Cardiomyocytes - a general description, the intercalated discs, the sarcomere, T-tubules and
Cardiac muscle consists of interlacing bundles of cardiomyocytes (cardiac muscle cells). Like skeletal muscle, cardiac muscle is striated with narrow dark and light bands, due to the parallel arrangement of actin and myosin filaments that extend from end to end of each cardiomyocyte. However, in comparison with skeletal muscle cells, cardiomyocytes are narrower and much shorter, being about 25µm mm wide and 100µm long. Cardiomyocytes are often branched, and contain one nucleus but many mitochondria, which provide the energy required for contraction.
A prominent and unique feature of cardiac muscle is the
presence of irregularly-spaced dark bands between cardiomyocytes. These bands are
discs, and they are located to areas where the
membranes of adjacent cardiomyocytes come very close together. Intercalated
discs are, from a mechanical standpoint, the structural entities that enable
contractile force to be transmitted from one cardiomyocyte to another. This
allows for the heart to work as a single
functional organ. By contrast, skeletal muscle consists of multinucleated
muscle fibers and exhibit no intercalated discs. A second feature of
cardiomyocytes is the sarcomere, which is also present skeletal muscle. The
sarcomeres give cardiac muscle their striated appearance and are the repeating
sections that make up myofibrils. Figure
1 is an immunofluorescence image of cardiomyocytes in culture and a representation
of cardiomyocyte structure. Several other characteristics are unique to muscle cells
and in particular to cardiomyocytes, as they provide cardiomyocytes with their
unique properties and constitute the main structural components that are
crucial for the function of these cells.
1) The intercalated discs. Different junctional complexes exist within the
intercalated disc. These junctions are essential for adhesive integrity,
morphogenesis, differentiation, and maintenance of cardiac tissue. In the
intercalated disc, intercellular adhesion molecules, gap junctions, and the
voltage-gated sodium channel complex form macromolecular complexes that interact
specifically to maintain cardiac structure and cardiomyocyte synchrony. The
intercalated discs consist of 3 main junctional complexes: desmosomes, adherens
junctions (fascia adherens in cardiac muscle), and gap junctions (Figure 2). Gap junctions are essential
for chemical and electrical coupling of neighbouring cells, whereas desmosomes and
adherens junctions constitute the mechanical intercellular junctions in
cardiomyocytes. Thus, adherens junctions link the intercalated disc to the actin
cytoskeleton and desmosomes attach to intermediate filaments.
vDesmosomes:The desmosomes constitute a
3-dimensional intercellular network that lends structural support to cardiac
tissue. They consist in a symmetrical protein complex, with each end residing
in the cytoplasm of one of a pair of adjacent cells, anchoring intermediate
filaments in the cytoskeleton to the cell surface. The middle bridges the
intercellular space between cytoplasmic membranes. Desmosomes are not only
important as structural and adhesive complexes. On the contrary, they have
important roles in tissue morphogenesis during development and wound healing.
To this end, proteins that constitute the desmosome often detach from the
macromolecular complex and translocate to other subcellular compartments, where
they participate in a variety of signaling pathways. Desmosomal distribution
and structure are intimately related to the primary role in strengthening
tissues exposed to continuous mechanical stress, and therefore are highly
conserved throughout vertebrate evolution. As illustrated in the image,
transmembrane desmosomal cadherins, desmoglein (DSG) and desmocollin (DSC),
bind the armadillo family proteins junctional plakoglobin (JUP) and plakophilin
(PKP), which in turn anchor the plakin family member desmoplakin (DSP). The
cytoplasmic plaque, which is further stabilized by lateral interactions among
these proteins, anchors the intermediate filament cytoskeleton to the desmosome
(Figure 3). Mutations in components of the desmosome underlie a variety of
cardiomyopathies, including arrhythmia syndromes and heart muscle disorders.
adherens junctions provide a strong mechanical connection of cardiomyocytes via
linkage to the actin cytoskeleton, which provides a uniform mechanical strength
to the heart. They keep the cells tightly together as the heart expands and
contracts. Adherens junctions are also the anchor-point where myofibrils are
attached, enabling transmission of contractile force from one cell to another.
