7.the physiology of muscle
TRANSCRIPT
The Physiology of Muscles
Part III
April, 2010
Objectives:
Know the major classes of muscles of the body.
Describe the molecular basis of muscle contraction.
Differentiate the roles of Ca2+ in skeletal, cardiac + smooth muscles.
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1. Introduction
1.1. General Points
a. Can be excited chemically, electrically + mechanically.
b. Contractile mechanisms (actin + myosin) that can be activated by AP.
1.2. Mass
a. 45-50% of the total body mass ( 600 muscles)
b. 40% skeletal muscles + 10% cardiac and smooth muscles (45-
50%).
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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.
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Classification
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2.1.1.1. Skeletal muscle
i. Have well developed cross striations (interdigitating thick and thin filaments).
ii. Voluntary muscle tissue.
iii. Cells are long and multinucleated.
iv. Contract only in response to stimuli (no syncytial bridges between cells).
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2.1.1.2. Cardiac muscle
i. Have cross striation (banding pattern of thick and thin filaments).
ii. Involuntary muscle tissue.
iii. Cells are branched and mononucleated.
iv. Have intercalated disc with gap junctions.
2.1.2. Non-striations/Smooth Muscle
Alternating dark and light bands are absent.
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2.1.2.1. Single unit smooth muscle (Visceral smooth muscle)
i. Are large sheets of mononucleated small cells.
ii. Have low resistance bridge of gap junctions.
iii. Show synchronous excitation and contractions. (= functional syncytium)
iv. Have unstable resting membrane potential.
v. Found in gut, ureter, small blood vessels and uterus.
2.1.2.2. Multiunit smooth muscles
i. Found in iris, lungs, hair roots and large arteries.
ii. Have no gap junctions but each cell receive ANS nerve terminal.
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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)
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3.0. Skeletal Muscle
• Interactions between the body and the external environment (maintenance of posture and movement, speech, respiration…).
3.1. Physiological classifications
3.1.1. Type I: Slow twitch oxidative fibers (red muscle)
i. Have slow myosin ATPase activity.
ii. High myoglobin content
iii. Many mitochondria and capillary
iv. Resistant to fatigue, high oxidative capacity
v. Muscles of the back and neck (strong gross sustained movt.)
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3.1.2. Type IIA: Fast oxidative-glycolytic fibers (red fibers)
i. Fast myosin ATPase activity
ii. Fatigable fibers
iii. Use glycolytic and oxidative ATP sources
3.1.3. Type IIB: Fast glycolytic fibers (white muscles)
i. Fast velocity of contraction
ii. Fast myosin ATPase activity
iii. Glycolysis is the main ATP source
iv. Few myoglobin, mitochondria and blood vessels are present.
v. Muscles of the hand extraocular muscles (fine, rapid, precise movt.)
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Structural arrangement and contractile unit
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3.2. Structural arrangement and contractile unit
Muscle ↓ epimysiumFasciculus (20 muscle fibers) ↓ perimysiumMuscle fiber (ɵ=10-100 µm, L=30cm, multinucleated) ↓ endomysium (Sarcolemma, sarcoplasm/myoplasm Sarcoplasm reticulumMyofibril (ɵ= 1-2µm, longitudinal, Sarcomere, 75% muscle vol., Z-line, α-actinin, desmin)
Myofilaments
Thick filaments Thin filaments
1500 molecules, myosin 3000 molecules, actin
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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. α-actinin: a protein that connects actin to the z-line.
7. Myoplasm/sarcoplsam: cytoplasm of the muscle cell.
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8. Desmin: a protein that links adjacent myofibrils, binding z lines to plm
9. Myosin: the thick contractile protein.
10. Actin: the thin contractile protein.
11. Dystropin: actin binding protein linking transmembrane protein, β-dystroglycan, in the sarcolemma with cytoplasmic protein syntrophins (α-dystroglycan, (sarcoglycan, α, β, γ, δ))
12. Titin: tethers myosin to z lines, serves as a scaffold for sarcomere. (prevents overstretching of sarcomere, ?cell signaling? Stretch sensor, Titinopathies)
13. Nebulin: a template protein which determines the precise size of actin
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Dystrophin-glycoprotein complex
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Dystrophin-glycoprotein complexMuscular dystrophies
• Duchenne muscular dystrophy • Becker Muscular dystrophy• Limb-girdle muscle dystrophy
Metabolic myopathies• McArdle syndrome
Ion channel myopathiesMany…types…
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3.3. Functional unit (Sarcomere)
a. It is the distance between two z-lines.
b. Responsible for the striated appearance.
3.3.1. Dimensions
a. The resting length of a sarcomere is 2µm-2.2µm.
b. At this length it generates the greatest force of contraction.
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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.
c. Thin filaments may extend into the A-band.
