Muscle tetanus

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Chapter 9 Muscle

1. Three classes of muscle tissues (Fig.9.1, muscle tissues)
     (1) Skeletal muscle
          Striated voluntary muscle
          Multinucleated cells
          Attached to bones
          Contraction through neural impulse
          Posture, support and movement of bones
     (2) Cardiac muscle
          Striated involuntary muscle
          Contraction through autonomic nervous system, pacemaker cells, and hormones
     (3) Smooth muscle
          Non-striated involuntary muscle
          Surrounds various hollow organs and tracts
          Contraction through autonomic nervous system and hormones

2. Skeletal muscle
   1) Functions of skeletal muscle
      (1) Produce movement
      (2) Maintain posture and body position
      (3) Support soft tissues
      (4) Guard entrances and exits
      (5) Maintain body temperature
   2) Structure (muscle structure)
      (1) Three layers of connective tissue
         (a) Epimysium
              Layer of collagen fibers
              Separate muscle from surroundings
         (b) Perimysium
              Layer of collagen and elastic fibers
              Has nerve and blood vessels
              Surround each fascicle (bundle of muscle fibers) -10-100 muscle fibers
         (c) Endomysium
              Layer of collagen and elastic fibers (loose connective tissue)
              Surround muscle fibers (above sarcolemma)
              Ties adjacent muscle fibers
              Has satellite cells (stem cells)
      (2) Tendon
            Bands of connective tissue (dense regular connective tissue)
            All three membranes are fused into tendon
            Attached to the bone (periosteum)
      (3) Sarcolemma (Muscle fiber)
            Cell membrane of muscle fiber
      (4) Sarcoplasm of skeletal muscle fiber

         Contains nuclei, enzymes, myofibrils, mitochondria, sarcoplasmic reticulum
   (5) Sarcoplasmic reticulum (Fig.9.11a,b)
         Endoplasmic reticulum in muscle fibers
         Encircles myofibrils –one unit is called 'cisterna'
         Cisterna contains high Ca++; low Ca++ in sarcoplasm
   (6) Transverse tubules (T tubules)
         Begin at the sarcolemma and extend into the sarcoplasm (no opening to sarcoplasm)
         Encircles between cisternae
         Contains extracellular fluid
         Running transversely to the muscle fibers
         Coordinate contraction of muscle fibers
         Electrical message travels through T tubules, and reaches myofibrils
   (7) Myofibrils
         Bundles of myofilaments
         Cylinder of 1-2mm in diameter
         Responsible for contraction of muscle fibers
         Attached to sarcolemma at the ends
         Energy for the contraction from mitochondria and glycogen granules
   (8) Myofilaments (myofilament)
         Protein filaments
         Composed of actin (thin filament) and myosin (thick filament)
         Basic components of muscle contraction
   (9) Sarcomere
         The smallest functional unit of muscle fiber –2.6mm
         Arrangement of actin and myosin filaments- banded appearance
            - Source of striation of muscular tissue
         Interactions between the thick and thin filaments of saromeres are responsible
             for muscle contraction
         Each myofibril contains about 10,000 sarcomeres
3) Sarcomere organization (Fig.9.2; Fig.9.3; Fig.9.4)
      - Arrangement of myofilaments
            Actin : Myosin = 2:1
            6 actin around 1 myosin (hexagonal)
            3 myosin around 1 actin (triangular)
      (1) Z line
            Actin filaments at either end bound to interconnecting proteins
            Boundary of each sarcomere
      (2) Zone of overlap
            Actin filaments passing through myosin filaments –overlapped area
      (3) M line
            Center of H zone
            Proteins that connect central portion of each myosin filaments
      (4) A band (dark area)
            Whole length of myosin filaments
            Actin filaments are partially present
            Includes H zone

