What is the significance of actin in cardiac muscle

Heart muscle also contains large amounts of a pigment called myoglobin. Myoglobin is similar to hemoglobin in that it contains a heme group an oxygen binding site. Myoglobin transfers oxygen from the blood to the muscle cell and stores reserve oxygen for aerobic metabolic function in the muscle cell.

While aerobic respiration supports normal heart activity, anaerobic respiration may provide additional energy during brief periods of oxygen deprivation. Lactate, created from lactic acid fermentation, accounts for the anaerobic component of cardiac metabolism.

Under more severe hypoxic conditions, not enough energy can be liberated by lactate production to sustain ventricular contraction, and heart failure will occur. Lactate can be recycled by the heart and provides additional support during nutrient deprivation.

The produced pyruvate can then be burned aerobically in the citric acid cycle also known as the tricarboxylic acid cycle or Krebs cycle , liberating a significant amount of energy. Privacy Policy. Skip to main content. Cardiovascular System: The Heart. Search for:. Cardiac Muscle Tissue. Microscopic Anatomy Cardiac muscle appears striated due to the presence of sarcomeres, the highly-organized basic functional unit of muscle tissue.

Learning Objectives Identify the microscopic anatomy of cardiac muscles. Key Takeaways Key Points Cardiac muscle, composed of the contractile cells of the heart, has a striated appearance due to alternating thick and thin filaments composed of myosin and actin. Actin and myosin are contractile protein filaments, with actin making up thin filaments, and myosin contributing to thick filaments. Together, they are considered myofibrils.

Myosin and actin adenosine triphosphate ATP binding allows for muscle contraction. It is regulated by action potentials and calcium concentrations. Adherens junctions, gap junctions, and desmosomes are intercalated discs that connect cardiac muscle cells. Gap junctions specifically allow for the transmission of action potentials within cells.

Key Terms intercalated discs : Junctions that connect cardiomyocytes together, some of which transmit electrical impulses between cells. Mechanism and Contraction Events of Cardiac Muscle Fibers Cardiac muscle fibers undergo coordinated contraction via calcium-induced calcium release conducted through the intercalated discs. The distance between Z-lines i. Chemical and physical interactions between the actin and myosin cause the sarcomere length to shorten, and therefore the myocyte to contract during the process of excitation-contraction coupling.

The interactions between actin and myosin serve as the basis for the sliding filament theory of muscle contraction. Myosin is a protein having a molecular weight of approximately , daltons. There are about molecules of myosin per thick filament. Each myosin contains two heads that are the site of the myosin ATPase, an enzyme that hydrolyzes ATP required for actin and myosin cross bridge formation.

These heads interact with a binding site on actin Figure 2. In addition, Z-disks contain actin crosslinking proteins that maintain regular spacing between filaments. Actin filaments extend from the Z-disk toward the center of the sarcomere but end before reaching the center. Actin filaments in sarcomeres associate with several other proteins. Nebulin extends from the Z-disk to the minus end of actin filaments and contacts the actin monomers in filaments.

Nebulin may function as a molecular ruler to determine the length of the filaments in the sarcomere. Actin filaments are also wrapped by tropomyosin that prevents myosin from binding to actin in the absence of calcium. The troponin complex associates with tropomyosin and contains a calcium binding protein. In the presence of calcium, troponin shifts the position of tropomyosin on actin filaments, exposing the myosin-binding sites on actin. Myosin filaments are assemblies of muscle myosin a type II myosin.

Muscle myosin contains an extremely long coiled coil domain at its C-terminus that allows it to assemble into filaments. Myosin filaments extend from the center M-line of the sarcomere toward each Z-disk. Myosin filaments are bipolar with motor domains on one side of the M-line oriented toward the Z-disk and the motor domains on the other side of the M-line oriented toward the opposite Z-disk.

As the motors in a myosin filament walk along actin filaments, they pull the Z-disks together, shortening the length of the sarcomere. Titan is probably the largest protein in the human genome and has multiple functions in the sarcomere.

