Muscle

1. Muscle Huan Ma（马欢），PhD Department of Physiology Room 515, Block C, Research Building School of Medicine, Zijingang Campus Email: mah@zju.edu.cn Tel: 88208068

2. Muscle Types of muscle: • Skeletal muscle • Cardiac muscle • Smooth muscle Striated muscle

3. Skeletal muscle骨骼肌 • Cardiac muscle 心肌 • Smooth muscle平滑肌

4. Muscle (cont.) • The sliding filament mechanism, in which myosin filaments bind to and move actin filaments, is the basis for shortening of stimulated skeletal, smooth, and cardiac muscles. • In all three types of muscle, myosin and actin interactions are regulated by the availability of calcium ions. • Changes in the membrane potential of muscles are linked to internal changes in calcium release (and contraction).

5. Muscle (cont.) • Neuronal influences on the contraction of muscles is affected when neural activity causes changes in themembrane potential of muscles. • Smooth muscles operate in a wide variety of involuntaryfunctions such as regulation of blood pressure andmovement of materials in the gut.

6. General process of excitation and contraction in skeletal muscle • Neuromuscular transmission • Excitation-contraction coupling • Muscle contraction

7. A single motor unit（运动单位） consists of a motor neuron and all of the muscle fibers it controls.

8. The vertebrate neuromuscular junction or motor end plate

9. 1. The exocytosis 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.

10. Nicotinic acetylcholine receptor 烟碱型乙酰胆碱受体 Acetylcholinesterase 乙酰胆碱酯酶

11. Structure of the nicotinic AChR

12. The effect of a local anesthetic on the AChR. A, Single-channel recording of nicotinic AChR expressed in a Xenopus oocyte. The patch was in the outside-out configuration, and the holding potential was −150 mV. The continuous presence of 1 μM ACh caused brief channel openings. B, This experiment is similar to that in A except that in addition to the ACh, the lidocaine analogue QX-222 (20 μM) was present at the extracellular surface of the receptor channel. Note that the channel opening is accompanied by rapid flickering caused by many brief channel closures. The time scale of the lower panel is expanded 10-fold. (Data from Leonard RJ, Labarca CG, Charnet P, et al: Evidence that the M2 membrane-spanning region lines the ion channel pore of the nicotinic receptor. Science 1988; 242:1578-1581.)

13. End plate potential (EPP) 终板电位 End-plate potentials elicited at the frog neuromuscular junction by stimulation of the motor neuron

14. Miniature end plate potential 微终板电位 • Small fluctuations (typically 0.5 mV) in the resting potential of postsynaptic cells. • They are the same shape as, but much smaller than, the end plate potentials caused by stimulation of the presynaptic cell. Miniature end plate potentials are considered as evidence for the quantal release of neurotransmitters at chemical synapses, a single miniature end plate potential resulting from the release of the contents of a single synaptic vesicle.

15. Evoked and spontaneous MEPPs. A, The investigators recorded V in frog skeletal muscle fibers that were exposed to extracellular solutions having a [Ca ] of 0.5 mM and a [Mg ] of 5 mM. These values minimize transmitter release, and therefore it was possible to resolve the smallest possible MEPP, which corresponds to the release of a single synaptic vesicle (i.e., 1 quantum). The investigators stimulated the motor neuron seven consecutive times and recorded the evoked MEPPs. In one trial, the stimulus evoked no response (0 quanta). In two trials, the peak MEPP was about 0.4 mV (1 quantum). In three others, the peak response was about 0.8 mV (2 quanta). Finally, in one, the peak was about 1.2 mV (3 quanta). In one case, a MEPP of the smallest magnitude appeared spontaneously. B, The histogram summarizes data from 198 trials on a cat neuromuscular junction in the presence of 12.5 mM extracellular Mg . The data are in bins with a width of 0.1 mV. The distribution has eight peaks. The first represents stimuli that evoked no responses. The other seven represent stimuli that evoked MEPPs that were roughly integral multiples of the smallest MEPP. The curve overlying each cluster of bins is a gaussian or “normal” function and facilitates calculation of the average MEPP for each cluster of bins. The peak values of these gaussians follow a Poisson distribution. (Data from Magleby KL: Neuromuscular transmission. In Engel AG, Franzini-Armstrong C [eds]: Myology, Basic and Clinical, 2nd ed, pp 442-463. New York, McGraw-Hill, 1994.)

