According to the sequence of their motor domain, myosins recently were classified into 35 classes [4]. Those myosins which form dimers and assemble into thick filaments are called conventional or type II myosins and were first roughly prepared and named by W. Kühne in 1863 [5].

Type II myosins (constituting around 35 % of the total skeletal muscle protein) are the motor proteins of all muscle types. They are composed of two heavy chains (MYH). Each MYH associates with two different light chains (MLC), the essential (ELC) and regulatory (RLC) light chains.

The MYH (e.g., chicken skeletal MYH = 1938aa, ≈200 kDa) can be proteolytically cleaved into a C-terminal 150 nm alpha-helical rod domain and a pear-shaped ≈ 20 nm N-terminal head domain with associated MLC, called subfragment 1 or S-1. Proteolytic cleavage of the myosin rod domain yields subfragment 2 (S-2) and light meromyosin (LMM). They contain multiple heptad-repeat sequences, allowing dimerization to form a coiled-coil superstructure. S-1 and S-2 together are termed heavy meromyosin (HMM). Limited proteolysis of S-1 produces (from N- to C-terminus) a 25 K, a 50 K (with a large cleft and the actin-binding sites), and a 20 K domain, the converter domain, and the α-helical lever arm. The ATPase binding site forms a cleft at the 25 K/50 K interface. The lever arm contains two IQ motifs in tandem, namely, IQ1 for ELC binding and IQ2 for RLC binding [6]. Full-length ELC is designated as alkali 1 (A1), while alternatively spliced ELC forms with the N-terminal 46aa deleted are termed alkali 2 (A2). The C-terminus of A1 with its four EF-hand domains binds to the myosin lever arm while its antenna-like N-terminus interacts with the thin filament.

The coiled-coil rod domains of myosin associate to form end-polar (striated muscles) or side-polar (smooth muscle) myosin filaments. Each end-polar myosin filament (≈1.6 μm in length, 100 nm in diameter; thick filament) contains about 300 myosin molecules. The myosin heads of end-polar thick filament project in a helical array with a periodicity of 42.9 nm and an axial interval of 14.3 nm – except for a 0.15 μm bare zone, where there are only overlapping myosin rods. The myosin heads bind as “cross-bridges” (XB) to specific sites on the actin filament for contraction generation. The myosin filament is associated with myosin-binding protein C (C-protein) at regular intervals.

Actin (which comprises about 19 % of total skeletal muscle protein) is a globular protein (G-actin) with a 5.5 nm diameter and molecular weight of 42 kDa. G-actin can be divided into four subdomains with a central ATP bound. G-actin molecules polymerize under physiological conditions to form a helical filamentous structure (F-actin) with a length of 1 μm and diameter of 50 nm (thin filament), each actin with a central ADP bound. In particular, subdomain 1 which contains both the N- and C-termini of actin is located at the periphery of the thin filament and available for myosin interactions. F-actin appears by electron microscopy as two twisting strands of globular subunits. The axial separation of the crossover points is about 35 nm; thus every 7th actin has the same orientation.

F-actin is anchored to the Z-line by its plus end (i.e., the filament site of preferential growth) and binds to the capping protein tropomodulin at its minus end. Myosin-S1 forms arrowhead complexes with actin filaments which point to the minus end (i.e., toward the center of the sarcomere). Hence, type II myosin is termed a minus-end-directed motor. The final thin filament contains about 200 actin monomers associated with regulatory troponin-tropomyosin complexes (ca. 30 tropomyosin molecules and ca. 30 troponin complexes) regularly spaced along the thin filament.

Tropomyosin (Tm) consists of two α-helical polypeptide chains, each of ca. 35 kDa, forming a ≈42-nm-long coiled coil. Tm molecules aggregate end to end to form continuous strands running along the actin filament. Interactions between tropomyosin and actin are electrostatic.