Titan is 1. Titan contacts the myosin filament at numerous points. Muscle contraction occurs through mutual sliding between the thick and thin filaments 1 , 2 by repeated association and dissociation of myosin head and actin filament coupled with ATP binding, hydrolysis and release by myosin head 3.

It is thought that the azimuthal position of Tm controls the access of myosin head to its binding surface on actin filament 5. This regulatory mechanism is specific to striated muscles. Structure of the thin filament has been analyzed by electron microscopy EM and image analysis 5 , 7 , 8 , 9 , 10 , Structures of component proteins have also been revealed either fully or partially 12 , 13 , 14 , However, the structure of the entire thin filament is not yet fully resolved at sufficiently high resolution to give insights into the regulatory mechanism.

Structural analysis of the thin filament is difficult because its symmetry and periodicity very much differ from those of actin filament. Actin filament is a helical assembly of actin subunits with a helical pitch of However, the repeating unit of the thin filament is a pair of large multimeric complexes, consisting of seven actin subunits, one Tm and one Tn in each of the long-pitch helical strand of actin with their axial stagger of Therefore, conventional helical image reconstructions using the helical symmetry of actin filament with a unit repeat of The density of Tm survives in helical image analysis simply because the Tm structure has seven homologous repeating units that approximately follows the actin symmetry along its long coiled coil structure 5 , 7.

It is also difficult to align images of Tn molecules on the thin filament due to their relatively small size. The molecular weight of Tn is approximately 80,, and this hetero-trimeric complex is not compactly folded, producing only a weak contrast in electron cryomicroscopy cryoEM images of the thin filament. We used recombinant Tm with alanine—serine or alanine—alanine—serine extension to mimic the N-terminal acetylation to stabilize the binding of Tm to actin filament 16 , as was successfully used in solving the cryoEM structure of actin filament—Tm complex at high resolution Addition of a fold excess of Tm and Tn over actin monomer to the sample solution of stoichiometric mixture also improved the efficiency in image collection of intact thin filament by markedly reducing the proportion of bare actin filament in the cryoEM images.

To visualize the density of Tn in the three-dimensional 3D image reconstruction, helical image reconstruction conventionally used for the structural analysis of actin filament cannot be used because it smears out the Tn density 5 , 7. As described in details in Methods and Supplementary Fig. Initial 3D image reconstructions and classifications were carried out with a relatively loose spherical mask large enough to cover a pair of Tn core domains on the two long-pitch actin strands because use of a tight mask dramatically reduced the number of remaining segments and even the images with a pair of Tn densities visibly attached to the filament were discarded.

We then made the mask gradually tighter, and for the final 3D classification, completely masked out actin and Tm from our density map to carry out focused classification 18 , thereby selecting segment images with a pair of Tn densities both at similar levels Supplementary Fig. The thin filament is oriented with the pointed end of actin filament top in Fig. The resolution of the 3D reconstruction is 6.

The quality and correctness of the 3D density map can be easily evaluated by nicely fitted atomic model of F-actin solved using the helical symmetry PDB:3MFP This also indicates that the binding of Tm and Tn alters neither the helical symmetry and axial repeat distance of actin filament nor the conformation of actin.

Approximately 12 actin subunits are shown with a pair of Tm coiled coils and a pair of the Tn ternary complexes consisting of the Tn core, TnI C extended upward from the core and TnT N attached closely to the head—tail junction of Tm near the bottom. The models are colored as: actin, beige; Tn, purple; and Tm, light blue and orange.

Actin filament is oriented with its pointed end top including all the other figures. The density of the core domain of Tn together with a long two-stranded coiled coil of Tm is visualized clearly on each strand of actin filament, with one of them at a higher position than the other by the axial rise of actin subunit along actin filament Fig.

The Tn core model thus built binds to each strand of actin filament over two actin subunits Fig. The model of full-length Tm including the head-to-tail junction formed by the N- and C-terminal regions of the two adjacent Tm subunits along actin filament has not been determined because all the cryoEM structural analysis have been done with the helical symmetry of actin filament 7 , Although the resolution of our map is not high enough to identify side chains, the structures of two-stranded coiled coil and the head-to-tail junction are clearly resolved to allow relatively reliable modeling.

