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Abstract The cardiovascular system functions under continuous cyclic mechanical stretch, with disruptions in mechanical and biochemical signals contributing to disease progression. In cardiovascular disorders, these disruptions activate cardiac fibroblasts (CFs) and promote cellular senescence, yet it remains unclear whether mechanical stimuli alone can initiate this phenotype. Here, primary murine CFs are exposed to uniaxial stretch, and systematically varied mechanical parameters assessed their role in senescence induction. Loss of stretch magnitude and increase in frequency, mimicking a pathologic hypertrophy and fibrosis, led to a senescence phenotype, identified through cell cycle arrest, decreased lamin B expression, and DNA damage. Mechanically‐induced CF senescence depends on p53/p21, whereas senescence triggered by oxidative stress or lamin A/C mutation proceeded via p16. Notably, mechanically‐induced premature senescence is accompanied by reduced levels of the nuclear envelope protein emerin. These findings demonstrate that altered mechanical signals are sufficient to trigger premature senescence and implicate compromised nuclear integrity in the underlying mechanism. 

Abstract The 2021 Summer Biomechanics, Bioengineering, and Biotransport Conference (SB3C) featured a workshop titled "The Elephant in the Room: Nuclear Mechanics and Mechanobiology." The goal of this workshop was to provide a perspective from experts in the field on the current understanding of nuclear mechanics and its role in mechanobiology. This paper reviews the major themes and questions discussed during the workshop, including historical context on the initial methods of measuring the mechanical properties of the nucleus and classifying the primary structures dictating nuclear mechanics, physical plasticity of the nucleus, the emerging role of the linker of nucleoskeleton and cytoskeleton (LINC) complex in coupling the nucleus to the cytoplasm and driving the behavior of individual cells and multicellular assemblies, and the computational models currently in use to investigate the mechanisms of gene expression and cell signaling. Ongoing questions and controversies, along with promising future directions, are also discussed.