Nucleo-cytoskeletal coupling controls intracellular deformation partitioning during cell stretching

Cells sense and transduce mechanical forces to regulate diverse biological processes, yet the mechanical stimuli that initiate these processes remain poorly understood. In particular, how nuclear and cytoplasmic deformations respond to external forces is unclear. Here, we developed a microscopy-based technique to quantify the extensional uniaxial strains of the nucleus and cytoplasm during cell stretching, enabling direct measurement of their bulk mechanical responses. Using this approach, we identified a previously unrecognized inverse relationship between nuclear and cytoplasmic deformation in epithelial monolayers. We demonstrate that nucleo-cytoskeletal coupling, mediated by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, regulates this anti-correlation (Pearson correlation coefficient approx. 0.3). Disrupting LINC abolished this relationship, revealing its fundamental role in intracellular deformation partitioning. Furthermore, we found that cytoplasmic deformation is directly correlated with stretch-induced nuclear shrinkage, suggesting a mechanotransduction pathway in which cytoplasmic mechanics influence nuclear responses. Lastly, multivariable analyses established that intracellular deformation can be inferred from cell morphology, providing a predictive framework for cellular mechanical behaviour. These findings refine our understanding of nucleo-cytoskeletal coupling in governing intracellular force transmission and mechanotransduction.