Академический Документы
Профессиональный Документы
Культура Документы
Part III
April, 2010
Objectives:
Know the major classes of muscles of the body. Describe the molecular basis of muscle contraction.
Part III
1. Introduction
1.1. General Points
6/9/2012
Part III
1.3. O2 consumption a. 25% total bodily O2 consumption at rest is consumed by the muscles.
b. During strenuous exercise this amount can increase as much as 10-20 times.
2. Types/Classification
2.1. Anatomical
2.1.1. Striations: Presence of alternating light and dark bands on the sarcolemma.
6/9/2012
Part III
Classification
6/9/2012
Part III
6/9/2012
Part III
6/9/2012
Part III
Part III
2.2. Physiological
2.2.1. Voluntary Muscle
Skeletal muscle (CNS, somatic neurons). 2.2.2. Involuntary muscle Cardiac muscle (Intrinsic + Extrinsic factors, ANS + Hormonal) Smooth muscle (Intrinsic + Extrinsic factors, ANS + Hormonal)
6/9/2012
Part III
Part III
12
13
14
15
Part III
Myofilaments
Part III
Terms
1. Epimysium: a connective tissue which ensheaths the entire muscle. 2. Perimysium: a connective tissue that ensheaths the fascicles 3. Endomysium: a sheath that covers each muscle fiber. Each one is the continuation of the other. 4. Sarcoplasmic Reticulum: a tubular network that divides the individual skeletal muscle fiber into myofibrils. 5. Sarcolemma: a true plasma membrane of skeletal muscle fiber.
6. -actinin: a protein that connects actin to the z-line. 7. Myoplasm/sarcoplsam: cytoplasm of the muscle cell.
6/9/2012
17
Part III
13. Nebulin: a template protein which determines the precise size of actin
6/9/2012
18
19
20
21
Dystrophin-glycoprotein complex
22
Dystrophin-glycoprotein complex
Muscular dystrophies Duchenne muscular dystrophy Becker Muscular dystrophy Limb-girdle muscle dystrophy Metabolic myopathies McArdle syndrome Ion channel myopathies Manytypes
23
Part III
6/9/2012
24
Part III
3.3.2. Molecular geometry Differences in Refractive indices hen viewed under polarized light. A-Band (A= Anisotropisch)* a. The darker area in the centre of the sarcomere. b. It is due to the orderly arrangement of thick filaments.
Part III
6/9/2012
26
Part III
I-Band (I= Isotropisch) a. The lighter area on either side of the z-lines. b. Each sarcomere contain half of the two I-bands.
Z-Line/Disc (Z = Zwischenscheibe) a. Dense line in the center of each light band. b. Separates one sarcomere from the next. c. It is the attachment site for the thin filaments.
6/9/2012
27
Part III
Part III
This model theorizes that sliding in of the filaments (thick & thin) toward the center of muscle and sarcomere is responsible for the shortening and force of contraction.
6/9/2012
29
Part III
2 heads Myosin head (cross-bridge) Actin-binding site ATP-binding site (ATPase) Hydrolyzes ATP
1 long tail form core of the thick filament d. 1 thick filament has 300 (500) myosin heads (294 in frog muscle). 1 cross-bridge has 2 identical heads
6/9/2012 The Physiology of Muscles 30
Myosin Filament
31
Part III
e. Orientation: i. Head projects out on either side of the H-zone to swivel in opposite directions to shorten the sarcomere. ii. During rapid contraction each head form 5 cycles/sec, thus sliding myosin & actin filaments by about 5m/sec. iii. In a resting muscle the cross-bridge is not attached to the thin filaments & is oriented perpendicularly to the myosin filaments. f. The thick filaments are suspended or assumed their central position in the sarcomere because of their attachments to the z-disc by titin.
6/9/2012
32
Part III
6/9/2012
33
34
Part III
3.4.3. Thin Filaments a. They are called actins. b. Dimensions : = 5nm, L = 1 m c. Components : 1. Globular proteins i. Actin (300-400 molecules, and molecular weight of 45kd)
6/9/2012
35
Actin Filaments
36
Part III
B. Troponins
~ Small globular units located at intervals along the tropomyosin molecules.
