Extremely Rapid Muscle Contractions Usually D - DOC

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					                                    Cell and Tissue Biology
                                            Muscle

H. Wayne Lambert, Ph.D.                                                    January 26, 2004


Ross et al.: Histology: A Text and Atlas, 4th ed.: pages 79-81; 146-147; 246-281; 455-456
Gartner & Hiatt, Color Atlas of Histology, 3rd ed.: pages 102-124
Wheater’s Functional Histology: A Text and Color Atlas, 4th ed.: pages 93; 97-115; 151
Junqueira and Carneiro: Basic Histology: A Text and Atlas, 10th ed.: pages 78-80; 87-89; 191-
213; 216

Laboratory Manual: pages 55-60; slides A12, A42, A44, A45, A47, A48, A49, A50, A78, A90,
B40, B51

OBJECTIVES -- As a result of attending the audiovisual presentations, reading/viewing the
textbook, atlas, notes, and participating in the histology laboratory, 1st year medical students
should understand and be able to:

    1.  Identify the distinguishing characteristics of skeletal, cardiac, and smooth muscle.
    2.  Describe examples of single-cell contractile unites and multi-cellular contractile units.
    3.  Tell how skeletal muscle formed during development (fusion of myoblasts).
    4.  Describe the connective tissue layers that surround the muscle fibers, fascicles, and
        collections of muscle fascicles? How do these layers contribute to tendons?
    5. Define the sarcolemma. Where are skeletal muscle nuclei in relation to it?
    6. Explain the differences between red, white, and intermediate muscle fibers.
    7. Describe the ultrastructural composition of a sarcomere. Understand the type of
        myofilaments and proteins that comprise each of the following regions:
                     a) A band
                     b) Z line
                     c) H band
                     d) I band
                     e) M line
    8. Depict a sarcomere both in the relaxed state and in the contracted state. Discuss its
        relation to muscle striations.
    9. Review how skeletal muscle contracts on a molecular basis (sliding filament model).
    10. Describe the morphology and function of the motor end plate.
    11. Describe the T-tubule - sarcoplasmic reticulum complex. Explain the roles that each
        plays in contraction of skeletal and cardiac muscle.
    12. Describe the basic morphology of muscle spindles or afferent nerve endings. Define the
        following:
                     a) Annulospiral or primary endings
                     b) Flower spray or secondary endings
    13. Define smooth muscle and be able to describe its appearance and location.
    14. Explain how contraction is elicited in smooth muscle. How does this differ from skeletal
        and cardiac muscle?
    15. Define cardiac muscle. How does it differ from skeletal and smooth muscle?
    16. Describe the location and morphology of intercalated disks.
    17. Discuss the incapacity of cardiac muscle to regenerate. How does the lack of
        regeneration seen in cardiac muscle compare with smooth and skeletal muscle?
                                 Cell and Tissue Biology
                                         Muscle

H. Wayne Lambert, Ph.D.                                              January 26, 2004

Note: The goal of this lecture is to identify and distinguish between skeletal, smooth, and
cardiac muscle in both light and electron microscopy. Table 1 highlights some of the
distinguishing characteristics that will help distinguish between these types of muscles.

Table 1: Comparison of the three muscle types
                                          MUSCLE TYPE
 Characteristics               Skeletal            Cardiac                  Smooth
 Nucleus                  Multinucleated;        Single Nucleus;      Single Nucleus;
                          Peripheral location    Central Location     Central Location
 Bands                    A and I bands          A and I bands        Absent
 Z-disks                  Present                Present              Absent; dense bodies
                                                                      are present
 T tubules                Present: triad         Present: diad        Absent; caveolae are
                          at AI junction         at Z-band            present
 Cell Junctions           Absent                 Gap junctions;       Gap junctions
                                                 desmosome;
                                                 fasciae adherens
 Neuromuscular            Present                Absent; intrinsic    Absent, intrinsic,
 Junction                                        contractions         neural, or hormonal
                                                                      contractions
 Stretch Receptors        Present                Absent               Absent

