3 Classification of the Muscle According to the structure: Striated Muscle, Smooth Muscle According to the nerve innervation: Voluntary Muscle, Involuntary Muscle According to the Function: Skeletal Muscle, Cardiac Contraction, Smooth Muscle
7 Illustration of the Neuromuscular Junction (NMJ)
8 New Ion Channel Players Voltage-gated Ca 2+ channel in presynaptic nerve terminal mediates neurotransmitter release Nicotinic Acetylcholine Receptor Channel in muscle neuromuscular junction (postsynaptic membrane, or end plate) mediates electrical transmission from nerve to muscle
9 Nerve Terminal Ca 2+ channels Structurally similar to Na + channels Functionally similar to Na + channels except activation occurs at more positive potentials activation and inactivation much slower than Na + channels
12 K+K+ Outside Inside Na + K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ ACh Ca 2+ induces fusion of vesicles with nerve terminal membrane. ACh is released and diffuses across synaptic cleft. ACh ACh binds to its receptor on the postsynaptic membrane Binding of ACh opens channel pore that is permeable to Na + and K +. Na + K+K+ Muscle membrane Nerve terminal Ca 2+
13 End Plate Potential (EPP) Outside Inside Muscle membrane Presynaptic terminal Muscle Membrane Voltage (mV) Time (msec) -90 mV VKVK V Na 0 Threshold Presynaptic AP EPP The movement of Na + and K + depolarizes muscle membrane potential (EPP) ACh Receptor Channels Voltage-gated Na Channels Inward Rectifier K Channels
14 Meanwhile... Outside Inside ACh ACh unbinds from its receptor Muscle membrane ACh so the channel closes ACh Nerve terminal ACh is hydrolyzed by AChE into Choline and acetate CholineAcetate Choline is taken up into nerve terminal Choline Choline resynthesized into ACh and repackaged into vesicle ACh
16 Neuromuscular Transmission Properties of neuromuscular junction 1:1 transmission: A chemical transmission which is designed to assure that every presynaptic action potential results in a postsynaptic one An unidirectional process Has a time delay. 20nm/0.5-1ms Is easily affect by drugs and some factors The NMJ is a site of considerable clinical importance
17 Clinical Chemistry Ach is the natural agonist at the neuromuscular junction. Tubocurarine is the primary paralytic ingredient in curare. Tubocurarine competes with ACh for binding to receptor- but does not open the pore. So tubocurarine is a neuromuscular blocking agent. Tubocurarine and other, related compounds are used to paralyze muscles during surgery. Carbachol is a synthetic agonist not hydrolyzed by acetylcholinesterase. Carbachol and related compounds are used clinically for GI disorders, glaucoma, salivary gland malfunction, etc. Suberyldicholine is a synthetic neuromuscular agonist. Related compounds are useful in the neuroscience research
18 Anticholinesterase Agents Anticholinesterase (anti-ChE) agents inhibit acetylcholinesterase （乙酰胆碱酯 酶） prolong excitation at the NMJ
19 1. Normal: ACh Choline + Acetate AChE 2. With anti - AchE: ACh Choline + Acetate anti - AChE Anticholinesterase Agents
21 Sarin and Sarin and Aum Shinrikyo( 奥姆真理教 ) Aum Shinrikyo( 奥姆真理教 ) is a Japanese religious cult obsessed with the apocalypse （启示，天启）. The previously obscure group became infamous in 1995 when some of its members released deadly sarin nerve gas into the Tokyo subway system, killing 12 people and sending more than 5,000 others to hospitals.
22 Sarin Sarin, which comes in both liquid and gas forms, is a highly toxic and volatile nerve agent developed by Nazi scientists in Germany in the 1930s. Chemical weapons experts say that sarin gas is 500 times more toxic than cyanide （氢化物） gas.
