A primer on global molecular responses to exercise in skeletal muscle: Omics in focus

• This study presents a history of omics approaches applied to skeletal muscle exercise research. • Skeletal muscle epigenome, transcriptome, and proteome/phosphoproteome are altered with acute and chronic resistance and endurance exercise. • Gain/loss of function preclinical studies reveal mechanisms from human omic findings and provide insights into exercise response heterogeneity and the effects of aging and biological sex. • Future studies on global molecular wiring in muscle using multiomics methods will help researchers and clinicians understand and improve skeletal muscle health and performance. • Integration of omics layers with advanced computational approaches—including information from single cell and nucleus omics technologies—will provide new insights into the molecular regulation of exercise in skeletal muscle. Advances in skeletal muscle omics has expanded our understanding of exercise-induced adaptations at the molecular level. Over the past 2 decades, transcriptome studies in muscle have detailed acute and chronic responses to resistance, endurance, and concurrent exercise, focusing on variables such as training status, nutrition, age, sex, and metabolic health profile. Multi-omics approaches, such as the integration of transcriptomic and epigenetic data, along with emerging ribosomal RNA sequencing advancements, have further provided insights into how skeletal muscle adapts to exercise across the lifespan. Downstream of the transcriptome, proteomic and phosphoproteomic studies have identified novel regulators of exercise adaptations, while single-cell/nucleus and spatial sequencing technologies promise to evolve our understanding of cellular specialization and communication in and around skeletal muscle cells. This narrative review highlights (a) the historical foundations of exercise omics in skeletal muscle, (b) current research at 3 layers of the omics cascade (DNA, RNA, and protein), and (c) applications of single-cell omics and spatial sequencing technologies to study skeletal muscle adaptation to exercise. Further elaboration of muscle's global molecular footprint using multi-omics methods will help researchers and practitioners develop more effective and targeted approaches to improve skeletal muscle health as well as athletic performance.