 Calcium Ion Binding      Troponin               Troponin             Calmodulin

 Regeneration             Limited                None                 High
                (Table derived from Dudek: High Yield Histology, 2nd ed.: page 47)

More information on the three types of muscle:
1) Skeletal muscle is composed of extremely elongated, multinucleated contractile cells,
   often described as muscle fibers, which are bound together by connective tissue.
   This type of muscle is often called striated muscle due to the highly organized
   arrangement of the myofilaments, contractile proteins of the muscle, which pushes its
   nuclei to the periphery of the muscle fibers. Contractions of skeletal muscle is quick,
   forceful, and usually under voluntary control.
2) Cardiac muscle has striations with centrally-located nuclei and intercalated disks.
   Fibers can branch, and contraction is involuntary, vigorous, and rhythmic. When cut
   in cross-section, cardiac muscle can be distinguished from smooth muscle by the
   large number of capillaries located between the muscle fibers



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3) Smooth muscle has no striations and the nuclei are centrally-located. Fusiform
   shaped cells whose contraction is slow and not subject to voluntary control.
Muscle: A quick introduction:
1) One of four basic tissue types in the body (epithelium, connective tissue, & nerves)
2) Most muscle cells are mesenchymal in origin.
3) Muscles, or multicellular contractile units, are characterized based upon their
   functional property: their ability to contract.
4) Muscle is responsible for movements of the body and for changes in size and shape of
   its internal organs due to its contractility. Motile forces are generated by interactions
   of the myofilaments: actin and myosin.
5) Myofilaments occupy bulk of cytoplasm, which is called sarcoplasm in muscle cells:
   (“sarkos” is Greek for “flesh”) and align to produce mechanical work.
           a) In skeletal muscle, the degree of alignment of the myofilaments is so
              organized within the cytoplasm that it pushes the nuclei to the periphery of
              the cell (muscle fiber).
           b) Most striking feature of the sarcoplasm is the high number of mitochondria.
              Some of the mitochondria contain electron-dense inclusions that have a
              paracrystalline structure. Note the myofilaments through the muscle fiber
              (muscle cell).
           c) The sarcolemma is the cell membrane or plasma membrane of the muscle
              fiber. The nuclei of skeletal muscle are located immediately under the
              sarcolemma on the periphery of the muscle fiber. Some histologists state
              the sarcolemma also includes the basal lamina (BL) and reticular lamina
              (RL), but this is not a concept that will be emphasized.

Single Cell Contractile Units
1) All cells are capable of some movement, but there are single cells whose dominant
   function is to contract. These contracting cells are called single cell contractile units,
   which include myoepithelial cells, pericytes, and myofibroblasts
2) myoepithelial cells – cells with numerous processes that work to expel secretions
   from glandular acini and move the secretion toward the excretory duct. More
   importantly, these cells prevent end-piece distension.
3) pericytes – cells found embracing the endothelial cells of capillaries and post-
   capillary venules. Though some suggest these cells act like smooth muscle (due to
   the presence of actin, myosin, and tropomyosin) around these vessels, new evidence
   indicates these cells act as undifferentiated mesenchymals cells to repair the
   endothelium of vessels or replace smooth muscle cells around the vessel.
4) myofibroblast – a connective tissue cell that functions in wound healing and may
   develop morphologic and functional characteristics of smooth muscle cells. It
   contains bundles of longitudinally oriented actin filaments and dense bodies that are
   seen in smooth muscle cells, but myofibroblasts lack a surrounding basal lamina.

Multicellular contractile units are called muscle
1) During development, each muscle fiber (or muscle cell) is formed by fusion of small,
   individual myoblasts, which are derived from mesenchyme. Myoblasts proliferate by




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    mitosis and fuse end to end to form myotubes, eventually developing into mature
    skeletal muscle.
 2) Therefore, skeletal muscle fibers are composed of elongated, cylindrical, and multi-
    nucleated contractile fibers (cells) that are surrounded and bound together by
    connective tissue (primarily collagenous in nature).
3) Remember that mature skeletal muscle cells do NOT undergo mitosis. However,
    during tissue injury, muscle can recruit muscle stem cells called satellite cells to
    proliferate leading to a limited degree of regeneration.