6/9/2012
37
38
Part III
6/9/2012
39
Part III
b. Contractile state: The invading action potential to T-Tubule Ca2+ released from SR binds to troponin C binding of troponin I to actin is weakened tropomyosin moves laterally uncovers binding sites for myosin heads contraction (in the presence of ATP).
Seven myosin-binding sites are uncovered for each molecule of troponin that binds a Ca2+.
6/9/2012
40
Part III
6/9/2012
41
Part III
3.5.2.2. Sarcoplasm Reticulum (SR) a. It is an internal tubular structure that runs between the myofibrils. b. It is closed at both ends. c. It is not continuous with the sarcolemma. d. Functions:
i. Stores Ca2+ in the terminal cisternae
(lateral sacs, 1calsequestrin = 43 Ca2+ )
Part III
6/9/2012
43
Part III
6/9/2012
44
Part III
Motor Unit
45
Motor Units
46
47
Neuromuscular Junction
48
Neuromuscular Junction
49
Neuromuscular Junction
50
Neuromuscular Junction
51
Part III
3.6.2. Events at the neuromuscular junction: 3.6.2.1. Presynaptic end (-motor neuron)
Opening of Ca2+ channels at the active zones Ca2+ permeability and entry of Ca2+ into -motor neuron axon terminals Release of Ach from the synaptic vesicles into the synaptic cleft
(200-300 vesicles/exocytosis)
6/9/2012 The Physiology of Muscles 52
Part III
3.6.2.2. Postsynaptic end Diffusion of Ach to Postjunctional membrane combination of Ach with nAchR (107-108, 2 subunit) on the motor endplate Conformational change opening of the gate permeability of the postjunctional membrane to Na+ and K+ Transient change in the Em depolarization EPP Depolarization of areas of muscle membrane adjacent to endplate and initiation of AP
6/9/2012 The Physiology of Muscles 53
Part III
Endplate Potential/EPP
i. A graded response (magnitude of depolarization No of open Ach channels ii. Transient (Ach is hydrolyzed to form choline and acetate). iii. Amplitude: 50mV iv. No voltage-gated Na+ and K+ channels at the endplate region ( No AP, Na+, K+ channels are located on the muscle membrane
contiguous to the endplate)
6/9/2012
54
Part III
v. Ionic basis of EPP: Ach activated channel Independent of membrane potential Em is between EK+ and ENa+ vi. EPP depolarizes the contiguous membrane regions by electronic conduction to threshold and AP is generated.
6/9/2012
55
56
Part III
3.6.3. Propagation of AP into the T-tubule & release of Ca2+ from the terminal cisternae A. Transverse Tubule (T-tubule) i. It is an invagination of the surface of the sarcolemma ii. It is found at the junction of A-I bands (at z-line in frog)
iii. One end of the tube is open to extracellular space, but its other end is closed.
iv. Function: rapid transmission of AP from the cell membrane to all the fibers on the muscle.
