Cytoskeleton

In addition to ID proteins, the cytoskeleton of car-diomyocytes consists of a sarcomeric skeleton (e.g., titin, a-actinin), true cytoskeletal proteins (i.e., intermediate filaments, microtubules, and actin), and membrane-associated proteins (e.g., dystrophin, spec-trin, talin, vinculin) [26]. This complex network stabilizes cellular organelles, maintains cell size and shape, and plays an active role during contraction/relaxation and intracellular signaling [27,28]. The perisarcomer cytoskeleton anchors to the lateral cell membrane in areas called costameres, which are composed of focal adhesion proteins. Therefore, the cytoskeleton responds to the physical and biochemical properties of the extracellular matrix.

Ultrastructural analysis of ARVC/D revealed an irregular or decreased cytoskeleton in the region of the Z band and cell membrane invaginations that form T-tubules (Fig. 6.3), as well as in the perinuclear area in many cardiomyocytes. The lateral costameres in some cells were numerous while in others, with decreased invagination of cell-membrane-forming T-tubules, were single or aggregated in the area of the cell membrane outside of the Z-band region (Fig. 6.3). These were not related to the presence of collagen in the extracellular space. Cytoskeletal alterations have been reported to be responsible for cellular contractile dysfunction [27,29]. It is also known that costameres are responsible for cell structural and functional integrity since they are involved in fixation of sarcomeres to the lateral sarcolemma and stabilization of T-tubules [27, 30]. It is not clear if the varied number of

  1. 6.3 • Fragment of a cardiomyocyte from ARVC/D heart in the region of cell membrane invagination forming T-tubule (T) with impaired intermediate filaments (arrow) connecting a Z-band region across the enlargement of interfib-rillary space to cell membrane costameres (arrowheads) and impaired Z-band (Z) and actin arrangement. Bar = 150 nm
  2. 6.3 • Fragment of a cardiomyocyte from ARVC/D heart in the region of cell membrane invagination forming T-tubule (T) with impaired intermediate filaments (arrow) connecting a Z-band region across the enlargement of interfib-rillary space to cell membrane costameres (arrowheads) and impaired Z-band (Z) and actin arrangement. Bar = 150 nm costamere junctions in cardiomyocytes of ARVC/D is related to the loss of intermediate filaments or abnormal strength linkage with extracellular matrix due to increasing fibrosis as the disease progresses. From experimental cell biology, it is known that an increased stiffness on the extracellular matrix induces a stronger integrin cytoskeleton link [31]. The number and quality of extracellular matrix binding components via membrane integrins with cell cytoskeleton affects a variety of intracellular signaling events. Both diminished cytoskeleton and increased or diminished number of costamere junctions could be related to cell death.

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