Cytoskeletal Proteins


 Cytoskeletal Proteins Background

One of the main functions of the cytoskeleton is to maintain the shape and size of the cardiac myocyte. Without this scaffold in place, the myocyte is hindered in its ability to carry out its cellular functions which are important for the maintenance of the cell. If there are alterations in the cytoskeletal proteins, then one might expect to find a change not only in the structure of the myocyte, but also a decrease in the function of the cardiac myocyte.

The cytoskeleton is important for maintaining cell size and cell shape as well as the structural integrity and mechanical resistance to the cardiac myocytes. The cytoskeleton also plays a role in cellular signaling by transmitting mechanical and biochemical signals between cells. The cytoskeleton is traditionally thought to consist of three major groups of proteins that range in diameter from the 7 nm microfilaments (actin), to the 10 nm intermediate filaments (desmin) and finally to the 25 nm microtubules (tubulin). Kostin and colleagues characterized the cytoskeleton into four different subgroups based on morphology and function: 1) sarcomeric skeleton including titin, α-actinin, and myomesin; 2) true “cytoskeletal” proteins including tubulin, desmin and actin; 3) membrane-associated proteins including vinculin, dystrophin, spectrin, talin, and ankyrin and 4) proteins in areas at the ends of the myocyte; the intercalated disc including desmin; the adherens junctions including N-cadherin, catenins and vinculin; and the gap junction, including connexin.

The true “cytoskeletal” proteins maintain the stability and integrity of the cardiac myocyte while the membrane-associated proteins connect the cardiac cytoskeleton to the extracellular matrix for additional stability. The proteins at the intercalated disc and adherens junctions attach to adjacent cells, providing additional stabilization and alignment of the sarcomere. α-Actinin connects the actin filaments and vinculin connects the actin cytoskeleton to the sarcolemma via talin and to adjacent cells. Desmin is localized at the Z-line to stabilize the sarcomeres. Figure 4 illustrates the location of microtubules in the heart; p-Tubulin is localized throughout the cytosol along the sarcomere and sarcoplasmic reticulum. These proteins were chosen to study because of their localization and possible function in the cardiac myocyte. α-Actinin is important in maintaining linkage between actin filaments, thus if there are alterations in the contractile proteins, α-actinin may be affected.

The cytoskeleton is dynamic because it can change its organization in response to increased stress or load on the sarcomere to ultimately minimize the stress and/or load. However, if the mechanical load is chronic, the cytoskeleton may remodel such that it is maladaptive to the heart, thus contributing to a decline in contractility. So far, intracellular calcium cycling has been the focus of impaired contractile function in failing hearts. However, the cytoskeleton plays a major role in maintaining the structure of the cardiac myocyte so that all cellular components are organized to allow contraction to occur. Thus it is reasonable to hypothesize that the cytoskeleton may contribute to impaired contractile function in failing hearts. Alterations in the cytoskeletal proteins during cardiac hypertrophy or heart failure could have a large impact on the structure and/or function of the cardiac myocyte, which is the focus of this research. The following cytoskeletal proteins have been investigated to determine if there are changes in protein expression or localization in cardiac myocytes from hypertrophied and failing human hearts and to determine the functional role of β-tubulin in the failing human heart.