Connective Tissue in Muscle
1) Found within and surrounding the muscle, the role of the connective tissue (CT) is to
   mechanically transmit the forces generated by contracting muscle fibers because, in
   most instances, individual muscle fibers do not extend from one end of the muscle to
   the other.
2) The CT enables a pathway for the nervous innervation and the blood supply to reach
   the muscle. Blood vessels penetrate the muscle within the connective tissue septa and
   form rich capillary networks.
3) The connective tissue of muscle is organized into three layers.
           a) Endomysium - delicate layer of reticular fibers that surrounds each
               individual muscle fiber. Only small-diameter capillaries and the finest
               neuronal branches are present within this CT layer.
           b) Perimysium - thicker CT layer that surrounds a group or bundle of muscle
               fibers forming muscle fascicles. Larger blood vessels and nerves travel in
               the perimysium.
           c) Epimysium – sheath of dense CT that surrounds collection of muscle
               fascicles that constitute the entire muscle. The major vascular and nerve
               supply of the muscle penetrates the epimysium.
4) All 3 layers of these CT layers coalesce at the end of muscles to form tendons.

There are three types of muscle fibers: red, white, and intermediate
1) Red fibers - small fibers named due to their high content of myoglobin, an oxygen
   binding protein that closely resembles hemoglobin. Red fibers can also be called
   aerobic fibers or type I fibers. These fibers make up the slow-twitch motor units.
   These fibers have greater resistance to fatigue, less muscle tension, myosin ATPase
   activity is greatest, large number of mitochondria, and found in limbs, back muscles,
   and breast muscles in migrating birds (aerobic). Red fibers are found in the long
   muscles of the back that function to maintain erect posture.
2) White fibers - large fibers with low amounts of myoglobin and mitochondria. White
   fibers can also be called anaerobic or type II fibers. These fibers make up fast twitch
   motor units. The white fibers fatigue rapidly, generate large peak muscle tension,
   rapid contractions and fine movements, and found in extraocular eye muscles and in
   the digits.
3) Intermediate fibers – as the name implies, these fibers are of intermediate size and
   in between the red and white fibers in size, pigment content, and mitochondria. All
   three types of these fibers can be visualized by utilizing special histochemical




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   reactions based on oxidative enzyme activity. These color differences in the fibers
   are not apparent in hematoxylin and eosin (H&E) stained sections.

The organization and interaction of the myofilaments
1) Cross-striations are easily seen in longitudinal sections of skeletal muscle, and, to a
   lesser extent, cardiac muscle due to the arrangement of actin and myosin. Light and
   dark bands can easily be seen in these types of muscle.
           a) I (isotropic) bands contain only thin myofilaments and are the light
               bands seen when using an electron microscope. These light I bands are
               monorefringent, meaning they do not alter the plane of polarized light.
           b) A (anisotropic) bands contain both thin and thick myofilaments and are
               the dark bands seen in EM. In polarized microscopy, these dark bands are
               birefringent (i.e. they alter the plane of polarized light in two planes).
           c) Z (from the German word Zwischenscheiben, which means “between
               disks”) bands are the most electron-dense and bisect the I bands. The
               basic contractile unit of striated muscle is the sarcomere, which is the
               portion of the myofibril between two adjacent Z-lines. α-Actinin anchors
               actin filaments to the Z-line and bundles these thin myofilaments in
               parallel arrays. Therefore, actin is attached to the Z-line and extends into
               the A band to the edge of the H band.
           d) H (from the German word Hell, which means “light”) bands contain only
               thick myofilaments and represent a light area in the middle of an A band.
               The H band is bisected by a narrow dense line called the M line.
           e) M (from the German word Mitte, which means “middle”) line is where
               adjacent myosin filaments are held in register at the center of the H zone
               by fine, transversely oriented fibers (myomesin) that constitute the M line.
2) Thin filaments (6-8 nm in diameter) are composed primarily of actin, but also have
   troponin and tropomyosin. These three proteins compose the I band and the non-H
   region of the A band.
3) Thick filaments (15 nm in diameter) - myosin; located in the A band. Myosin runs
   the length of the A band, but does not enter the I band. Myosin is connected to the
   Z-line by the protein titin.
4) Remember the “Sliding Filament Theory” states that the I and H bands shorten
   during contraction and the Z bands are drawn closer, decreasing the length of the
   sarcomere. There is no change in the length of the A bands (see Table 2).

