Muscle Contraction and Motor Unit Chapter 9 Motor System - 1 Muscle Contraction and Motor Unit

Content Skeletal Muscle Contraction Motor Unit

Reference – Text Book P71– 82 P482-483 UNIT XI The Nervous System: C. Motor and Integrative Neurophysiology P160-163

Section I Skeletal Muscle Contraction Signal Transmission Through Neuromuscular Junction Molecular Mechanism of Muscle Contraction Factors that Affect the Efficiency of Muscle Contraction

Part I Signal Transmission Through the Neuromuscular Junction

Skeletal Muscle Innervation

Illustration of the Neuromuscular Junction (NMJ)

New Ion Channel Players Voltage-gated Ca2+ 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

Neuromuscular Transmission Myelin Axon Axon Terminal Skeletal Muscle

Neuromuscular Transmission: Step by Step - - Nerve action Depolarization of terminal opens Ca channels Nerve action potential invades axon terminal - + + - + + Look here

Na+ Na+ Na+ Na+ K+ Na+ K+ Na+ K+ K+ Na+ Na+ K+ Na+ Na+ Na+ K+ K+ Na+ Binding of ACh opens channel pore that is permeable to Na+ and K+. ACh binds to its receptor on the postsynaptic membrane ACh is released and diffuses across synaptic cleft. Ca2+ induces fusion of vesicles with nerve terminal membrane. ACh ACh ACh Nerve terminal Ca2+ Ca2+ Na+ Na+ Na+ Na+ K+ Na+ K+ Na+ K+ K+ ACh Na+ Na+ Na+ K+ Outside Muscle membrane Na+ Na+ Inside K+ K+ Na+ K+ K+ K+ K+ K+ Na+ K+ Na+

End Plate Potential (EPP，终板电位) The movement of Na+ and K+ depolarizes muscle membrane potential (EPP) VNa EPP Muscle Membrane Voltage (mV) Threshold Presynaptic terminal -90 mV VK Time (msec) Presynaptic AP Outside Muscle membrane Inside Voltage-gated Na Channels ACh Receptor Channels Inward Rectifier K Channels

Meanwhile ... ACh ACh ACh Choline resynthesized ACh is hydrolyzed by into ACh and repackaged into vesicle Choline is taken up into nerve terminal ACh is hydrolyzed by AChE into Choline and acetate ACh unbinds from its receptor so the channel closes Nerve terminal Choline ACh Acetate ACh Outside Muscle membrane Inside

Structural Reality

Neuromuscular Transmission Properties of neuromuscular junction 1:1 transmission: An unidirectional process Has a time delay. 20nm/0.5-1ms easily affect by drugs and some factors The NMJ is a site of considerable clinical importance

Clinical Chemistry Related compounds are Ach is the natural useful in the neuroscience research Suberyldicholine is a synthetic neuromuscular agonist. Ach is the natural agonist at the neuromuscular junction. Carbachol and related compounds are used clinically for GI disorders, glaucoma, salivary gland malfunction, etc. Tubocurarine and other, related compounds are used to paralyze muscles during surgery. Tubocurarine competes with ACh for binding to receptor- but does not open the pore. So tubocurarine is a neuromuscular blocking agent. Carbachol is a synthetic agonist not hydrolyzed by acetylcholinesterase. Tubocurarine is the primary paralytic ingredient in curare.

Anticholinesterase Agents Anticholinesterase (anti-ChE 胆碱酯酶抑制剂) agents inhibit acetylcholinesterase （乙酰胆碱酯酶） prolong excitation at the NMJ

Anticholinesterase Agents 1. Normal: ACh Choline + Acetate AChE 2. With anti - AchE: ACh Choline + Acetate anti - AChE

Uses of anti-ChE agents Clinical applications (Neostigmine, 新斯的明, Physostigmine毒扁豆碱) Insecticides (organophosphate 有机磷酸酯) Nerve gas (e.g. Sarin 沙林，甲氟膦酸异丙酯。一种用作神经性毒气的化学剂))

VX NERVE AGENT

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 Ca2＋ channels Reduced ACh release

Botulinum toxin antiserum (肉毒杆菌毒素抗血清） The symptoms of Myasthenia Gravis could be relieved by Atropine Botulinum toxin antiserum (肉毒杆菌毒素抗血清） Curare Halothane （氟烷） Neostigmine