Adherens junctions are constructed from cadherins and catenins. Cadherins (in
cardiomyocytes N-Cadherin is the main cadherin) are transmembrane proteins that
zip together adjacent cells in a homophilic manner over a distance of
0.2–0.5 μm. At the adherens junctions the apposing membranes become
separated by ∼ 20 nm. The transmembrane cadherins form complexes with
cytosolic α-, β-, γ- (plakoglobin), and p120 catenin, thereby establishing the
connection to the actin cytoskeleton (Figure 4).
junctions mediate direct communication between adjacent cells. These
intercellular channels connect the cytoplasm of neighboring cells, enabling
passive diffusion of various compounds, like metabolites, water and ions, up to
a molecular mass of 1000 Da. Thereby they warrant electrical and metabolic
communication between cells. Gap junctions are present in nearly all tissues
and cells throughout the entire body. In cardiac muscle gap junctions ensure a
proper propagation of the electrical impulse which triggers sequential and
coordinated contraction of the cardiomyocytes. A gap junction channel consists
of twelve connexin proteins, six of which are contributed by each cell. The six
connexin subunits form a hemi-channel in the plasma membrane, which is called a
connexon. A connexon docks to another connexon in the intercellular space to create
a complete gap junction channel. The intercellular space between adjacent cells
at the site of a gap junction is 3.5 nm (Figure 5). Connexins form a large protein
family of highly related though functionally distinct connexins. In the
ventricular myocardium the most important connexin isoform is Connexin43
2) The sarcomere.
main function of cardiomyocytes concerns cardiac contraction. To this end,
cardiomyocytes are equipped with bundles of myofibrilsthat contain myofilamentsand represent 45 to 60 per cent of the volume of
cardiomyocytes (Figure 6). The
myofibrils are formed of distinct, repeating units, termed sarcomeres.
The sarcomeres represent the basic contractile units of the myocyte, and are
defined as the region of myofilament structures between two Z-lines. The
distance between Z-lines ranges in human hearts from about 1.6 to 2.2μm. The
sarcomere is composed of thick and thin filaments.
The thick filamentsare composed of myosin, a protein with a molecular weight of approximately 470 kilodaltons.
There are about 300 molecules of myosin per thick filament. Each myosin
contains two heads that are the site of the myosin ATPase, that hydrolyzes ATP
required for actin and myosin cross bridge formation. These heads interact with
a binding site on actin (Figure 7).
The thin filamentsare composed of the proteins
that form the regulatory protein complex: actin, tropomyosin, and troponin (Figure 7). Actin is a globular protein arranged as a chain of
repeating units, forming two strands of an alpha helix. Interdigitated between
the actin strands are rod-shaped proteins termed tropomyosin. There are 6-7 actin
molecules per tropomyosin. Attached to the tropomyosin at regular intervals is
the troponin complex, which is made up of three subunits:troponin-T(TN-T), which attaches
to the tropomyosin;troponin-C(TN-C), which serves
as a binding site for Ca++duringexcitation-contraction coupling(four Ca++can
bind per TN-C); and troponin-I(TN-I),
which inhibits the myosin binding site on the actin.
The arrangement of thick and thin filaments makes
possible cardiac contraction, which is discussed
elsewhere and gives cardiomyocytes a characteristic banded pattern previously shown on Figure 6:
Z-lines.A sarcomere is defined as the segment between two
neighbouring Z-lines (or Z-discs, or Z bodies). In electron micrographs of
cross-striated muscle, the Z-line (from
the German "Zwischenscheibe", the
disc in between the I bands) appears as a series of dark lines.
I-band. Surrounding the Z-line is the region of the I-band (for isotropic). I-band is the zone of thin filaments that is not superimposed by thick filaments.
A-band. Following the I-band is the A-band (for anisotropic). Named for their properties under a polarising microscope. An A-band contains the entire length of a single thick filament.
H-zone.Within the A-band is a paler region called the H-zone (from the German "heller", brighter). Named for their lighter appearance under a polarisation microscope. H-band is the zone of the thick filaments that is not superimposed by the thin filaments.
M-line. Within the H-zone is a thin M-line (from the German "Mittelscheibe", the disc in the middle of the sarcomere) formed of cross-connecting elements of the cytoskeleton.
