Mechanical stresses govern myoblast fusion and myotube growth

Myoblast fusion into myotubes is critical for muscle formation, growth and repair. While the cellular and molecular mechanisms regulating myoblast fusion are increasingly understood, the role of biomechanics in this process remains largely unexplored. Here, we reveal that a dynamic feedback loop between evolving cell mechanics and cell-generated stresses shape the fusion of primary myoblasts in vitro. Applying principles from active nematics, we show that myoblast and myotube patterning follows physical rules similar to liquid crystal organization. Remarkably, fusion predominantly occurs at comet-shaped topological defects in cellular alignment, which we identified as regions of high compressive stress. We further find that this stress-driven organization depends on extracellular matrix (ECM) deposition, which mirrors the nematic order of the cell population. Our integrated data, supported by active nematics-based mathematical modeling, accurately predict self-organization patterns and mechanical stresses that regulate myoblast fusion. By revealing the essential role of biomechanics and ECM interplay in myogenesis, this work establishes a foundational framework for understanding biomechanical principles in morphogenesis.