Prat II Molecular Mechanism of Muscle Contraction

Structure of Skeletal Muscle: Microstructure Sarcolemma （肌管系统） Transverse (T) tubule Longitudinal tubule (Sarcoplasmic reticulum, SR 肌浆网) Myofibrils （肌原纤维） Actin 肌动蛋白 (thin filament) Troponin （肌钙蛋白） Tropomyosin （原肌球蛋白） Myosin 肌球蛋白 (thick filament)

Within the Sarcoplasm Triad （三联管） Transverse tubules （横管） Sarcoplasmic reticulum - Storage sites for calcium Terminal cisternae - Storage sites for calcium

Sarcomeres bundle of alternating thick and thin filaments join end to end to form myofibrils Thousands per fiber, depending on length of muscle Alternating thick and thin filaments create appearance of striations

Thick filament: Myosin (肌球蛋白，head and tail) Thin filament: Actin 肌动蛋白, Tropomyosin 原肌球蛋白, Troponin (肌钙蛋白 calcium binding site)

What protein is the principle component of skeletal muscle thick filaments? actin myosin troponin calmodulin tropomyosin

Molecular Mechanism of Muscular Contraction The sliding filament model 肌丝滑行 Muscle shortening is due to movement of the actin filament over the myosin filament Reduces the distance between Z-lines

The Sliding Filament Model of Muscle Contraction

Changes in the appearance of a Sarcomere during the Contraction of a Skeletal Muscle Fiber

Energy for Muscle Contraction ATP is required for muscle contraction Myosin ATPase breaks down ATP as fiber contracts

Nerve Activation of Individual Muscle Cells (cont.)

Excitation/contraction coupling Action potential along T-tubule causes release of calcium from cisternae of TRIAD Cross-bridge cycle

Begin cycle with myosin already bound to actin

1. Myosin heads form cross bridges Myosin head is tightly bound to actin in rigor state Nothing bound to nucleotide binding site

2. ATP binds to myosin Myosin changes conformation, releases actin

3. ATP hydrolysis ATP is broken down into: ADP + Pi (inorganic phosphate) Both ADP and Pi remain bound to myosin

4. Myosin head changes conformation Myosin head rotates and binds to new actin molecule Myosin is in high energy configuration

5. Power stroke Release of Pi 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.

6. Release of ADP Myosin head is again tightly bound to actin in rigor state Ready to repeat cycle

A + M l ADP l Pi AlMlADPlPi A – M l ATP AlM THE CROSS-BRIDGE CYCLE Relaxed state Crossbridge energised Crossbridge attachment A + M l ADP l Pi Ca2+ present A – M l ATP AlMlADPlPi Crossbridge detachment Tension develops ADP + Pi ATP AlM A, Actin; M, Myosin

Cross Bridge Cycle

Rigor mortis Myosin cannot release actin until a new ATP molecule binds Run out of ATP at death, cross-bridges never release

Rigor mortis is caused by buildup of lactic acid lack of Ca2 depletion of glycogen lack of ATP. deficient acetylcholine receptors.

Need steady supply of ATP! Many contractile cycles occur asynchronously during a single muscle contraction Need steady supply of ATP!

Regulation of Contraction Tropomyosin blocks myosin binding in absence of Ca2+ Low intracellular Ca2+ when muscle is relaxed

Ca+2 binds to troponin during contraction Troponin-Ca2+ pulls tropomyosin, unblocking myosin-binding sites Myosin-actin cross-bridge cycle can now occur

How does Ca2+ get into cell? Action potential releases intracellular Ca2+ from sarcoplasmic reticulum (SR) SR is modified endoplasmic reticulum Membrane contains Ca2+ pumps to actively transport Ca2+ into SR Maintains high Ca2+ in SR, low Ca2+ in cytoplasm

Ca2+ Controls Contraction Ca2+ Channels and Pumps Release of Ca2+ from the SR triggers contraction Reuptake of Ca2+ into SR relaxes muscle 19

Structures involved in EC coupling - Skeletal Muscle - T-tubule sarcolemma out in sarcoplasmic reticulum voltage sensor? junction foot

Dihydropyridine （DHP, 双氢吡啶） 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, a voltage-gated Ca2+ channel In skeletal muscle, voltage-sensing protein undergoes voltage-dependent conformational changes 20