3) T-tubules.In muscle cells including cardiomyocytes, the sarcolemma (i.e.
the plasma membrane) forms deep invaginations known as T-tubules (transverse
tubules) (Figure 8). These
invaginations allow depolarisation of the membrane to penetrate quickly to the
interior of the cell. In cells without t-tubules, the wave of calcium ions propagates
from the periphery of the cell into the center. However, such a system would
first activate the peripheral sarcomeres and then the deeper sarcomeres,
resulting in sub-maximal force production. The t-tubules make it possible that current
is simultaneously relayed to the core of the cell, and this means that a larger
instantaneous force is produced by triggering SR Ca2+release near to all sarcomeres simultaneously. In
fact, the t-tubules restrict diffusion of the extracellular fluid, creating a
microdomain of ions of a concentration that is relatively stable in comparison
with the wider extracellular space. This may also be a mechanism to prevent
rapid changes in the extracellular fluid from adversely affecting calcium-induced
morphology and energy metabolism in cardiomyocytes.
been described as "the powerhouse of the cell" because they generate
most of the cell's supply of adenosine triphosphate (ATP).Mitochondria
are composed of compartments that carry out specialised functions, and they include
the outer membrane, the intermembrane space, the inner membrane, and the
cristae and matrix (Figure 9).
cell types, mitochondria adjust their morphology and location depending on
energy needs and metabolic conditions of the cell. In cardiomyocytes, the
relationship between mitochondrial morphology and location, and function does
not seem to be so dependent on cell energy demands: Re-organisation of these
organelles depends on the cellular environment and architecture constraints - a
large amount of myofilaments, presence of a rigid cytoskeleton and a densely
packed mitochondrial network. Moreover, the arrangement of the different
organelles between them is so crucial for cardiac cell function that
mitochondrial morphology has to be efficiently controlled. Compared to any
other cell type, mitochondria from adult cardiomyocytes exhibit the highest
density of cristae. However, different types of mitochondria can be distinguished
within cardiomyocytes, and their morphological features are usually defined
according to their location: intermyofibrillar mitochondria, subsarcolemmal
mitochondria and perinuclear mitochondria.
mitochondria are strictly ordered between rows of
contractile proteins, apparently isolated from each other by repeated arrays of
T-tubules, and in close contact with myofibrils and sarcoplasmic reticulum. They
are mainly devoted to the energy supply of myosin and SR-ATPases. Intermyofibrillar
are elongated in shape with usually one mitochondrion existing per sarcomere. They
are 1.5–2.0 μm in length, and their cristae structures also displayed curved
vSubsarcolemmal mitochondriapresent a
lower degree of organisation and are probably mainly involved in other roles
such as ion homeostasis. They are located beneath the sarcolemma and are more
variable in length (0.4–3.0 μm), possessing closely packed cristae.
organized in clusters and are most probably involved in transcription and
translation processes. They are mostly spherical in shape with lengths ranging
from 0.8 to 1.4 μm. These mitochondria contain well-developed curved cristae
with relatively little matrix area.
the energy demands derived from cardiomyocyte function, the adult
cardiomyocytes contain numerous mitochondria, which can occupy at least 30% of
cell volume. Adult cardiomyocytes meet >90% of of the energy requirements by
oxidative phosphorylation (OXPHOS) in the mitochondria. Fatty acid oxidation
predominates over the oxidation of other nutrients under normal physiological
conditions. During periods of stress cardiomyocytes are flexible, and can
obtain energy by oxidizing glucose, lactate, amino acids, and ketone bodies. In
fact, the ability of to adapt their metabolism to substrate availability
results critical for their contraction balance under different physiological
and pathophysiological conditions. Proliferation of foetal cardiomyocytes
during cardiac development is characterised by high rates of glycolysis and
lactate production. Only <15% of the ATP is produced by the fatty acid
Summary.Cardiomyocytes are the main responsible for heart
contraction. The unique structural features discussed here allow them for specialised functions. However, cardiac function needs to be understood in the context of
the cardiac tissue, in which other cell types and structures are important
in order to get a coordinated cardiac contraction that adapts to the physiological
needs of the organ.
A tour of a cardiomyocyte
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