Nuclear decoupling is part of a rapid protein-level cellular response to high-intensity mechanical loading

Our current understanding of cellular mechano-signalling is based on static models, which do not replicate the dynamics of living tissues. Here, we examined the time-dependent response of primary human mesenchymal stem cells (hMSCs) to cyclic tensile strain (CTS). At low-intensity strain (1 hour, 4% CTS at 1 Hz) morphological changes mimicked responses to increased substrate stiffness. As the strain regime was intensified (frequency increased to 5 Hz), we characterised rapid establishment of a broad, structured and reversible protein-level response, even as transcription was apparently downregulated. Protein abundance was quantified coincident with changes to protein conformation and post transcriptional modification. Furthermore, we characterised changes within the linker of nucleo- and cytoskeleton (LINC) complex of proteins that bridges the nuclear envelope, and specifically to levels of SUN domain-containing protein 2 (SUN2). The result of this regulation was to decouple mechano-transmission between the cytoskeleton and the nucleus, thus conferring protection to chromatin.