The troponin (Tn) complex consists of three components, TnI, TnT, and TnC, with a total molecular weight of ≈80 kDa. Tn complexes are located every 35 nm on F-actin (i.e., every seven actins along the long pitch helix), probably at the sites of overlap between neighboring tropomyosin molecules. TnT (≈36 kDa) is a rod-like protein (18.5 nm long) which binds with its C-terminal half to both TnI and TnC and with its N-terminal half to both Tm and actin. TnI (≈24 kDa) holds the Tn complex together by binding to both TnC and actin. Cardiac TnI has a ≈30aa N-terminal extension with several phosphorylation sites. TnC (≈18 kDa) is the Ca²⁺ sensor of the contractile apparatus. It has a dumbbell-like shape with an N- and a C-terminal lobe. Binding of Ca²⁺ to TnC at the low-affinity sites at the N-lobe (two sites in skeletal, one site in cardiac TnC) represents the physiological trigger regulating contraction. The C-lobe of TnC (containing two high-affinity Ca²⁺/Mg²⁺ binding sites) interacts with TnI and TnT.

In addition to the regulatory Tn-Tm complexes, F-actin associates with nebulin filaments (skeletal muscle ~700 kDa) or its smaller cardiac homologue nebulette (~100 kDa). Nebulin binds to actin and Tn-Tm complexes and is anchored to the C-terminus of the Z-disk, where it binds via its N-terminus to tropomodulin. Nebulin and nebulette act as molecular rulers that determine thin filament length and may also modulate actomyosin interactions.

Cardiomyocytes have characteristic passive as well as active properties. Passive elasticity, i.e., tension generated upon stretch during rest, mainly depends on the elastic titin filaments. Furthermore, compression of titin spring elements during sarcomere shortening may provide the restoring force that sets the sarcomere length to resting levels when activation ceases.

An activated cardiomyocyte contracts, i.e., generates force and shortens with a load. Force generation without shortening is termed isometric and shortening at constant load/force generation, isotonic. The energy for muscle contraction comes from the hydrolysis of ATP. Hydrolyzed ATP can rapidly be resynthesized by different metabolic processes. ATP could effectively be resynthesized by transfer of P_i from phosphocreatine to ADP through the activity of creatine kinase (Lohmann reaction). Adenylate kinase (or myokinase) produces ATP by conversion of two ADP molecules to one ATP and one AMP molecule, which is removed by AMP deaminase to form inosine monophosphate and NH₄. In the heart, ATP is mainly synthesized through aerobic metabolism, i.e., conversion of glucose, fatty acids, and lactate to acetyl CoA and subsequent oxidation to CO₂ and H₂O in the mitochondria (Krebs cycle, electron transport chain). Hence oxygen consumption of the heart (around 0.1 ml/g/min) is high, accounting for approximately 10 % of the total oxygen consumption of the body.

Mechanochemical energy transformation is accomplished by cyclic interaction of the cross-bridges (XBs) with the thin filament. During this process, the XBs bind independently, generate force through a conformational change (the power stroke), and detach from the thick filaments (the cross-bridge theory; [7]). Recent X-ray crystallographic 3-D analysis of myosin-S1 fixed at different states of the XB cycle revealed the domain movements. According to a recently modified model [8] (Fig. 17.2), ATP binds to the ATP-binding cleft of the myosin XB (M), which causes the rapid detachment of the XB from the actin (A) filament (A + M-ATP). ATP is hydrolyzed, forming the M-ADP-Pi state (pre-power-stroke state, lever arm up, 50 K-cleft open). The M-ADP-Pi state weakly attaches to actin through ionic interactions (A-M-ADP-P_i). Releasing Pi then forms a strong stereospecific actin-binding state required for the power stroke of the XB (A-M-ADP). The power stroke is executed by movement of the myosin lever arm by ≈10 nm (lever arm down, 50 K-cleft closed). Detachment of the force-generating XB from the actin filament is achieved by the release of ADP and binding of ATP and restoration of the lever arm of the XB to its non-force-generating position (recovery stroke). In the absence of ATP, the nucleotide-free XBs remain strongly bound to the actin filament producing a rigor mortis state (A-M; lever arm down, 50 K-cleft closed; the swinging lever arm model [9]). Crystal structures have also shown that a small conformational change in the ATP-binding domain of the XB (movement of 0.5 nm) is amplified into the ≈10 nm movement of the lever arm.