H-Band (H = Hensen’s disc, ?Hell?)
a. It contains only myosin tails (no myosin heads/no cross-bridges)
b. There are no thin filaments.
c. When the muscle is relaxed * Germanic words The Physiology of Muscles
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M-line (M= Mittelmembran)
a. Site of the reversal polarity of the myosin molecules in each of the thick filaments.
b. It vertically bisects the H-Band
c. It contains 2 important proteins:
• Myomesin: a structural protein that links neighboring thick filaments
• Creatinine Phosphokinase: an enzyme that maintains adequate ATP conc. in working muscle
fibers.
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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.
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NB
1. During muscular contraction:
a. There is NO CHANGE in length of either the thick or the thin filaments.
b. H-zone disappears and Z-line gets considerably darker.
c. There is shortening of the sarcomere (↓ I-band and H zone, and A-band remains κ)
2. a. When a muscle increases its length → ↑ in the No of sarcomeres(NOT the length of each sarcomere)
b. The length of thick & thin filaments of sarcomeres is identical in a neonate & in the adult muscle.
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3.4. Molecular Basis of Contraction
3.4.1. Sliding-Filament Model (Hanson & Huxley, 1955)
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.
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3.4.2 Thick Filament
a. It is called myosin (an actin-binding protein).b. Dimensions: ɵ = 11-18 nm, L = 1.6 µmc. Composition of Myosin:
2 heavy chains = 200,000 x 2 = 400kd4 light chains = 20,000 x 4 = 80kd
480kd
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
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Myosin Filament
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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 5µm/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.
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Geometrical orientation of myosin and actin
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Geometrical orientation of myosin and actin
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3.4.3. Thin Filaments
a. They are called actins.b. Dimensions : ɵ = 5nm, L = 1 µmc. Components :
1. Globular proteins
i. Actin (300-400 molecules, and molecular weight of 45kd)
Globular -Actin (G-actin) or
Fibrillar- Actin (F-actin, a polymer of G-actins)
ii. Troponin (50 molecules)
2. Non-Globular proteins: tropomyosin (40-60 molecules, 70kD)
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Actin Filaments
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3.4.4 Regulatory proteins
A. Tropomyosin
a. A rod-shaped molecule stretched along each strand of thin filament.
b. 1 tropomyosin molecule covers seven actin monomers in an actin filament.
c. It blocks the binding sites of myosin on actin.
B. Troponins
~ Small globular units located at intervals along the tropomyosin molecules.
a. Troponin T: it binds other troponin components to tropomyosin (37kD).
b. Troponin I: inhibits the interaction of myosin with actin (24kD)
c. Troponin C: it has the binding site for Ca2+ that initiates contraction (18kD)
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3.5. Molecular mechanisms of regulating muscle contraction 3.5.1. Regulatory Role of Troponin-Tropomyosin System a. Resting state: Troponin I and Tropomyosin covers the sites where myosin heads bind to actin. (At rest: interaction of thick and thin filaments is inhibited).
• Troponin-Tropomyosin complex is called “Relaxing-Protein” because it inhibits the interaction between myosin and actin.
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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+.
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3.5.2. Regulatory action of calcium
2 tubular networks (Sarcotubular system) that are involved with Ca2+:
3.5.2.1. Transverse Tubule (T-tube)
a. It is an invagination of the surface of the muscle membrane (sarcolemma).
b. It is found at the junction of A-band and I-band (at z-line in frog).
c. One end of the tube is open to the extracellular space, but its other end is closed.
d. Function: Rapid transmission of the action potential from the cell membrane to all the fibers on the muscle.
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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+ )
ii. Uptake and release of Ca2+
• Calsequestrin is sarcoplasmic protein that binds Calcium.
• Triad: 2 lateral sacs + 1 transverse tubule
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3.5.3. Regulation of ATP
a. Actin + myosin + ATP + Ca2+ → CONRACTION
b. Actin + myosin + ATP - Ca2+ → RELAXATION
c. ATP is needed for relaxation
d. In the absence of Ca2+ ATP is not hydrolyzed.
e. 3 ATP molecules are needed:
i. For the formation of the actinmyosin complex
ii. For the initiation of relaxation.
iii. To pump out Ca2+ from the sarcoplasm to sequester it into the SR (Ca2+ - Mg2+ pump)
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3.6.1. Excitation-Contraction Coupling/ Electromechanical Coupling
Def. ~ is the process of linking ∆Em/AP to muscle contraction.
• Electrical events precedes mechanical events (2ms, 100ms)
• Twitch
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Motor Unit
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Motor Units
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Motor Unit and NMJ
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Neuromuscular Junction
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AP in presynaptic α-motor neuron terminals
Depolarization of plasma membrane of the presynaptic α-motor neuron axon terminals[Δ 30mV]
Opening of Ca2+ channels at the active zones →↑Ca2+ permeability and entry of Ca2+ into α-motor neuron axon terminals
Release of Ach from the synaptic vesicles into the synaptic cleft(200-300 vesicles/exocytosis)
3.6.2. Events at the neuromuscular junction:
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3.6.2.2. Postsynaptic end
Diffusion of Ach to Postjunctional membrane → combination of Ach with nAchR (107-108, 2α 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
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Endplate Potential/EPP
i. A graded response (magnitude of depolarization α 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)
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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.
