Transcriptional Remodeling of Human Skeletal Muscle Following Sleep Restriction in Postmenopausal Women

Sleep is a critical regulator of metabolic health, but its impact on skeletal muscle remains underexplored. Given the muscle's pivotal role in glucose metabolism, energy homeostasis, and immune signaling, understanding how insufficient sleep affects global transcriptomic responses in skeletal muscle is of significant interest. In a randomized crossover design, skeletal muscle biopsies were collected from healthy postmenopausal women following four nights of habitual or restricted sleep (40% reduction). RNA-seq was performed on 7 paired samples and analyzed using differential expression (DE), gene correlation, pathway enrichment, and transcription factor motif analysis. Global DE analysis revealed modest transcriptomic shifts, with 9 genes consistently altered across multiple DE methods. Gene set enrichment analysis showed upregulation of oxidative phosphorylation and myogenesis pathways and downregulation of immune and inflammatory signaling during sleep restriction. Differential correlation analysis identified substantial reorganization in gene co-expression networks, particularly within RNA degradation and ribosomal pathways. Transcription factor and motif analyses suggested YY1 as a possible key mediator of transcriptional reprogramming during sleep restriction. Motif analysis confirmed enrichment of YY1 binding sites among differentially correlated genes, further implicating its role in linking circadian disruption, metabolic stress, and immune modulation. Sleep restriction for 4-nights triggers subtle but biologically meaningful changes in skeletal muscle transcriptomes. The simultaneous upregulation of mitochondrial and structural genes, alongside downregulation of immune-related genes, reflects a complex adaptive response. YY1 appears to be a central regulatory node linking sleep loss to muscle dysfunction, with implications for metabolic resilience, inflammation, and tissue repair.