23 NMJ Diseases Myasthenia Gravis （重症肌无力） Autoimmunity to ACh receptor Fewer functional ACh receptors Low “safety factor” for NM transmission Lambert-Eaton syndrome （ 兰伯特 - 伊 顿综合征 ， 癌性肌无力综合征 ） Autoimmunity directed against Ca 2 ＋ channels Reduced ACh release Low “safety factor” for NM transmission
25 Skeletal Muscle Human body contains over 400 skeletal muscles 40-50% of total body weight Functions of skeletal muscle Force production for locomotion and breathing Force production for postural support Heat production during cold stress
26 Fascicles: bundles, CT(connective tissue) covering on each one Muscle fibers: muscle cells
28 Within the sarcoplasm Transverse tubules Sarcoplasmic reticulum -Storage sites for calcium Terminal cisternae - Storage sites for calcium Triad （三 联管）
29 Microstructure of Skeletal Muscle (myofibril)
30 Sarcomeres Sarcomere 肌小节 : bundle of alternating thick and thin filaments Sarcomeres join end to end to form myofibrils Thousands per fiber, depending on length of muscle Alternating thick and thin filaments create appearance of striations
32 Myosin head is hinged Bends and straightens during contraction Myosin 肌球蛋白
33 Thick filaments (myosin) Bundle of myosin proteins shaped like double- headed golf clubs Myosin heads have two binding sites Actin binding site forms cross bridge Nucleotide binding site binds ATP (Myosin ATPase) Hydrolysis of ATP provides energy to generate power stroke
35 Thin filaments (actin) Backbone: two strands of polymerized globular actin – fibrous actin Each actin has myosin binding site Troponin Binds Ca 2+ ; regulates muscle contraction Tropomyosin Lies in groove of actin helix Blocks myosin binding sites in absence of Ca 2+
37 III Molecular Mechanism of Muscular Contraction The sliding filament model Muscle shortening is due to movement of the actin filament over the myosin filament Reduces the distance between Z-lines
38 The Sliding Filament Model of Muscle Contraction
39 Changes in the appearance of a Sarcomere during the Contraction of a Skeletal Muscle Fiber
40 Cross-Bridge Formation in Muscle Contraction
41 Energy for Muscle Contraction ATP is required for muscle contraction Myosin ATPase breaks down ATP as fiber contracts
42 Nerve Activation of Individual Muscle Cells (cont.)
43 Action potential along T-tubule causes release of calcium from cisternae of TRIAD Cross-bridge cycle Excitation/contraction coupling
45 1. Myosin heads form cross bridges Myosin head is tightly bound to actin in rigor state Nothing bound to nucleotide binding site
46 2. ATP binds to myosin Myosin changes conformation, releases actin
47 3. ATP hydrolysis ATP is broken down into: ADP + P i (inorganic phosphate) Both ADP and P i remain bound to myosin
48 4. Myosin head changes conformation Myosin head rotates and binds to new actin molecule Myosin is in high energy configuration
49 5. Power stroke Release of P i from myosin releases head from high energy state Head pushes on actin filament and causes sliding Myosin head splits ATP and bends toward H zone. This is Power stroke.
50 6. Release of ADP Myosin head is again tightly bound to actin in rigor state Ready to repeat cycle
51 THE CROSS-BRIDGE CYCLE ATP ADP + P i A M A – M ATP A M ADP P i A + M ADP P i Relaxed state Crossbridge energised Crossbridge attachment Tension develops Crossbridge detachment Ca 2+ present A, Actin; M, Myosin
53 Rigor mortis Myosin cannot release actin until a new ATP molecule binds Run out of ATP at death, cross-bridges never release
54 Many contractile cycles occur asynchronously during a single muscle contraction Need steady supply of ATP!
55 Regulation of Contraction Tropomyosin blocks myosin binding in absence of Ca 2+ Low intracellular Ca 2+ when muscle is relaxed
56 Ca +2 binds to troponin during contraction Troponin-Ca +2 pulls tropomyosin, unblocking myosin-binding sites Myosin-actin cross-bridge cycle can now occur
57 How does Ca 2+ get into cell? Action potential releases intracellular Ca 2+ from sarcoplasmic reticulum (SR) SR is modified endoplasmic reticulum Membrane contains Ca 2+ pumps to actively transport Ca 2+ into SR Maintains high Ca 2+ in SR, low Ca 2+ in cytoplasm
The action potential triggers contraction How does the AP trigger contraction? This question has the beginning (AP) and the end (contraction) but it misses lots of things in the middle! We should ask: how does the AP cause release of Ca from the SR, so leading to an increase in [Ca] i ? how does an increase in [Ca] i cause contraction?
