Compartment-Specific Transcriptional Remodelling Defines Denervation and Geriatric Muscle Regeneration

Neuromuscular decline involves motor, junctional, myofibre and niche dysfunction, but whether these components remodel as a coordinated system is unresolved. We harmonised 654,053 locally audited single-cell or single-nucleus profiles from two human ageing cohorts and four mouse studies spanning denervation, injury, reinnervation and exercise, retaining the donor, animal or library as the inferential unit. Denervation produced 4311 cell-type-specific differential-expression results, with the largest number of detected gene effects in type IIB myonuclei. Competitive animal-pseudobulk testing identified eight FDR-supported compartment-programme results; six denervation-sensitivity results remained supported after each single-gene deletion, whereas the FAP matrix-inflammatory and type IIB junctional results were gene-sensitive. During geriatric regeneration, all eight annotated broad compartments varied over time, and 26 of 34 analysis-defined biologically applicable compartment-programme tests were significant after FDR correction. Tests of human ageing, restricted age-by-time interactions and mitochondrial perturbation did not survive multiplicity correction. The human results are hypothesis-generating, and neither RNA scores nor predicted cell communication establish functional recovery. This resource supports compartment-specific transcriptional responses within denervation and geriatric injury designs; it does not establish a conserved recovery axis across the six contexts.