Lamin A/C protects chromatin accessibility during mechanical loading in human skeletal muscle.

BACKGROUND: Skeletal muscle nuclei (myonuclei) are subjected to high mechanical stress which plays a critical role in muscle tissue integrity and plasticity. Here we investigated the role of lamin A/C in dampening the effects of acute mechanical stretch on chromatin states and its downstream effects on gene expression. METHODS: We studied control and lamin A/C-deficient human myotubes both at baseline and following a mechanical stress mimicking acute muscle exercise. Chromatin accessibility and transcriptional responses were assessed using ATAC-seq (assay for transposase-accessible chromatin with sequencing) and RNA-seq, respectively. RESULTS: We found that stretch-induced nuclear deformations in lamin A/C-deficient myotubes but not in controls, and was associated with a widespread increase in chromatin accessibility, mainly affecting promoter regions. Concordantly, mechanical stress also increased the levels of H3K4me3 euchromatin marks and decreased heterochromatin-associated H3K27me3 in A-type lamin-deficient myotubes. Additionally, mechanical stress led to the downregulation of transcriptional pathways involved in histone deacetylation, DNA methylation, and muscle differentiation, while pathways related to cytokine activity, extracellular matrix organization, and cell adhesion were upregulated. CONCLUSIONS: Overall, lamin A/C deficiency amplifies the chromatin response to mechanical stress, leading to enhanced promoter accessibility and activation of stress DNA damage-related gene pathways. These findings underscore the role of lamin A/C in maintaining chromatin stability under mechanical strain.