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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.
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B. Sarcoplasm Reticulum (SR)
i. It is an internal tubular structure that runs between the myofibrils.
ii. It is closed at both ends.
iii. It is not continuous with the sarcolemma.
iv. Functions:
• Stores Ca2+ in the terminal cisternae (lateral sacs)
• Uptake and release of Ca2+
NB
• Calsequestrin is sarcoplasmic protein that binds Ca2+
(1 calsequestrin = 43 Ca2+ )• Triad: 2 lateral sacs + 1 transverse tubule
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3.6.3.1. Release of Ca2+ from the Terminal Cisternae
i. Voltage - gated Ca2+ channel (DHPR)
a. Found in the transverse tubule.
b. It is a pentamer (α1,α2, β, γ, δ)
c. Voltage sensor which is responsible for triggering Ca2+ release from the SR and for EC coupling.
d. Sensitive to a drug called Dihydroperidine which can block this voltage-gated channels.
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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 → 10µmol/l
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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): actin-binding site
• ATP binding site (ATPase): hydrolyzes ATP
3.6.4.2. Thin Filaments
a. Actins
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Myosin and actin
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Myosin-actin complex
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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
iii. It blocks the binding sites of myosin on actin.
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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
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DHPR and RyR Calcium channels
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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).
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3.6.5. Generation of Tension
Cross-bridge cycle: 4 steps
1.Binding of the cross-bridge to actinA+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 filamentA.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 ATP hydrolysis
NB. Tension is generated by repetitive cross-bridge cycling.
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3.6.6. Relaxation of Muscle. a.Removal of Ca2+ from the Myoplasm (<0.1µmol/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+ :
i. Troponin returns to its original conformational state.
ii. Tropomyosin inhibition of Myosin-Actin interaction is restored.
iii. Cross-bridge cycling stops and the muscle is returned to its resting state.
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Regulatory function of ATP
i.Actin + Myosin +ATP + Ca2+ Contraction
ii.Actin+ Myosin + ATP – Ca2+ Relaxation
iii.In the absence of Ca2+ ATP is not hydrolyzed.
iv.3 ATP molecules are needed:
a. For energizing the myosin cross-bridges
b. For dissociation of actinmyosin complex and initiation of relaxation
c. To pump out Ca2+ from the sacroplasm to sequester it into the SR (Ca2+-Mg2+ - pump)
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Changes
a.Banding
• H-zone: Disappears• Z-line: Gets considerably darker• I-band: Narrower/smaller• A-band: κ
b. Contractile proteins: NO CHANGE in length of myosin or actin
c. Sarcomere: Shortens
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Changes in banding pattern
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Changes in banding pattern
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Ion channels involved:
i.Voltage-gated Ca2+ channels (active zone, α-motor neuron)
ii. Ligand-gated cationic channels (Ligand-gated Na+ channels, motor endplate)
iii. Voltage-gated Na + channel (contiguous to the motor endplate).
iv. Voltage-gated Ca2+ channel (t-tubule)
v. RyR Ca2+-release channel (SR)
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SummaryDischarge 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
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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
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Steps in relaxation
Ca2+ pumped back into SR↓
Release of Ca2+ from troponin↓
Cessation of interaction between actin and Myosin
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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.
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e. It disappears when muscle fibers are autolysed by lysosomal enzymes released after death.
f. It starts to disappear 14hrs after death and completed in 24hrs. High environmental temperature accelerates the appearance and disappearance of rigor mortis.
g. The extent of rigor mortis is used medically to determine the time of death.
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4.0. CARDIAC MUSCLE 4.1. Introduction
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, α-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 over- stretching during periods of increased venous return).
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4.2. Cardiac Muscle Vs Skeletal Muscle
4.2.1. Cardiac Muscle.
1.A cardiac myocyte has a single nucleus which is smaller (ɵ = 15-20 µm, L = 100µm)
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 desmosomesii. Connect the thin filament of the myofibrils of adjacent cells.
(Mechanical + electrical coupling)
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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.
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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.
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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
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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)
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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.
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4. The myofilaments are :
a. Thick filaments: myosin
b. Thin filaments: actin and tropomyosin (No troponin)
c. Thick and thin filaments are dispersed through out the cell. They are not arranged in strictly ordered pattern.
d. Thin filaments are attached to dense bodies (functional equivalents of Z)
i. DENSE BODIES: are found in cell membrane and cytoplasm composed of -actinin.
5. Tubules: T-tubules are absent and the SR is rudimentary
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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.
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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:
i. Stimulation by a neurotransmitter (receptor-activated Ca2+ channel)
ii. Voltage-operated Ca2+channels
iii. Release from SR(SR-IP3R) (IP3R = inositol triphosphate receptors)
3. The light chains are dephosphorylated by the enzyme Myosin Light Chain Phosphorylase.
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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