Desmin is Critical to the Nuclear Architecture of Cardiomyocytes

Abstract

Long-term changes in mechanical stress on the heart are known to induce pathological remodeling, but the signaling pathways underlying the conversion of mechanical stress into transcriptional changes have not been established. Previous reports indicate that strain in the myocyte is transmitted to the nucleus at least in part by desmin, and it has been suggested that desmin may interact with the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex. Further, both gain and loss of function mutations in desmin are associated with the development of cardiomyopathy. Taken together, these observations raise questions about the role that desmin may play in myocyte sensing of and the transcriptional response to mechanical stress. To assess the role desmin plays in nuclear structure and transcriptional regulation, we acutely knocked down desmin using shRNA in adult cardiomyocytes. Initial fluorescence images indicate that desmin knockdown leads to a decrease in nuclear volume and large rearrangements (wrinkling) of the nuclear lamina. Electron microscopy on nuclei in these myocytes reveals dramatic nuclear structural changes following desmin knockdown. The disruptions of the lamina accompany large scale inward folding of the nuclear membrane, more than tripling membrane concave area. Additionally, the electron-dense chromatin regions typically associated with perilaminar heterochromatic domains expand to larger areas reaching, in many cases, hundreds of nanometers deeper into the interior of the nucleus. We also note substantial transcriptional and epigenetic changes resulting from desmin knockdown. These results suggest that desmin plays a critical role in maintaining nuclear architecture, and could form a link between mechanical stimuli acting on cardiomyocytes and their transcriptional results in the nucleus.