Heart Muscle Structure and Function

• Cardiac muscle cells are striated, containing sarcomeres.
• Cardiac cells are electrically connected through gap junctions, forming a functional syncytium.
• T tubules are present in cardiac muscle.
• The sarcoplasmic reticulum is present.
• Mitochondria are present.
• The conducting system is present.
• Secretory activity occurs in cardiac muscle.

Heart Muscle Structure

• Cardiac muscle features a branched structure.
• Intercalated discs are present.
• Gap junctions are present.
• Sarcomeres measure 1.8 μm.
• Contractile proteins are present.
• Regulatory proteins are present.
• Cardiac muscle is under autonomic innervation.

Sarcomeric Proteins

• Contractile proteins include actin and myosin.
• Regulatory proteins include troponin and tropomyosin.
• Other proteins include titin and nebulin.

Sarcoplasmic Reticulum Function

• The sarcoplasmic reticulum stores, releases, and uptakes Ca2+ at a concentration of 1 mmol/l.
• Calsequestrin is located in the terminal cisterns of the sarcoplasmic reticulum.
• Ryanodine receptors are calcium channels located in the terminal cisterns of the sarcoplasmic reticulum.
• Ryanodine receptors bind calcium and release it from the sarcoplasmic reticulum, triggering calcium-induced calcium release (CICR).
• The calcium pump of the sarcoplasmic reticulum is in the longitudinal tubules and is inhibited by non-phosphorylated phospholamban.

Diade Structure

• The diade consists of the sarcolemma, T-tubule, sarcoplasmic reticulum (SR), calcium channel (CaL), and ryanodine receptor (RyR2).

Sarcomere Features

• Sarcomeres are about 1.7 μm in length.
• They contain actin and myosin.
• They contain troponin and tropomyosin.

Thin Filament Composition

• Thin filaments are made of actin, tropomyosin, and the troponin complex (subunits C, I, T).

Thick Filament Structure

• Thick filaments have tail and head regions with a flexible hinge region in the myosin molecule.

Cross-bridge Formation

• At a Ca2+ concentration of 10-7 mol/l, the actin/troponin/tropomyosin complex does not bind myosin.
• At a Ca2+ concentration of 10-5 mol/l, cross-bridges form with myosin.

Excitation-Contraction Coupling in Cardiomyocytes

• The process starts with depolarization of the sarcolemma.
• An action potential opens ICaL channels.
• The intracellular (IC) Ca2+ concentration increases.
• Ryanodine receptors open, causing calcium-induced calcium release (CICR).
• The IC Ca2+ concentration increases further to 10-5 mol/l.
• Calcium binds to troponin C (TnC).
• Contraction begins.

Calcium Handling Cycle

• The outer cycle involves ICaL(DHP), sarcolemmal Ca-ATPase, and NCX.
• The inner cycle involves the Ca channel SR (RyR) and Ca-ATPase SR.

Molecular Mechanism of Muscle Contraction

• Troponin binds with Ca2+.
• Active sites of actin are uncovered.
• The myosin (M) head binds ATP.
• Myosin splits ATP into ADP and phosphate (P).
• A cross-bridge forms.
• Phosphate is released.
• The myosin head moves, and ADP is released.
• A new ATP molecule binds.
• The myosin head disconnects from actin (A).
• ATP splits into ADP and P.
• The myosin head erects.
• The cycle repeats.

Muscle Relaxation

• Ca2+ is transported to the sarcoplasmic reticulum (SERCA II) and the extracellular fluid (NCX, Ca2+-ATPase).
• Ca2+ releases from troponin C.
• Active sites are blocked.

Sarcomere Dynamics

• During contraction, the A band stays the same length while the I band shortens.
• During relaxation, the I band extends and the H zone is visible.

Tension-Length Relationship

• Cardiac muscle has a higher resistance to stretch compared to skeletal muscle.
• Stretching cardiac or skeletal muscle increases resting tension (RT).
• Stimulation leads to maximal contraction and greater total tension (TT).
• The force produced by contraction at a given length is the active tension (AT).
• The bell-shaped dependence of active tension on muscle length aligns with the sliding filament theory.
• Stretching cardiac muscle beyond its optimal sarcomere length is hard, due to the rapid increase in resting tension.

