Lammerding J, Schulze PC, Takahashi T et al.Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Invest 113:370-378

Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 03/2004; 113(3):370-8. DOI: 10.1172/JCI19670
Source: PubMed


Mutations in the lamin A/C gene (LMNA) cause a variety of human diseases including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and Hutchinson-Gilford progeria syndrome. The tissue-specific effects of lamin mutations are unclear, in part because the function of lamin A/C is incompletely defined, but the many muscle-specific phenotypes suggest that defective lamin A/C could increase cellular mechanical sensitivity. To investigate the role of lamin A/C in mechanotransduction, we subjected lamin A/C-deficient mouse embryo fibroblasts to mechanical strain and measured nuclear mechanical properties and strain-induced signaling. We found that Lmna-/- cells have increased nuclear deformation, defective mechanotransduction, and impaired viability under mechanical strain. NF-kappaB-regulated transcription in response to mechanical or cytokine stimulation was attenuated in Lmna-/- cells despite increased transcription factor binding. Lamin A/C deficiency is thus associated with both defective nuclear mechanics and impaired mechanically activated gene transcription. These findings suggest that the tissue-specific effects of lamin A/C mutations observed in the laminopathies may arise from varying degrees of impaired nuclear mechanics and transcriptional activation.

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    • "In addition, the localization of various components of the LINC complex is severely disturbed in these cells (Hale et al. 2008; Chen et al. 2012, 2014), and the connection of the nuclei to TAN lines is weakened or lost (Folker et al. 2011). Importantly, this defective nucleocytoskeletal coupling appears to ultimately lead to defects in mechanotransduction, as reflected by the impaired activation of NFkB (Lammerding et al. 2004) and Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) (Swift et al. 2013; Bertrand et al. 2014) and MKL/SRF signaling (Ho et al. 2013). "
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    ABSTRACT: The intermediate filament proteins, A- and B-type lamins, form the nuclear lamina scaffold adjacent to the inner nuclear membrane. B-type lamins confer elasticity, while A-type lamins lend viscosity and stiffness to nuclei. Lamins also contribute to chromatin regulation and various signaling pathways affecting gene expression. The mechanical roles of lamins and their functions in gene regulation are often viewed as independent activities, but recent findings suggest a highly cross-linked and interdependent regulation of these different functions, particularly in mechanosignaling. In this newly emerging concept, lamins act as a "mechanostat" that senses forces from outside and responds to tension by reinforcing the cytoskeleton and the extracellular matrix. A-type lamins, emerin, and the linker of the nucleoskeleton and cytoskeleton (LINC) complex directly transmit forces from the extracellular matrix into the nucleus. These mechanical forces lead to changes in the molecular structure, modification, and assembly state of A-type lamins. This in turn activates a tension-induced "inside-out signaling" through which the nucleus feeds back to the cytoskeleton and the extracellular matrix to balance outside and inside forces. These functions regulate differentiation and may be impaired in lamin-linked diseases, leading to cellular phenotypes, particularly in mechanical load-bearing tissues. © 2015 Osmanagic-Myers et al.; Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · Feb 2015 · Genes & Development
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    • "Cardiac tissues from Lmna −/− mice had also lower SRF and actin transcript levels than those of wildtype littermates, and activation of SRF expression in response to left ventricular pressure-overload was impaired in Lmna +/− mice, demonstrating disturbed MKL1-SRF (Ho et al., 2013) mechanosignaling in vivo. As consequence of the impaired mechanosignaling, Lamin A/C deficient or defective cardiomyocytes undergo apoptosis faster than normal cardiomyocytes under mechanical stress (Lammerding et al., 2004). The expression of DCM-causing Lamin A/C E82K mutation in mouse heart tissues activates the two major signalling pathways of apoptosis. "
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    ABSTRACT: Lamin A/C is a structural protein of the nuclear envelope and cardiac involvement in Lamin A/C mutations was one of the first phenotypes to be reported in humans, suggesting a crucial role of this protein in the cardiomyocytes function. Mutations in LMNA gene cause a class of pathologies generically named ‘Lamanopathies’ mainly involving heart and skeletal muscles. Moreover, the well known disease called Hutchinson-Gilford Progeria Syndrome (HGPS) due to extensive mutations in LMNA gene, in addition to the systemic phenotype of premature aging, is characterized by the death of patients at around 13 typically for a heart attack or stroke, suggesting again the heart as the main site sensitive to Lamin A/C disfunction. Indeed, the identification of the roles of the Lamin A/C in cardiomyocytes function is a key area of exploration.One of the primary biological roles recently conferred to Lamin A/C is to affect contractile cells lineage determination and senescence. Then, in differentiated adult cardiomyocytes both the ‘structural’ and ‘gene expression hypothesis’ could explain the role of Lamin A in the function of cardiomyocytes. In fact, recent advances in the field propose that the structural weakness/stiffness of the NE, regulated by Lamin A/C amount in NE, can ‘consequently’ alter gene expression.This article is protected by copyright. All rights reserved
    Full-text · Article · Jul 2014 · Biology of the Cell
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    • "However, there is evidence that actin contributes to the anchoring of nuclei in different locations (Zhang et al., 2002, 2010; Puckelwartz et al., 2009). Additionally, there is substantial evidence from experiments in cell culture that nuclear proteins interact with actin and that these interactions can influence nuclear structure (Nikolova et al., 2004; Lüke et al., 2008; Khatau et al., 2009), cellular rheology (Maniotis et al., 1997; Lammerding et al., 2004), and nuclear movement and positioning (Luxton et al., 2010). "
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    ABSTRACT: Muscle disease as a group is characterized by muscle weakness, muscle loss, and impaired muscle function. Although the phenotype is the same, the underlying cellular pathologies, and the molecular causes of these pathologies, are diverse. One common feature of many muscle disorders is the mispositioning of myonuclei. In unaffected individuals, myonuclei are spaced throughout the periphery of the muscle fiber such that the distance between nuclei is maximized. However, in diseased muscles, the nuclei are often clustered within the center of the muscle cell. Although this phenotype has been acknowledged for several decades, it is often ignored as a contributor to muscle weakness. Rather, these nuclei are taken only as a sign of muscle repair. Here we review the evidence that mispositioned myonuclei are not merely a symptom of muscle disease but also a cause. Additionally, we review the working models for how myonuclei move from two different perspectives: from that of the nuclei and from that of the cytoskeleton. We further compare and contrast these mechanisms with the mechanisms of nuclear movement in other cell types both to draw general themes for nuclear movement and to identify muscle-specific considerations. Finally, we focus on factors that can be linked to muscle disease and find that genes that regulate myonuclear movement and positioning have been linked to muscular dystrophy. Although the cause-effect relationship is largely speculative, recent data indicate that the position of nuclei should no longer be considered only a means to diagnose muscle disease.
    Full-text · Article · Dec 2013 · Frontiers in Physiology
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