Z disc A band (myosin) I band (actin) Z disc M line Z disc sarcoplasmic reticulum t-tubules junctional feet Triad Contractile proteins in striated muscle are organised into sarcomeres T-tubules and sarcoplasmic reticulum are organised so that Ca release is directed toward the regulatory (Ca binding) proteins The association of a t-tubule with SR on either side is often called a ‘triad’ （三联管） (tri meaning three) Structures involved in EC coupling
Structures involved in EC coupling - Skeletal Muscle - out in voltage sensor? junction foot sarcoplasmic reticulum sarcolemma T-tubule
61 Ca 2+ Controls Contraction Ca 2+ Channels and Pumps Release of Ca 2+ from the SR triggers contraction Reuptake of Ca 2+ into SR relaxes muscle So how is calcium released in response to nerve impulses? Answer has come from studies of antagonist molecules that block Ca 2+ channel activity
63 Dihydropyridine Receptor In t-tubules of heart and skeletal muscle Nifedipine and other DHP-like molecules bind to the "DHP receptor" in t-tubules In heart, DHP receptor is a voltage-gated Ca 2+ channel In skeletal muscle, DHP receptor is apparently a voltage-sensing protein and probably undergoes voltage-dependent conformational changes
64 Ryanodine Receptor The "foot structure" in terminal cisternae of SR Foot structure is a Ca 2+ channel of unusual design Conformation change or Ca 2+ -channel activity of DHP receptor apparently gates the ryanodine receptor, opening and closing Ca 2+ channels Many details are yet to be elucidated!
out in voltage sensor (DHP receptor) junctional foot (ryanodine receptor) sarcoplasmic reticulum sarcolemma T-tubule Skeletal muscle The AP: moves down the t-tubule voltage change detected by DHP （双氢吡啶） receptors DHP receptor is essentially a voltage-gated Ca channel is communicated to the ryanodine receptor which opens to allow Ca out of SR activates contraction
Cardiac muscle The AP: moves down the t-tubule voltage change detected by DHP receptors (Ca channels) which opens to allow small amount of (trigger) Ca into the fibre Ca binds to ryanodine receptors which open to release a large amount of (activator) Ca (CACR) Thus, calcium, not voltage, appears to trigger Ca release in Cardiac muscle! out in voltage sensor & Ca channel (DHP receptor) junctional foot (ryanodine receptor) sarcoplasmic reticulum sarcolemma T-tubule
The Answers! Skeletal The trigger for SR release appears to be voltage (Voltage Activated Calcium Release- VACR) The t-tubule membrane has a voltage sensor (DHP receptor) The ryanodine receptor is the SR Ca release channel Ca 2+ release is proportional to membrane voltage Cardiac The trigger for SR release appears to be calcium (Calcium Activated Calcium Release - CACR) The t-tubule membrane has a Ca 2+ channel (DHP receptor) The ryanodine receptor is the SR Ca release channel The ryanodine receptor is Ca-gated & Ca release is proportional to Ca 2+ entry
68 Transverse tubules connect plasma membrane of muscle cell to SR
69 Ca 2+ release during Excitation-Contraction coupling Ryanodyne R Ca-release ch. Action potential on motor endplate travels down T tubules
70 Voltage -gated Ca 2+ channels open, Ca 2+ flows out SR into cytoplasm Ca 2+ channels close when action potential ends. Active transport pumps continually return Ca 2+ to SR Ca ATPase (SERCA)
71 Excitation-Contraction Coupling Depolarization of motor end plate (excitation) is coupled to muscular contraction Nerve impulse travels along sarcolemma and down T-tubules to cause a release of Ca 2+ from SR Ca 2+ binds to troponin and causes position change in tropomyosin, exposing active sites on actin Permits strong binding state between actin and myosin and contraction occurs ATP is hydrolyzed and energy goes to myosin head which releases from actin
IV Factors that Affect the Efficiency of Muscle Contraction
74 Tension and Load The force exerted on an object by a contracting muscle is known as tension. The force exerted on the muscle by an object (usually its weight) is termed load. According to the time of effect exerted by the loads on the muscle contraction the load was divided into two forms, preload and afterload.
75 Preload Preload is a load on the muscle before muscle contraction. Determines the initial length of the muscle before contraction. Initial length is the length of the muscle fiber before its contraction. It is positively proportional to the preload.
76 The Effect of Sarcomere Length on Tension The Length – Tension Curve Concept of optimal length
77 Types of Contractions I Twitch: a brief mechanical contraction of a single fiber produced by a single action potential at low frequency stimulation is known as single twitch. Tetanus: It means a summation of twitches that occurs at high frequency stimulation
78 Effects of Repeated Stimulations Figure 10.15
80 Afterload Afterload is a load on the muscle after the beginning of muscle contraction. The reverse force that oppose the contractile force caused by muscle contraction. The afterload does not change the initial length of the muscle, But it can prevent muscle from shortening because a part of force developed by contraction is used to overcome the afterload.
81 Afterload on muscle is resistance Isometric Length of muscle remains constant. Peak tension produced. Does not involve movement Isotonic Length of muscle changes. Tension fairly constant. Involves movement at joints Resistance and speed of contraction inversely related Types of Contractions (II)