17. Pharmacology of the vertebrate neuromuscular junction. Many of the proteins that are involved in synaptic transmission at the mammalian neuromuscular junction are the targets of naturally occurring or synthetic drugs. The antagonists are shown as minus signs highlighted in red. The agonists are shown as plus signs highlighted in green.

18. General process of excitation and contraction in skeletal muscle • Neuromuscular transmission • Excitation-contraction coupling • Muscle contraction

19. Excitation-contraction coupling • Transmission of action potential (AP) along T tubules • Calcium release caused by T tubule AP • Contraction initiated by calcium ions

20. 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.

21. 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.

22. 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.

23. EC coupling in skeletal muscle

24. Mechanisms of Ca removal from the cytoplasm

25. General process of excitation and contraction in skeletal muscle • Neuromuscular transmission • Excitation-contraction coupling • Muscle contraction

26. Skeletal muscles are attached to the skeleton by tendons. Skeletal muscles typically contain many, many muscle fibers

27. Plasma membrane invaginations

28. The sarcomere is composed of: thick filaments called myosin, anchored in place by titin fibers, and thin filaments called actin, anchored to Z-lines .

29. 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.

30. Sarcomere structures in an electron micrograph.

31. Filaments

32. Myosin filament (thick filament) • Myosin

33. Actin filament (thin filament) • Actin • Tropomyosin • Troponin

34. Titin

35. Sarcotubular system (1) Transverse Tubule (2) Longitudinal Tubule Sarcoplasmic reticulum

36. Molecular mechanisms of contraction Sliding-filament mechanism

37. Contraction (shortening): 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.

38. Contraction: myosin’s cross-bridges bind to actin; the crossbridges then flex to slide actin.

39. 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.

40. 4. Partial hydrolysis of the bound ATP energizes or “re-cocks” the bridge. 2. The full hydrolysis and departure of ADP + Picauses the flexing of the bound cross-bridge. 3. Binding of a “new” ATP to the cross-bridge uncouples the bridge. The myosin-binding site on actin becomes available, so the energized cross-bridge binds. 1. The cross-bridge cycle requires ATP

41. The myosin-binding site on actin becomes available, so the energized cross-bridge binds. 1.

42. 2. The full hydrolysis and departure of ADP + Picauses the flexing of the bound cross-bridge.

43. 3. Binding of a “new” ATP to the cross-bridge uncouples the bridge.

44. 4. Partial hydrolysis of the bound ATP energizes or “re-cocks” the bridge.

45. 4. Partial hydrolysis of the bound ATP energizes or “re-cocks” the bridge. 2. The full hydrolysis and departure of ADP + Picauses the flexing of the bound cross-bridge. 3. Binding of a “new” ATP to the cross-bridge uncouples the bridge. The myosin-binding site on actin becomes available, so the energized cross-bridge binds. 1. The cross-bridge cycle requires ATP

46. Roles of troponin, tropomyosin, 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.

47. The role of Ca in triggering the contraction of skeletal and cardiac muscle

49. Mechanics of single-fiber contraction • Muscle tension – the force exerted on an object by a contracting muscle • Load – the force exerted on the muscle by an object (usually its weight) • Isometric contraction – a muscle develops tension but does not shorten (or lengthen) (constant length) • Isotonic contraction – the muscle shortens while the load on the muscle remains constant (constant tension)

50. Twitch contraction • The mechanical response of a single muscle fiber to a single action potential is know as a TWITCH