Abstract 519: Desmin Protects Cardiomyocyte Nuclei From Microtubule-dependent Collapse

• Published in: Circulation research Vol. 125; no. Suppl_1
• Main Authors: Heffler, Julie, Shah, Parisha P, Robison, Patrick, Phyo, Sai, Veliz, Kimberly, Bogush, Alexey, Rhoades, Joshua, Jain, Rajan, Prosser, Benjamin L
• Format: Journal Article
• Language: English
• Published: 02.08.2019
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.125.suppl_1.519

Abstract only Alterations to mechanical forces have been long-appreciated to be sufficient to drive cardiac pathophysiological remodeling; however, the mechanism by which cardiomyocytes sense and transduce mechanical stressors remains poorly understood. In part, mechanical forces can be transduced to transcriptional responses by direct strain transmission to the nucleus via the Linkers of the Nucleo- and Cytoskeleton (LINC) complex, which couples the cytoskeleton to the nuclear lamina and DNA. While LINC complex mutations are known to cause cardiomyopathy, cytoskeletal-LINC interactions are understudied in the cardiomyocyte. To probe these interactions, we acutely disrupted the LINC complex as well as microtubules, actin, and intermediate filaments and assessed the consequences on baseline nuclear homeostasis in the cardiomyocyte. Our result show that a balance of microtubules and desmin intermediate filaments is required to maintain nuclear shape and the fidelity of the nuclear envelope and lamina. Upon acute depletion of desmin (or Nesprin-3, its binding partner in the LINC complex), microtubules drive infolding of the nuclear membrane. This results in DNA damage, a loss of genome organization, and broad transcriptional changes. Desmin knockdown also causes compromised excitation-contraction coupling and contractile function. Together, our data suggest that a balance of forces imposed by intermediate filaments and microtubules is required to maintain nuclear structure and genome organization in the cardiomyocyte, and that this process is important for maintaining proper myocyte health and function.