         (5) I band (light area)
               Area between two A bands
               Only actin filaments are present
         (6) H Zone
               Myosin filaments only zone -without actin filaments
         (7) Actin filaments (light chains) (actin filaments)
               Twisted two strands of actin molecules (globular polypeptide chain)
               Actin molecules have active sites which interact with myosin
               Active sites are covered by tropomyosin at resting stage
               Troponin molecules are bond by tropomyosin and actin filaments
         (8) Myosin filaments (heavy chains) (Fig.9-7)
               Myosin molecule is composed of two large polypeptide heavy chains
                  and four smaller light chains.
               One myosin filament is composed with 2 heads (contains both heavy
                  and light chain) and one tail (contains two heavy chains)
               Heads are extended to the outside forming “cross-bridge”
               Each head has two binding sites (one for actin and the other for ATP)
               Myosin heads interact with actin molecules during contraction
4. Molecular mechanisms of contraction
         -Sliding-filament mechanism (Fig.9.5, sarcomere
            By contraction, H zone disappear, I band narrower, and Z line getting closer
   1) Control of muscle fiber contraction
            Neuromuscular junction
            Each skeletal muscle fiber is controlled by a motor neuron at a single
                  neuromuscular junction
      (1) Motor unit (Fig.9.13)
            Definition: One motor neuron and its connected muscle fibers
            Smaller is more sensitive and fine control
            Larger motor unit provide greater power
            2-3 motor units in eye lid muscle vs. 1000 motor units in calf muscle
      (2) Synaptic knob
            Ends of axon or branch of axon
            Embraces sarcolemma
            Cytoplasm contains mitochondria and synaptic vesicles (contains
      (3) Synaptic cleft
            A narrow space between synaptic knob and sarcolemma
            Contains acetylcholinesterase, which breaks ACh
      (4) Motor end plate
            Membrane (sarcolemma) where ACh receptors are present
   2) Process of muscle contraction (Fig.9.15, Table 9.2)
      A. Transfer of action potential
         (1) Arrival of action potential
         (2) Influx of Ca++
                Ca++ would travel into synaptic terminal through voltage-gated

            Ca++ allows Ach containing vesicles to move down to synaptic
                    terminal membrane (presynaptic membrane)
      (3) Release of Ach into synaptic cleft
      (4) The binding of Acetycholine (ACh) at the motor end plate (postsynaptic
           ACh binds to receptors on sarcolemma, then changes membrane
                 permeability to Na+
           Degradation of ACh by acetylcholinesterase into acetic acid and choline
           Influx of Na+ into sarcolemma creates action potential
      (5) The conduction of action potentials through sarcolemma
   B. Contraction and relaxation of skeletal muscle fiber (Fig. 9.12)
      (1) Action potentials spread over sarcolemma, T-tubules, cisternae
      (2) Action potential triggers sudden, massive release of Ca++ from
              cisternae (lateral sac)
      (3) Ca binds to troponin (troponin)
            Ca++ binding to troponin leads tropomyosin to slide
            Tropomyosin reveals myosin-binding site (active site) of actin
      (4) cross-bridge binds to myosin filament
            Contraction of filaments through cross-bridge movement
      (5) Ca++ removal into sarcoplasmic reticulum by active transportation
            (Ca++-ATPase activity)
      (6) Repositioning of tropomyosin after loosing Ca++
            Conceals active sites
      (7) Relaxes muscle filaments
   C. Cross-bridge cycle (Fig. 9.8)
      (1) Under the presence of Ca++, energized myosin heads (ADP+P) bind
              to actin filament
      (2) Heads move toward the center of sarcomere, and release ADP
              -Muscle contraction
      (3) Binding of ATP to myosin heads leads to detachment of
      (4) Hydrolysis of ATP to ADP+P energizes myosin head
           -Separates myosin head from actin
           -Ready for next cycle
   D. Conclusion of muscle contraction process (muscle,,
3) Components on muscle contraction (Fig.9.9)
   (1) ATP (Table 9.1)
         A) Energize myosin head (ADP+P on myosin head)
              ATP is allosteric modulator of myosin head
                 -Binding of ATP to myosin head weakens cross-bridge
                       binding to actin
                 -Change the affinity
              ATP to ADP+P at the myosin head by myosin ATPase
                 -Needed to bind to active site of actin filament
         B) Reabsorption of Ca++ into sarcoplasmic reticulum is active transport
         C) Binding of ATP to the myosin head disconnects corss-bridge