Muscle Fiber Types

• Skeletal muscle has somatic innervation, regular sarcomeres (2.1-2.2 μm), diameters up to 100 μm and up to 200,000 μm in length.
• Cardiac muscle has autonomic innervation by way of varicosities, regular sarcomeres (1.7-1.8 μm), diameters ca. 10 μm and ca. 50 μm in length
• Smooth muscle has autonomic innervation by way of varicosities, no sarcomeres, but has dense bodies. Diameters up to 5 μm typically, but up to 200 μm in length

Excitation-Contraction Coupling in Skeletal Muscle

• Involves the neuromuscular junction.
• An action potential (AP) occurs in the muscle fiber that propagates.
• Calcium is released from the sarcoplasmic reticulum, and binds to troponin C.
• The contractile apparatus is activated, leading to contraction of the muscle fiber.

Skeletal Muscle ECC

• T-tubules, regular sarcoplasmic reticulum, and triads are present.
• A motor end-plate is present.
• Electrical ECC occurs.
• Regulatory proteins are troponin and tropomyosin.

Cardiac Muscle ECC

• Has T-tubules, sarcoplasmic reticulum, and diads.
• No motor end-plate exists.
• Chemical ECC (CICR) occurs.
• Regulatory proteins are troponin and tropomyosin.

Smooth Muscle ECC

• Caveoli are present; T-tubules are absent.
• Sarcoplasmic reticulum is rare or absent.
• No motor end-plate.
• Calcium-mediated ECC chemical occurs.
• Regulatory proteins are calmodulin and tropomyosin.

Skeletal Muscle Contraction

• Tight binding occurs in the rigor state. The cross-bridge is at a 45° angle related to the filaments.
• ATP binds to myosin, and myosin dissociates from actin.
• ATPase activity hydrolyzes ATP, and ADP and Pi remain bound to myosin.
• Phosphate release initiates the power stroke. The myosin head rotates on its hinge, pushing the actin filament.
• At the end of the power stroke, the myosin head releases ADP and assumes the tightly bound rigor state.

Cardiac Muscle Contraction

• Myosin heads hydrolyze ATP and become reoriented and energized.
• Myosin heads bind to actin, forming cross-bridges.
• Myosin heads rotate toward the center of the sarcomere (power stroke).
• As myosin heads bind ATP, the cross-bridges detach from actin.
• The contraction cycle continues if ATP is available and Ca2+ level in the sarcoplasm is high.

Smooth Muscle Contraction

• A stimulating ligand causes Receptor activation.
• PLC is activated.
• PIP2 is activated
• IP3+ DAG is produced.
• Ca2+ is released.
• Contraction occurs at Ca2+ =0.1μ Μ.
• MLC kinase complex occurs
• MMyosin phosphate + Actin occurs
• Myosin-light chain phosphatase occurs.

Skeletal Muscle Humoral Regulation

• Indirect, mainly trophic effects.

Cardiac Muscle Humoral Regulation

• Beta 1 adrenergic receptors (β1AR) stimulate adenylyl cyclase (AC) via Gs.
• AC increases cAMP, activating protein kinase A (PKA).
• PKA phosphorylates targets, with regulation by phosphatases PP1 and PP2A.
• Activation of alpha 1 adrenergic receptors stimulates phospholipase C (PLC) via Gq.
• PLC increases IP3 and DAG.
• IP3 increases intracellular calcium, activating protein kinase C (PKC).

Smooth Muscle Humoral Regulation

• Increases in intracellular Ca2+ (such as by influx through L-type Ca2+ channels) as well as Gq-coupled receptor activation, or activation of Rho-kinase all lead to contraction by phosphorylation of the myosin light chain.
• Beta-adrenergic receptor signalling increases cAMP and inhibits Myosin Light Chain Kinase, thus leading to relaxation.