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The Cardiomyopathy Lamin A/C D192G Mutation Disrupts Whole-Cell Biomechanics in Cardiomyocytes as Measured by Atomic Force Microscopy Loading-Unloading Curve Analysis.

Lanzicher T, Martinelli V, Puzzi L, Del Favero G, Codan B, Long CS, Mestroni L, Taylor MR, Sbaizero O - Sci Rep (2015)

Bottom Line: Our results suggested that the LMNA D192G mutation increased maximum nuclear deformation load, nuclear stiffness and fragility as compared to controls.Furthermore, chemical disruption of the actin cytoskeleton by cytochalasin D in control cardiomyocytes mirrored the alterations in the mechanical properties seen in mutant cells, suggesting a defect in the connection between the nucleoskeleton, cytoskeleton and cell adhesion molecules in cells expressing the mutant protein.These data add to our understanding of potential mechanisms responsible for this fatal cardiomyopathy, and show that the biomechanical effects of mutant lamin extend beyond nuclear mechanics to include interference of whole-cell biomechanical properties.

View Article: PubMed Central - PubMed

Affiliation: Department of Engineering and Architecture, University of Trieste, Via Valerio 2, 34127, Trieste Italy.

ABSTRACT
Atomic force microscopy (AFM) cell loading/unloading curves were used to provide comprehensive insights into biomechanical behavior of cardiomyocytes carrying the lamin A/C (LMNA) D192G mutation known to cause defective nuclear wall, myopathy and severe cardiomyopathy. Our results suggested that the LMNA D192G mutation increased maximum nuclear deformation load, nuclear stiffness and fragility as compared to controls. Furthermore, there seems to be a connection between this lamin nuclear mutation and cell adhesion behavior since LMNA D192G cardiomyocytes displayed loss of AFM probe-to-cell membrane adhesion. We believe that this loss of adhesion involves the cytoskeletal architecture since our microscopic analyses highlighted that mutant LMNA may also lead to a morphological alteration in the cytoskeleton. Furthermore, chemical disruption of the actin cytoskeleton by cytochalasin D in control cardiomyocytes mirrored the alterations in the mechanical properties seen in mutant cells, suggesting a defect in the connection between the nucleoskeleton, cytoskeleton and cell adhesion molecules in cells expressing the mutant protein. These data add to our understanding of potential mechanisms responsible for this fatal cardiomyopathy, and show that the biomechanical effects of mutant lamin extend beyond nuclear mechanics to include interference of whole-cell biomechanical properties.

No MeSH data available.


Related in: MedlinePlus

(A) AFM force-deformation curves for CT, WT and MT cells respectively. (B) CT and MT deformation behavior. CT follows quite well a cubic relationship with respect to deformation (ε3) while MT cells show a relationship close to ε3/2.
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f5: (A) AFM force-deformation curves for CT, WT and MT cells respectively. (B) CT and MT deformation behavior. CT follows quite well a cubic relationship with respect to deformation (ε3) while MT cells show a relationship close to ε3/2.

Mentions: In our case, if the AFM vertical displacement up to 500 nm is analyzed, MT cells display a behavior different from that of both MT and WT cells (Fig. 5A). None of the cells considered follow a relation with (ε1/2), CT and WT cells follow quite well a cubic relationship with respect to deformation (ε3) while MT cells show a relationship close to ε3/2 (see Fig. 5B) confirming also in this way that the MT nucleus is stiffer.


The Cardiomyopathy Lamin A/C D192G Mutation Disrupts Whole-Cell Biomechanics in Cardiomyocytes as Measured by Atomic Force Microscopy Loading-Unloading Curve Analysis.

Lanzicher T, Martinelli V, Puzzi L, Del Favero G, Codan B, Long CS, Mestroni L, Taylor MR, Sbaizero O - Sci Rep (2015)

(A) AFM force-deformation curves for CT, WT and MT cells respectively. (B) CT and MT deformation behavior. CT follows quite well a cubic relationship with respect to deformation (ε3) while MT cells show a relationship close to ε3/2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555041&req=5

f5: (A) AFM force-deformation curves for CT, WT and MT cells respectively. (B) CT and MT deformation behavior. CT follows quite well a cubic relationship with respect to deformation (ε3) while MT cells show a relationship close to ε3/2.
Mentions: In our case, if the AFM vertical displacement up to 500 nm is analyzed, MT cells display a behavior different from that of both MT and WT cells (Fig. 5A). None of the cells considered follow a relation with (ε1/2), CT and WT cells follow quite well a cubic relationship with respect to deformation (ε3) while MT cells show a relationship close to ε3/2 (see Fig. 5B) confirming also in this way that the MT nucleus is stiffer.

Bottom Line: Our results suggested that the LMNA D192G mutation increased maximum nuclear deformation load, nuclear stiffness and fragility as compared to controls.Furthermore, chemical disruption of the actin cytoskeleton by cytochalasin D in control cardiomyocytes mirrored the alterations in the mechanical properties seen in mutant cells, suggesting a defect in the connection between the nucleoskeleton, cytoskeleton and cell adhesion molecules in cells expressing the mutant protein.These data add to our understanding of potential mechanisms responsible for this fatal cardiomyopathy, and show that the biomechanical effects of mutant lamin extend beyond nuclear mechanics to include interference of whole-cell biomechanical properties.

View Article: PubMed Central - PubMed

Affiliation: Department of Engineering and Architecture, University of Trieste, Via Valerio 2, 34127, Trieste Italy.

ABSTRACT
Atomic force microscopy (AFM) cell loading/unloading curves were used to provide comprehensive insights into biomechanical behavior of cardiomyocytes carrying the lamin A/C (LMNA) D192G mutation known to cause defective nuclear wall, myopathy and severe cardiomyopathy. Our results suggested that the LMNA D192G mutation increased maximum nuclear deformation load, nuclear stiffness and fragility as compared to controls. Furthermore, there seems to be a connection between this lamin nuclear mutation and cell adhesion behavior since LMNA D192G cardiomyocytes displayed loss of AFM probe-to-cell membrane adhesion. We believe that this loss of adhesion involves the cytoskeletal architecture since our microscopic analyses highlighted that mutant LMNA may also lead to a morphological alteration in the cytoskeleton. Furthermore, chemical disruption of the actin cytoskeleton by cytochalasin D in control cardiomyocytes mirrored the alterations in the mechanical properties seen in mutant cells, suggesting a defect in the connection between the nucleoskeleton, cytoskeleton and cell adhesion molecules in cells expressing the mutant protein. These data add to our understanding of potential mechanisms responsible for this fatal cardiomyopathy, and show that the biomechanical effects of mutant lamin extend beyond nuclear mechanics to include interference of whole-cell biomechanical properties.

No MeSH data available.


Related in: MedlinePlus