Background: Spinal muscular atrophy (SMA) is a severe neurodegenerative disorder characterized by the progressive loss of motor neurons in the spinal cord, leading to muscle weakness and atrophy. It is caused by homozygous deletions or mutations in the SMN1 gene, resulting in reduced levels of survival motor neuron (SMN) protein, which is essential for axonal maintenance, and neuromuscular function. Beyond the primary loss of motor neurons, recent studies reveal that muscle-intrinsic molecular alterations actively influence the course and outcome of SMA. To dissect the molecular mechanisms underlying muscle pathology in these conditions, we applied single-nucleus RNA sequencing (snRNA-seq) and single-nucleus ATAC sequencing (snATAC-seq) to skeletal muscle biopsies from SMA type III patients and matched controls. We identified remodeling of the cellular composition, with an increase in FAPs, satellite cells, adipocytes, and endothelial cells. Pseudobulk analysis revealed distinct patterns of transcriptional dysregulation across cellular populations, including downregulation of mitochondrial and ribosomal pathways, upregulation of extracellular matrix organization, vascular development, and synaptic remodeling programs. We observed an upregulation of genes associated with neuromuscular junction maintenance (Musk, Colq, Lrp4, Col19a1, Col25a1) and axon guidance (Bdnf, Efna5, Ntn1, Robo2) in myofiber nuclei, suggesting a compensatory attempt to stabilize motor innervation. Chromatin accessibility profiling uncovered more than 27,000 differentially accessible regions in SMA muscle, with enrichment of promoter-proximal sites linked to transcriptional regulators of atrophy and regeneration.