Myofibril contraction and cross-linking drive nuclear movement to the periphery of skeletal muscle

Nuclear movements are important for multiple cellular functions and are driven by polarized forces generated by motor proteins and cytoskeleton. During skeletal myofiber formation or regeneration, nuclei move from the center to the periphery of the myofiber for proper muscle function. Centrally located nuclei are also found in different muscle disorders. Using theoretical and experimental approaches, we demonstrate that nuclear movement to the periphery of myofibers is mediated by centripetal forces around the nucleus. These forces arise from myofibril contraction and cross-linking that “zip” around the nucleus in combination with tight regulation of nuclear stiffness by lamin A/C. In addition, an Arp2/3 complex containing Arpc5L together with γ-actin is required to organize desmin to cross-link myofibrils for nuclear movement. Our work reveals that centripetal forces exerted by myofibrils squeeze the nucleus to the periphery of myofibers.