Skeletal Muscle Physiology （骨骼肌生理） Huawei Liang, PhD Email: [email protected] Structure of skeletal muscle （肌纤维） （肌束） ( 肌纤维 ) ( 肌原纤维 ) ( 肌节 ) Skeletal muscles typically contain many, many muscle fibers. The sarcomere（肌节）is composed of thick filaments（粗肌丝）called myosin（肌球蛋白）, anchored in place by titin fibers, and thin filaments（细肌丝）called actin（肌动蛋白）, anchored to Z-lines . A cross section through a sarcomere shows that: • each myosin can interact with 6 actin filaments, and • each actin can interact with 3 myosin filaments. Sarcomere structures in an electron micrograph. Filaments Myosin filament (thick filament) • Myosin（肌球蛋白） 横桥 Actin filament (thin filament) • Actin（肌动蛋白） • Tropomyosin（原肌球蛋白） • Troponin（肌钙蛋白） Titin（肌联蛋白） 肌联蛋白源自M线，并沿肌 球蛋白纤维伸展，通过肌 节的A带，最后到达Z线。 肌联蛋白是高度弹性的分 子，因此在肌收缩和舒张 时保持肌球蛋白纤维位于 肌节的中心。 Sarcotubular system（肌管系统） (1) Transverse Tubule 横管 (2) Longitudinal Tubule 纵管 Sarcoplasmic reticulum 肌浆网 （三联管） Molecular mechanisms of contraction（收缩） Sliding-filament mechanism 肌丝滑行机制 Contraction: myosin binds to actin, and slides it, pulling the Z-lines closer together, and reducing the width of the I-bands. Note that filament lengths have not changed. Contraction: myosin’s cross-bridges bind to actin; the cross-bridges then flex to slide actin. Click here to play the Sarcomere Shortening Flash Animation The thick filament called myosin is actually a polymer of myosin molecules, each of which has a flexible cross-bridge that binds ATP and actin. The cross-bridge cycle requires ATP 1. The myosin-binding site on actin becomes available, so the energized cross-bridge binds. 2. 4. Partial hydrolysis of the bound ATP energizes or “re-cocks” the bridge. 3. The full hydrolysis and departure of ADP + Pi causes the flexing of the bound cross-bridge. Binding of a “new” ATP to the cross-bridge uncouples the bridge. Click here to play the Cross-bridge cycle Flash Animation Roles of troponin (肌钙 蛋白), tropomyosin (原肌 球蛋白), and calcium in contraction In relaxed skeletal muscle, tropomyosin blocks the cross-bridge binding site on actin. Contraction occurs when calcium ions bind to troponin; this complex then pulls tropomyosin away from the cross-bridge binding site. Excitation-contraction coupling 骨骼肌的兴奋-收缩耦联 • Transmission of action potential (AP) along T tubules • Calcium release caused by T tubule AP • Contraction initiated by calcium ions The latent period between excitation and development of tension in a skeletal muscle includes the time needed to release Ca++ from sarcoplasmic reticulum, move tropomyosin, and cycle the cross-bridges. The transverse tubules bring action potentials into the interior of the skeletal muscle fibers, so that the wave of depolarization passes close to the sarcoplasmic reticulum, stimulating the release of calcium ions. The extensive meshwork of sarcoplasmic reticulum assures that when it releases calcium ions they can readily diffuse to all of the troponin sites. Passage of an action potential along the transverse tubule opens nearby voltage-gated calcium channels, the “ryanodine receptor,” located on the sarcoplasmic reticulum, and calcium ions released into the cytosol bind to troponin. The calcium-troponin complex “pulls” tropomyosin off the myosin-binding site of actin, thus allowing the binding of the cross-bridge, followed by its flexing to slide the actin filament. Removal of intracellular calcium ions • Sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) • Calsequestrin 钙扣压素 Regulation of SERCA by phospholamban (受磷蛋白) • Dephosphorylated state: phospholamban inhibits the activity of SERCA by decreasing its affinity for Ca2+ • Phosphorylated state: phospholamban enhances the activity of SERCA by increasing its affinity for Ca2+ General process of excitation and contraction in skeletal muscle 骨骼肌兴奋收缩的基本过程 • Neuromuscular transmission • Excitation-contraction coupling • Muscle contraction A single motor unit consists of a motor neuron and all of the muscle fibers it controls. The neuromuscular junction (神经-肌肉接头) is the point of synaptic contactbetween the axon terminal of a motor neuron and the muscle fiber it controls. Action potentials in the motor neuron cause Acetylcholine (乙酰胆碱) release into the neuromuscular junction. Muscle contraction follows the delivery of acetylcholine to the muscle fiber. 1. The exocytosis (出胞) of acetylcholine from the axon terminal occurs when the acetylcholine vesicles merge into the membrane covering the terminal. 2. On the membrane of the muscle fiber, the receptors for acetylcholine respond to its binding by increasing Na+ entry into the fiber, causing a graded depolarization. 3. The graded depolarization typically exceeds threshold for the nearby voltage-gate Na+ and K+ channels, so an action potential occurs on the muscle fiber. End plate potential (EPP) 终板电位 Click here to play the Neuromuscular Junction Flash Animation Click here to play the Action Potentials and Muscle Contraction Flash Animation Factors of affecting contractile performance of skeletal muscle • Preload 前负荷 • Afterload 后负荷 • Contractility 肌肉的收缩能力 Two basic types of contraction • Isometric contraction 等长收缩: a muscle develops tension but does not shorten (or lengthen) (at a constant length) • Isotonic contraction 等张收缩: the muscle shortens while the load on the muscle remains constant (at a constant tension) iso = same tonic = tension metric = length Tension increases rapidly and dissipates slowly Shortening occurs slowly, only after taking up elastic tension; the relaxing muscle quickly returns to its resting length. • Parameters to evaluate contractile performance – – – – Force Shortening Duration Velocity Effect of Preload (initial length 初长度) Short sarcomere: actin filaments lack room to slide, so little tension can be developed. Length-tension relation Optimal-length sarcomere: lots of actin-myosin overlap and plenty of room to slide. Long sarcomere: actin and myosin do not overlap much, so little tension can be developed. Effect of Afterload Load-velocity relation Effect of Contractility Summation of Contraction • Twitch 单收缩 • Tetanus 强直收缩 – Incomplete Tetanus – Complete Tetanus Frequency-tension relation Mechanism for greater tetanic tension Successive action potentials result in a persistent elevation of cytosolic calcium concentration Summary • Terms – – – – – End plate potential Cross-bridge Excitation-contraction coupling Active tension Isometric contraction & Isotonic contraction • Describe the molecular mechanisms of muscle contraction • List the important factors that affect contractile performance of skeletal muscle Genernal Questions • How does the relationship of actin and myosin explain the length-tension curve of skeletal muscle? • “Muscle is a machine for converting chemical into mechanical energy.” Analyze and discuss this statement. The End.