6/9/2012
57
58
Part III
B. Sarcoplasm Reticulum (SR) i. It is an internal tubular structure that runs between the myofibrils.
Part III
3.6.3.1. Release of Ca2+ from the Terminal Cisternae i. Voltage - gated Ca2+ channel (DHPR)
6/9/2012
60
Part III
ii. Ca2+- Release Channel (RyR) a. Found in sarcoplasm reticulum membrane. b. It is a tetramer. c. Sensitive for a drug called ryanodine. d. Malignant Hyperthermia Depolarization of the T-tubule Opening of DHPR - RyR Ca2+ channels (Connected by a foot process whose length is 20nm) Release of calcium Calcium flows out of the terminal cisternae into the sarcoplasm [Ca2+] : 0.1 10mol/l 61
62
Part III
3.6.4. The Activation of Muscle Proteins 3.6.4.1. Thick Filaments a. Myosin (an actin binding protein) b. 2 distinct structures: Myosin head (cross bridge): ATP binding site (ATPase): 3.6.4.2. Thin Filaments a. Actins actin-binding site hydrolyzes ATP
6/9/2012
63
Part III
6/9/2012
64
65
Myosin-actin complex
66
Part III
b. Troponins: Small globular units located at intervals along tropomyosin molecules. i. Troponin T: it binds other troponin components to tropomyosin ii. Troponin I: inhibits the interaction of myosin with actin iii. Troponin C: it has the binding site for Ca2+ that initiates contraction Tropomysoin i. A rod-shaped molecule stretched along each strand of thin filament. ii.1 tropomyosin molecule covers seven actin monomers
6/9/2012
67
68
69
Part III
Resting state i. Interaction of thick and thin filaments is inhibited ii. Troponin I & tropomyosin covers the sites where myosin heads bind to actin Activated States: Influx of Ca2+ Binds to Troponin C (4 Ca2+) Conformational change in troponin Tropomyosin moves aside Exposes the myosin-binding sites on actin Myosin cross-bridge on the thick filament is exposed to actin filaments
70
Part III
6/9/2012
71
72
73
Part III
NB a. Amount of Ca2+ released from the SR is proportional to Em (- 20mV is minimum) b. Caffeine enhance calcium release delay fatigue (2nd messenger c AMP) c. Agents or stimulants that decrease the threshold & prolong the duration of AP Ca2+ release from SR force of contraction (in heart muscle).
6/9/2012
74
Part III
6/9/2012
75
Part III
76
Part III
3.6.5. Generation of Tension Cross-bridge cycle: 4 steps 1. Binding of the cross-bridge to actin A+M* . ADP. Pi A.M* + ADP + Pi
Actin binding
2. Bending of the cross-bridge producing movement of thin filament. A. M*. ADP. Pi A.M*.+ ADP + Pi
Cross-bridge movement
3. Detachment of the cross-bridge from the thin filament A.M+ ATP A+ M.ATP
Cross-bridge dissociation from actin
4. The cross-bridge returns to its original upright position to repeat the cycle.
M.ATP
M*. ADP. Pi
77
78
79
80
81
82
83
Part III
3.6.6. Relaxation of Muscle. a. Removal of Ca2+ from the Myoplasm (<0.1mol/l) into the SR.
b. For Ca2+ removal from the sarcoplasm the third ATP is consumed by Ca2+-Mg2+ -ATPase
c. After removal of Ca2+ :
iii. Cross-bridge cycling stops and the muscle is returned to its resting state.
d. Breakdown of Ach by AchE.
6/9/2012 The Physiology of Muscles 84
Part III
Relaxation
86
Part III
Changes
a. Banding
6/9/2012
87
88
Part III
6/9/2012
89
Part III
iii. Voltage-gated Na + channel (contiguous to the motor endplate). iv. Voltage-gated Ca2+ channel (t-tubule) v. RyR Ca2+-release channel (SR)
6/9/2012
90
91
Part III
Summary Discharge of motor neuron Release of Ach at motor endplate Binding of Ach to nAchR gNa+ and gK + in endplate membrane Generation of EPP Generation of AP in muscle fibers
6/9/2012 The Physiology of Muscles 92
Part III
Generation of AP in muscle fibers Inward spread of depolarization along T-tubules Release of Ca2+ from terminal cisterns of SR and diffusion to thick and thin filaments Binding of Ca2+ to troponin C, uncovering myosin-binding sites on actin Formation of cross-linkages between actin and myosin and sliding of thin on thick filaments, producing movement
6/9/2012 The Physiology of Muscles 93
Part III
Steps in relaxation
Ca2+ pumped back into SR Release of Ca2+ from troponin Cessation of interaction between actin and Myosin
6/9/2012
94
Part III
Rigor Mortis a. It is a state of muscle contracture, ie., contraction produced without AP and not followed by relaxation. b. It is a contracture which occurs in the muscles after death. It starts in small muscles (2-3hrs) after death and involves all muscles in 12 hrs. c. The rigidity is due to depletion of ATP from the muscle. Calcium diffuses out of the SR & can not be recollected by the Calcium pump. d. Calcium initiates muscle contraction using the remaining ATP molecules, relaxation does not occur because calcium is not recollected back into the SR, and no ATP is available to disconnect the myosin heads from actin.
6/9/2012 The Physiology of Muscles 95
Part III
6/9/2012
96
Part III
a. The physiological basis of heart pumping (contracting of the heart) is to propel blood through the circulatory system.
b. It has SAME contractile machinery with some degree of modification.