      (2) Calcium
            Mostly contained in sarcoplasmic reticulum
            Released by impulse from T-tubule
            Sarcoplasmic Ca++ concentration is 10-7
              -Need to be 10-6 for muscle contraction
      (3) Sliding of myosin filaments during muscle contraction
            Lead to the changes in microstructure of muscle
      (4) Time line of action potential and muscle contraction (Fig. 9.10)
            Latent period
              - Period from stimulation to muscle contraction
              - Represents time of impulse travel to sarcoplasmic reticulum
              - About 10msec.
            Muscle fiber contraction and relaxation take about 100msec
5. Disruption of neuromuscular signaling
   (1) Preoccupation of neurotransmitter’s receptor
           Ex) Curare: Inhibits muscle contraction (*asphyxiation)
   (2) Inhibition of acetylcholinesterase activity
           Ex) Nerve gases
   (3) Inhibition of neurotransmitter release from vesicle
           Ex) Botulism
6. Mechanics of single fiber contraction
   1) Tension vs. load
        Tension: Force exerted on an object by a contracting muscle
        Load: Force exerted on the muscle by an object (weight)
        Isotonic contraction:
              Muscle length shortened while tension is applied
        Isometric contraction:
              Muscle tension does not cause muscle shortening
              Pushing wall, holding weight
   2) Twitch
           Single muscular contraction and relaxation upon single stimulus
       A. Isometric twitch (Fig. 9.16a)
            Latent period: Time between arrival of action potential and start of
            Contraction time: Time from start of tension to peak of tension
            Ca++-ATPase activity in sarcoplasmic reticulum has the major role on
                    fast twitch muscle
               -7.5msec. in eye muscle, 100msec. in calf muscle fibers
       B. Isotonic twitch (Fig. 9.16b)
            Compare to isometric,
                 Longer latent period
                 Shorter duration time
            Characteristics (Fig. 9.17)
                Heavier load produces….
                 (1) Longer latent period
                 (2) Velocity of shortening is slower

                 (3) Shorter duration
                 (4) Slower contraction
                 (5) Shorter distance
   3) Load-Velocity relation (Fig. 9.18)
        Load = Tension : Isometric tension
        Load > Tension: Isotonic lengthening, heavier gets higher velocity
        Load < Tension: Isotonic shortening, lighter gets higher velocity
   4) Frequency-Tension relation
        A. Summation (Fig.9.19)
              Second twitch rides piggyback on the first twitch
        B. Tetanus (Fig.9.20)
                 Sustained muscular contraction by repetitive stimulation
             (1) Incomplete tetanus (Unfused T.)
                    Gradual increase of contraction by increasing stimulation frequency
             (2) Complete tetanus (Fused T.)
                    Smooth sustained contraction
   5) Length-Tension relation (Fig.9.21)
         Maximum isometric tension on optimal length (Io)
         Less than 60% or more than 175% of optimal length cause no active
              tension from stimulus
          (i) Overlap of actin filaments
          (ii) Collision between Z line and myosin head
          (iii) No contact between myosin heads and actin filaments
7. Skeletal muscle energy metabolism
   1) Sources of ATP production (Fig.9.22)
      A) Glycolysis (active muscle)
          Major role on intensive muscle contraction
          Continued ATP production after using other sources
          Small amount of ATP produced
          Anaerobic metabolism produces lactic acids
      B) Oxidative phosphorylation (moderate muscle)
          Major role on moderate muscular activities
          Large amount of ATP produced
          Takes time to produce ATP
          Blood glucose and fatty acid are major sources
      C) Creatine phosphate (CP) (resting muscle)
          5 times higher than ATP during resting period
          Rapid source of ATP production under lack of ATP
          CP + ADP --- C + ATP
          Small amount of ATP would be provided
   2) Oxygen debt
       Demand on oxygen after aggressive exercise due to increased oxidative
          phospholyration to produce ATP, creatine phosphate, and glycogen to normal level
        *ATP level is not extremely low (to prevent rigor complex formation)
   3) Muscle fatigue (Fig.9.23)
       Decline in muscle tension as a result of prior contraction.