The model of the head-to-tail junction Fig. Interestingly, the N-terminal side of this Tm-bound TnT N binds to actin, stabilizing the Tm—Tn binding to actin filament, and this explains why many disease-causing mutations are found in this region of TnT After having the model building completed for actin filament, Tm and Tn core as much as possible, we subtracted the model density from the 3D map to identify the densities of the remaining parts of Tn.

The densities are separated into two parts, one red above and the other dark blue below the Tn core as shown in Fig. We identified the upper density red as a C-terminal region of TnI and the lower one dark blue as an N-terminal region of TnT, part of which has already been modeled above, based on the continuity of the densities from the Tn core domain.

The C-terminal region of TnI comprising the inhibitory region residues — , regulatory switch residues — and mobile region residues — is present as a mostly continuous density red extending up along and between actin strand and Tm coiled coil from the C-terminal end Gly of the TnI helix within the Tn core.

TnT N residues 87— fitted to the map extends further down beyond the head-to-tail junction and reaches nearly the bottom of the third actin subunits below the Tn core from which the TnT N density extends. This means that the entire Tn structure is extremely elongated, binding to actin filament over seven actin subunits, of which the upper four are bound by TnI C and the Tn core and the bottom three of the opposite strand are bound by TnT N Fig.

Interestingly, because of this TnT N density bridging two Tm strands, the distance between the Tn core and the Tm head-to-tail junction is longer on one face of the thin filament Tn1, the upper one than the other Tn2, the lower one by one actin subunit Fig. The difference map produced by subtracting the model density of actin filament with Tm from the cryoEM 3D reconstruction is presented at a relatively low contour level to visualize the entire Tn structure of the thin filament in Fig.

The sequence regions of Tn covered in the model are indicated in Supplementary Fig. The difference in the relative positions of the Tn core and TnT N between the pair is clear while the conformations of the TnI C chains are the same. Most of all, the Tn core shows a large change in its position and orientation together with the azimuthal shift of Tm relative to actin filament, forming more intimate interactions with actin subunits Fig.

These conformational changes are depicted in Supplementary Movie 1. Two different views are presented. But now we clearly see a rolling motion of Tm on the surface of actin filament with their contact points as pivots Supplementary Movie 1 and also a significant variation in the shift distance along the Tm coiled coil depending on the position along the coiled coil Fig.

The azimuthal shift around the head-to-tail junction is markedly smaller than the other part near and above the Tn core where the shift distance is close to what has been shown in the previous studies by EM helical image analysis of various types of the thin filaments. This is likely due to TnT N binding to Tm in this region and its N-terminal side also binding to actin filament, restraining the Tm shift.

The quality of the 3D maps was high enough to allow the reliable docking of available crystal structures of Tn fragments part by part together with Tm and actin filament to build the atomic models of almost entire thin filament in the two functional states. Since the crystal structure of the Tn core PDB:4Y99 13 except for the TnC N-lobe consisting of TnI residues 42—, TnT residues —, TnC residues 93— fitted to the 3D map quite well in both maps, the positions and orientations of the Tn core are now defined much more accurately than ever before.

Beside the details of the Tn core structures, the full length Tm structures with the head—tail junction as well as the N-terminal extension of TnT and the C-terminal extension of TnI below and above the Tn core, respectively, are well visualized to allow the modeling of these parts albeit the accuracy is somewhat limited.

The inhibitory role of the TnI C chain downstream from Gly has been characterized well by biochemical studies 24 , 25 , It is now visualized in the structures of the thin filament in the two states. This TnI C chain as well as the Tn core themselves also strongly contribute to the blocking of myosin head access over four myosin binding sites of actin filament Fig. Model colors are the same as in Fig.

The models are viewed obliquely from the pointed end of actin filament. This causes Tm to move around on the actin filament surface short orange arrows together with TnT N near the head-to-tail junction of Tm, thereby exposing some of the myosin head binding sites shaded in light gray to allow actin—myosin interactions light pink.

The E.