A cellular cross-species RNA-seq atlas captures the transcriptional dynamics of myogenesis

Comparative analyses revealed shared global features of myogenesis but also distinct regulatory trajectories. Human differentiation showed early upregulation followed by suppression of metabolic and stress-related pathways, while structural and ECM-associated programs remained persistently elevated. In contrast, mouse C2C12 cells displayed early inflammatory activation and later enrichment of metabolic and contractile pathways typical of mature myotubes.

Ortholog-based integration demonstrated decreasing cross-species correlation over time, indicating progressive reinforcement of species-specific differentiation programs. We additionally compared this bulk RNA-seq with tissue-derived myotubes from single-cell muscle datasets to determine which transcriptional programs are conserved in the in vitro models or which emerge only in vivo. This analysis delineates the conserved and context-specific features of myogenesis, identifying pathways that reflect culture-specific artifacts in both human and mouse muscle cells.