      A. Muscle fatigue depends on,
        (1) Type of skeletal muscle fiber
        (2) Intensity and duration of contraction
        (3) Degree of muscular development
      B. Mechanisms involved in muscle fatigue
        (1) Conduction failure
             Due to increased K+ level at T-tubule
             Inactivation of Na+ channels
        (2) Lactic acid buildup
             Alters protein conformation including actin and myosin
        (3) Inhibition of cross-bridge cycling
             Increased ADP and P concentration hinders detachment from cross-bridge
        (4) Central command fatigue
             Not directly related with mechanical muscular fatigue
             Failure in cerebral cortex -lack of 'will to win'
8. Types of skeletal muscle fibers
   1) Fast vs. slow fibers
         Determined by ATPase activity on myosin head
           -4 times faster on fast fibers
          Produce same tension during contraction
          Fast muscle fibers are dominant in eye lids and hands
          Slow muscle fibers are dominant in back and calf muscle
   2) Oxidative vs. glycolytic fibers (red muscle fibers)
       A) Oxidative fibers/ Red muscle fibers
            High population of mitochondria and myoglobin
              *Myoglobin has one polypeptide chain with one iron molecule
            Surrounded by dense blood capillaries
            Small diameter
       B) Glycolytic fibers/ White muscle fibers
            Large glycogen storage
            Large diameter
            High glycolytic enzymes
   3) Types of skeletal muscle fibers (Fig.9.25, Table 9.3)
       A) Slow-oxidative fibers: Type I
            Low ATPase activity, high oxidative capacity
            For long term endurance
       B) Fast-oxidative fibers: Type IIa, Intermediate fiber
            High in both ATPase activity and oxidative capacity
       C) Fast-glycolytic fibers: Type IIb
            High in both ATPase activity and glycolytic capacity
            Recruited for intensive contraction
            Fatigue rapidly
       *No slow glycolytic fibers
9. Whole muscle contraction
   1) Control of muscle tension
      A. Factors determining muscle tension

       (1) Tension developed by each fiber (Table 9.4)
              Action potential frequency
              Fiber length
              Fiber diameter
       (2) Number of active fiber (Fig.9.13)
              Number of fibers per motor unit
              Number of active motor units
       (3) All things considered (Fig. 9.26)
  2) Control of shortening velocity
       Determining factors
          (1) Type/size of motor units
          (2) Load on the muscle
          (3) Type of muscle fibers
  3) Muscle adaptation to exercise
     A. Anaerobic endurance
          Ability to support sustained, powerful muscle contractions through anaerobic
          Performed by fast muscle fiber
          Examples: Short distance dash, swim, and weight- lifting
          Training: Frequent, brief, intensive workouts
          Effects: Enlargement (hypertrophy) of stimulated glycolytic muscle fibers
     B. Aerobic endurance
          Ability to contract for a lengthy period of time by getting energy from
            mitochondrial activity
          Muscle contraction can continue for an extended period
          Glucose is an energy source
          Increase in mitochondria and blood vessels
          Examples: Jogging, distance swimming, and marathon
          Training: sustained low levels of muscular activity
          Effects: Increase in oxidative muscle fibers
     C. Atrophy
          Decrease in muscle mass
          Denervation atrophy
          Disuse atrophy
     D. Hypertrophy
          Enlargement of fibers rather than increase in number of fibers
10. Skeletal muscle diseases
  1) Muscle cramps
        Involuntary tetanic contraction of skeletal muscles
        Electrolyte imbalance from dehydration
  2) Hypocalcemic tetany
        Decreased Ca++ level in extracellular fluid opens Na+ channels
        Increased muscle contraction from spontaneous action potential propagation
  3) Muscular dystrophy
        Progressive degeneration of skeletal and cardiac muscle fibers

       Dystrophin is responsible -membrane protein
           The gene for dystrophin is huge, containing 79 exons spread out over 2.3 million base
              pairs of DNA
           This single gene represents about 0.1% of the entire human genome (3 x 109 bp) and
              is almost half the size of the entire genome of E. coli
           Mutation affects structural integrity of plasma membrane
     (1) Duchenne muscular dystrophy (DMD) (Fig.9.31)
           X-linked recessive disorder
           No dystrophin is synthesized and DMD
     (2) Becker muscular dystrophy (BMD).
           Part of the peptide chain is removed
           Milder than DMD
  4) Myasthenia Gravis
      Muscle fatigue and weakness
      Decrease of Ach receptors -Shows about 20% of receptors from normal junction
      Chronic autoimmune disease -Produces autoantibody targeting receptors
      Experimental animals injected with serum from human patients develop the signs of
         myasthenia gravis
      Newborns of mothers with myasthenia gravis often show mild signs of the disease for a
         short time after their birth

