Molecular dissection of the cellular response to mechanical stress

Abstract

AbstractThe response of cells to mechanical stress is crucial for many cellular functions, yet its molecular mechanisms are not yet fully understood. Previous studies of the cellular response to mechanical stress were performed on cultured cells or isolated muscle fibers devoid of cell and/or tissue contexts. Thus, the emerging results were limited to the specific cell types or tissues analyzed and dependent on the growth matrix elasticity. In the present study, we looked for changes in early gene expression in response to mechanical whole body stretching of living C. elegans. Our transcriptome analysis revealed upregulation of genes involved in cuticle development, stress response and several signaling pathways such as WNT, TGFβ, AMPK and Hedgehog signaling. These findings indicate that protecting against mechanical insults entails providing additional support to the mechanically resilient protective cuticle, and that proper recovery from mechanical stretching requires an intact Hedgehog signaling pathway. Recent findings suggest an important role for the nuclear lamina in mediating cellular mechanical response. The nuclear lamina is composed mainly of lamins, which are nuclear intermediate filament-type proteins needed, among other functions to maintain nuclear integrity. One particular area of interest are laminopathies, which are caused by mutations in lamin. Stretched animals expressing the Emery Dreifuss Muscular Dystrophy (EDMD) linked L535P lamin mutation, showed further upregulation of cytoskeleton organization, cellular respiration and mitochondrial protein-unfolding stress response genes, most likely to compensate for aberrant muscle tissue function. These findings provide a broad multi-dimensional picture of the in vivo genetic response of live animals to mechanical stress, highlighting previously unreported mechano-sensitive genes and molecular pathways.