Ryanodine (利阿诺定 ) Receptor The "foot structure" in terminal cisternae of SR Foot structure is a Ca2+ channel of unusual design Conformation change or Ca2+ -channel activity of DHP receptor gates the ryanodine receptor, opening and closing Ca2+ channels Many details are yet to be elucidated! 21

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 out in voltage sensor (DHP receptor) junctional foot (ryanodine receptor) sarcoplasmic reticulum sarcolemma T-tubule

Cardiac muscle The AP: moves down the t-tubule voltage change detected by DHP receptors (Ca2+ channels) which opens to allow small amount of (trigger) Ca2+ into the fibre Ca2+ binds to ryanodine receptors which open to release a large amount of (activator) Ca2+ (CACR) Thus, calcium, not voltage, appears to trigger Ca2+ release in Cardiac muscle! out in voltage sensor & Ca channel (DHP receptor) junctional foot (ryanodine receptor) sarcoplasmic reticulum sarcolemma T-tubule

Comparison Skeletal Cardiac The trigger for SR release appears to be calcium (Calcium Activated Calcium Release - CACR) The t-tubule membrane has a Ca2+ channel (DHP receptor) The ryanodine receptor is the SR Ca release channel The ryanodine receptor is Ca- gated & Ca release is proportional to Ca2+ entry 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 Ca2+ release is proportional to membrane voltage

Summary: Excitation-Contraction Coupling

The Ca2+ required for skeletal muscle contraction is released from the sarcoplasmic reticulum enters the cell due to the opening of voltage regulated Ca2+ channels from the T tubules. is actively transported into the cell. is released from mitochondria.

What structures carry the action potentials into the interior of the muscle to cause muscle contraction? T tubules terminal cisternae DHP receptor Ryanodine ceceptor

Part III Factors that Affect the Efficiency of Muscle Contraction

Tension 张力 and Load 负荷 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.

Preload 前负荷 Preload Initial length load on the muscle before muscle contraction. Determines the initial length of the muscle before contraction. Initial length the length of the muscle fiber before its contraction. positively proportional to the preload.

The Effect of Sarcomere Length on Tension The Length – Tension Curve Concept of optimal length

Types of Contractions I Twitch 单收缩: a brief mechanical contraction of a single fiber produced by a single action potential at low frequency stimulation is known as single twitch. Tetanus 强直收缩: summation of twitches that occurs at high frequency stimulation

Effects of Repeated Stimulations Figure 10.15

1/sec 5/sec 10/sec 50/sec

Afterload 后负荷 Afterload load on the muscle after the beginning of muscle contraction. reverse force that oppose the contractile force caused by muscle contraction. does not change the initial length of the muscle prevent muscle from shortening

Types of Contractions (II) Afterload is resistance Isometric 等长 Length of muscle remains constant. Peak tension produced. Does not involve movement Isotonic 等张 Length of muscle changes. Tension fairly constant. Involves movement at joints Resistance and speed of contraction inversely related

Isotonic and Isometric Contractions

Resistance and Speed of Contraction

Muscle Power Maximal power occurs where the product of force (P) and velocity (V) is greatest (P=FV) Max Power= 4.5units X

_______ refer to muscle contractions that produce a shortening muscle with a constant contraction strength at a given load. Treppe contractions Isotonic contractions Twitch contractions Isometric contractions

Section 2. Motor Unit a single motor neuron (a motor) and all (extrafusal) muscle fibers it innervates the physiological functional unit in muscle (not the cell) All cells in motor unit contract synchronously

Extrafusal Muscle: innervated by Alpha motor neuron Intrafusal muscle: innervated by Gamma motor neurons

Motor units and innervation ratio Fibers per motor neuron Extraocular muscle 3:1 Gastrocnemius 2000:1 （腓肠肌） Purves Fig. 16.4

The muscle cells of a motor unit are not grouped, but are interspersed among cells from other motor units The coordinated movement needs the activation of several motors

Overview - organization of motor systems Motor Cortex Brain Stem Spinal Cord -motor neuron Final common pathway Skeletal muscle

Final common path - -motor neuron (-) muscle fibers (+) (-) axon hillock motor nerve fiber NM junction Schwann cells Receptors? acetylcholine esterase Transmitter?

  Final Common Pathway, a motor pathway consisting of the motor neurons by which nerve impulses from many central sources pass to a muscle in the periphery

Smooth, sustained muscle contractions in vivo are due to synchronous activation of motor units True False