(Actins, myosin, meromyosin, c-protein, nebulin, -actinin, tropomodulin)
c. REGULATION is done by intrinsic and extrinsic factors: neuronal (ANS) + hormonal. d. In the course of an average life span the heart will contract = 72 beats x 60 min x 24hrs x 365d x 70 years = 3x109 e. Abundance of connective tissue (prevent muscle rupture, prevent overstretching during periods of increased venous return).
6/9/2012 The Physiology of Muscles 97
Part III
2. Has abundant amount of mitochondria (30%) + myoglobin which makes it fatigue resistant (myoglobin facilitates the transport of oxygen from the sarcolemma to the mitochondria)
3. A cardiac cells are joined end-to-end by intercalated discs: i. Attach one cell to the next by means of desmosomes ii. Connect the thin filament of the myofibrils of adjacent cells.
(Mechanical + electrical coupling)
6/9/2012
98
99
Part III
6/9/2012
100
Part III
iii. Contain gap junctions which is synchronizing the contractions of heart muscle cells. 4. The T-tubule is larger and it is found at z-line 5. The SR - makes contact with T-tubule and the cell membrane.
6/9/2012
101
Part III
4.3. Excitation-Contraction Coupling/Electrochemical Coupling (Cardiac Vs Skeletal) 4.3.1. Cardiac Muscle. 1. Ca2+- release from the SR is triggered by Ca2+ (not by membrane Depolarizations). (Extracellular Ca2+ SR (is responsible for prolonged plateau phase). 2. T-Tubule (DHPR) contains Ca2+ channel (through which Ca2+ enters the cell during the AP).
3. SR-RyR containing Ca2+- release channel is opened by influx of Ca2+ from the T-Tubule.
6/9/2012
102
103
104
Part III
4. Amount of Ca2+- release from the SR in under physiologic control. a. Hormones (catecholamines) the amount of Ca2+ entering the cell IC Ca2+ b. Pump (Na+-Ca2+ Exchanger, 1Ca2+, 3Na+) is increasing the Ca2+ in the cell. Clinical correlates
Familial cardiomyopathic hypertrophy Hypertrophy
6/9/2012
105
106
107
Part III
5.0. SMOOTH MUSCLE 5.1. Introduction a. It is important in regulation of the airways, blood vessels, GIT, and hollow organs (bladder, uterus...) b. It is controlled by intrinsic factors (inherent rhythmicity): ANS + HORMONES. c. It produces slower and longer-lasting contractions (slow and sustained) (rates of cross-bridge cycling LATCH STATE maintain TONE and little energy consumed)
6/9/2012
108
Part III
109
110
Part III
5.2. Smooth Muscle Vs Striated Muscle. 5.2.1. Smooth Muscle. 1. It has NO STRIATIONS (sparse thick filaments and absence of transverse registration). 2. Has elongated spindle shaped cells with a single nucleus (L = variable size, attached in series to bear equal stress). 3. Sarcomeres are absent.
6/9/2012
111
Part III
6/9/2012
112
Part III
5.3. Excitation - Contraction Coupling (Smooth M.Vs Striated M.) Cross-bridge cycling is regulated by Ca2+- induced phosphorylation of myosin. 1. Myosin cross-bridge has 4 light chain 2. Myosin can not bind to actin unless one of these light chains (LC20) is phosphorylated.
6/9/2012
113
Part III
a. Phosphorylation of LC20 is by Myosin Light Chain Kinase (activated by Calmodulin, 4Ca2+, Kinase - calmodulin - Ca2+- complex)
b. Ca2+ can enter the cell in a variety of ways:
6/9/2012
114
Part III
115
116
117
118
119
120
121
122
123
Summary ECC smooth muscle Binding of Ach to mAchR Increased Ca2+ influx into the cell Activation of calmodulin-dependent myosin light chain kinase Phosphorylation of myosin Increased myosin ATPase activity and binding of myosin to actin Contraction Dephosphorylation of myosin by myosin light chain phosphatase Relaxation, or sustained contraction due to the latch bridge and other mechanisms 124