed distinctive gene expression programs between responses to neuro-muscular degeneration and muscle trauma. Collectively, these data reveal MuSCs sense synaptic perturbations during aging and neuro-muscular deterioration, and can exert support for the NMJ, particularly in young muscle. Highlights Transcriptional landscapes of single satellite cells from different ages before and after injury as well as neurodegenerative models before and after nervous rescue A population of satellite cells reside in close proximity to neuromuscular synapse, which are lost with age Denervation promotes satellite cell engraftment into post-synaptic regions of young as opposed to aged muscle

Single Cell Deconstruction of Muscle Stem Cell Heterogeneity During Aging Reveals Sensitivity to the Neuromuscular Junction