Section B. Smooth Muscle
1. Structure (Fig.9.32,33)
     Muscle fibers are smaller than skeletal muscle fibers
     Spindle shaped cells
     Actin : myosin = 10:1
     No troponin or tropomyosin on actin filaments
     Organized diagonally to long axis
     Actin filaments bind to dense body (Z line in skeletal muscle)
     Myosin filaments are stacked vertically -"stretchy"
2. Contraction
   1) Characters of smooth muscle contraction
      (1) Slow and sustained contraction
              -Myosin ATPase in smooth muscle fibers is slow in action
              -Enters a 'latch state': Provides longer contraction period
      (2) Requires less energy
      (3) Greater forces over longer periods of time
      (4) Contraction can be maintained in low intracellular Ca++
   2) Contraction process (Fig.9.34,35)
      (1) Ca++ influx from extracellular fluid
      (2) Ca++ activates calmodulin
      (3) Activated calmodulin activates myosin light-chain kinase (MLCK)
      (4) Activated MLCK phosphrylates myosin light chain by using ATP on myosin heads
      (5) Phosphorylated myosin heads (ADP + P) bind to actin filaments
      (6) Contraction of muscle
      (7) Myosin light chain phosphatase (MLCP) inactivates myosin heads

      (8) Dissociation of myosin-actin bond by ATP binding
   3) Relaxation of smooth muscle
         -Associated with low intracellular calcium level
      (1) 3Na+/Ca++ exchanger
      (2) Sarcolemmal Ca++ -ATPase
      (3) Reuptake by the sarcoplasmic reticulum
3. Sources of cytosolic Ca++
   1) Extracellular Ca++
         Voltage-gated channels
         10,000 times higher than cytoplasm
   2) Sarcoplasmic reticulum
         Near to sarcolemma: Respond to membrane action potential directly
         Farther to sarcolemma: Respond to signals from membrane receptors through
4. Membrane activation (Table 9.5)
   1) Activation inputs
       (1) Spontaneous action potentials
            Action potential production in absence of stimuli
            Pacemaker potential (Fig.9.36)
            Heart and intestine
       (2) Neurotransmitters from autonomic neuron (Fig.9.37,38)
            No motor end-plate region
            Postganglionic autonomic neuron branches making axon varicosities
            One muscle fiber with several neuronal influences
            Same neurotransmitter may exert different actions based on receptor character
                (Example) Norepinephrine
                       On alpha-adrenergic receptor: vascular constriction
                       Beta-2-adrenergic receptor: relaxation of bronchiole
       (3) Hormones
            Oxytocin: contraction of myoepithelial cells in breast
         *Hormonal Modification of Smooth Muscle
            (i) High progesterone (pregnancy) reduce the number of gap junctions
                  - Behave like multiunit smooth muscle (relatively quiescent)
            (ii) High estrogen (term) causes smooth muscle hypertrophy and increases gap junctions
                  - Behave as a single unit smooth muscle
       (4) Local factors
            Paracrine agents
                  Nitric oxide (NO): muscle relaxation
            Oxygen concentration
            Osmolarity/ ionic concentration
       (5) Stretch
            Mechanosensitive ion channels

     5. Types of smooth muscle

                               Single unit                              Multiunit
                  Whole muscle responds to            Each fiber responds independently of its
General Character
                  stimulation as a single unit        neighbors
                  Small intestine, colon, uterus,     Ciliary muscle, iris muscles, bronchial
Organs            urinary bladder, ureters, lymph     muscle, tracheal muscle, vas deferens, and
                  vessels, and smaller arterioles     GI sphincters, and larger blood vessels
Gap junction & Many gap junctions, innervation
                                                      Less gap junctions, higher innervation
innervation       sparse
Depolarization    Slow Wave Potentials, rhythmical    Stable
Effect            Plasticity: relaxation              Tone: blood vessels and GI sphincters
                  Pace maker cells, nerve, hormone,   Nerve (autonomic nerve system) and
                  paracrine agents, stretch           hormones

     *Characteristics of muscle fibers (Table 9.6)

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Description: Muscle tetanus