Nuclear Mechanics in Disease

Abstract

Over the past two decades, the biomechanical properties of cells have emerged as key players in a broad range of cellular functions, including migration, proliferation, and differentiation. Although much of the attention has focused on the cytoskeletal networks and the cell’s microenvironment, relatively little is known about the contribution of the cell nucleus. Here, we present an overview of the structural elements that determine the physical properties of the nucleus and discuss how changes in the expression of nuclear components or mutations in nuclear proteins can affect not only nuclear mechanics but also modulate cytoskeletal organization and diverse cellular functions. These findings illustrate that the nucleus is tightly integrated into the surrounding cellular structure. Consequently, changes in nuclear structure and composition are highly relevant to normal development and physiology and can contribute to many human diseases, such as muscular dystrophy, dilated cardiomyopathy, (premature) aging, and cancer.

Lamins at a glance

“…Lamins are important for the incorporation and spacing of nuclear pores (Al-Haboubi et al, 2011;Goldberg et al, 1995;Osouda et al, 2005;Smythe et al, 2000), regulation of nuclear size (Levy and Heald, 2010), and the shape and mechanical properties of the nucleus (reviewed by Zwerger et al, 2011). Cells lacking lamins A and C have fragile nuclei that are more deformable under mechanical strain and which display altered mechanotransduction signaling (Broers et al, 2004;Lammerding et al, 2004).…”

“…The 'structural hypothesis' suggests that LMNA mutations render the nucleus more fragile, causing cell death and progressive disease in mechanically stressed tissues such as muscle (Zwerger et al, 2011). This idea is supported by findings that skeletal muscle from patients with EmeryDreifuss muscular dystrophy (EDMD) and mouse models of the disease contain fragmented nuclei (Arimura et al, 2005;Fidziańska and Hausmanowa-Petrusewicz, 2003;Fidziańska et al, 1998;Markiewicz et al, 2002b;Mounkes et al, 2005;Nikolova et al, 2004); cells lacking lamins A and C have decreased nuclear stiffness and increased nuclear fragility (Broers et al, 2004;Lammerding et al, 2004), and Lmna -/-mice develop severe muscular dystrophy and dilated cardiomyopathy (Sullivan et al, 1999).…”

Impaired mechanical response of an EDMD mutation leads to motility phenotypes that are repaired by loss of prenylation

“…One of the models attempting to explain laminopathies is the mechanical model. According to this model, a defective nuclear mechanical response originating from specific lamin A mutations causes cells to be more susceptible to damage, leading to cell death and progressive tissue deterioration in mechanically stressed tissues (Zwerger et al, 2011). To date, the changes in nuclear deformation, in response to strain application, caused by lamin mutations have been demonstrated only on isolated cells or tissue .…”

Global transcriptional changes caused by an EDMD mutation correlate to tissue specific disease phenotypes inC. elegans

“…Mechanically stressed tissues are particularly susceptible as they are constantly under strain, and therefore damage is initially observed in these cells. 19 Indeed, dominant expression of the L535P EDMD-linked lamin mutation in C. elegans caused the muscle nuclei to become more rigid, altering their mechanical response to strain. Restoring proper muscle nuclear response rescued disease phenotypes in these animals.…”