Neural Cues and Genomic Clues: NGS Insights into Neurogenic Sarcopenia and Muscle Atrophy

Sarcopenia is a progressive loss of skeletal muscle mass and strength with major clinical and economic consequences. While traditional models emphasize mitochondrial dysfunction, inflammation, and proteostasis imbalance, emerging data highlight a neurogenic component involving motor neuron loss, fiber denervation, neuromuscular junction remodeling, and disrupted trophic signaling. To synthesize current evidence on neurogenic mechanisms of sarcopenia revealed by next-generation sequencing and related multi-omics, to map molecular networks across cell types, and to outline translational opportunities for diagnostics and targeted therapy. A narrative review of human and animal studies indexed in PubMed, Web of Science, and Scopus through November 2025. Search terms combined sarcopenia, denervation, neuromuscular junction, neurotrophic signaling, genomics, transcriptomics, epigenomics, single-cell, and spatial transcriptomics. Eligible studies reported omics or physiological endpoints related to neuromuscular function. Convergent omics data support a central role of the nervous system in the onset and progression of sarcopenia. Genetic and regulatory factors linked to denervation, transcriptomic signatures of junctional disassembly, and cell-specific dysfunctions in motor neurons, Schwann cells, satellite cells, and fibro-adipogenic progenitors have been identified. Epigenetic and transcriptional networks underlying neuromuscular homeostasis, along with candidate circulating biomarkers, provide targets for clinical translation. Neurogenic sarcopenia represents a tractable target for precision prevention and therapy. Integration of multi-omics, artificial intelligence, and advanced models such as innervated organoids and NMJ-on-chip systems can accelerate target validation and enable personalized strategies to preserve neuromuscular function.