Table 2: Changes in contacted and relaxed muscle
 Band              Contracted Muscle                         Stretched Muscle
 A Band            No Change                                 No Change
 I Band               Shortens                             Lengthens
 H Band               Shortens                             Lengthens
 Z disks              Move closer together                 Move farther apart
                        (Table derived from Dudek: High Yield Histology, 2nd ed.: page 43)

5) ATP and calcium are needed for a contraction to take place.


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Note: Do not forget the importance of troponins T, C, and I, as well as tropomyosin, but
remember that there are more than 20 structural and regulatory proteins within the
sarcomere. The specific actions of each protein can be elucidated with additional reading.
6) Remember, sarcomeres are present in skeletal and smooth muscle, but in smooth
    muscle, the myofilaments are not arranged as meticulously. Smooth muscle cells
    have cytoplasmic dense bodies (equivalent to Z disks), which contain α-actinin.

Calcium is crucial to muscular contraction
1) Since calcium is needed for interaction of myofilaments, the sarcoplasmic reticulum
   and a transverse tubular system (or T system) allow rapid delivery and removal of
   calcium.
2) These two structures form a membranous network around each muscle fiber.
3) The T system is an invagination of the plasma membrane that forms a hollow
   cylinder that runs into the sarcoplasmic reticulum from the outside of the cell. Its
   fluid content is equivalent to the extracellular fluid. Therefore, the T-tubule system
   transmits surface membrane excitation (an action potential) to terminal cisterns (or
   sacs) of the sarcoplasmic reticulum. This action potential causes the terminal
   cisternae to release their stores of calcium ions. This calcium release facilitates
   muscle contraction.
4) The Sarcoplasmic Reticulum is a storehouse for calcium and is composed of a
   longitudinal part and the terminal cisternae, which abuts T-tubule. The terminal
   cisternae are dilated sacs of sarcoplasmic reticulum that store, release, and
   reaccumulate calcium ions.
5) Calcium is released following depolarization of the muscle fiber as the T tubule
   system transmits surface membrane excitation to these storage sacs.
6) The location of the T tubule and the terminal cisternae within the sarcomere can help
   in the identification of the muscle type.
           a) skeletal muscle – a triad is located at the AI junction within the
               sarcomere. This triad consists of a T tubule flanked on either side by two
               terminal cisternae.
           b) cardiac muscle – a diad, which consists of a T tubule flanked by one
               terminal of the sarcoplasmic reticulum, is located at the Z-disk.
           c) smooth muscle – have numerous invaginations of the plasma membrane
               called caveolae, which are equivalent to T tubule.

Skeletal muscle fibers are richly innervated by motor neurons
1) An axon will lose its myelin sheath and abut against the middle of individual muscle
   fibers-- motor end plate or neuromuscular junction (NMJ).
2) The cell membrane of the muscle fiber is thrown into junctional folds (invaginations
   of the sarcolemma) and represents the postsynaptic membrane where acetylcholine
   (Ach) will eventually bind to nicotinic Ach receptors, allowing an influx of sodium
   ions and depolarization of the postsynaptic membrane called an endplate potential.
3) Each motor neuron can branch and innervate many muscle fibers -- motor unit.
4) Neuromuscular junctions represent a means of extrinsic stimulation only present in
   skeletal muscle.




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5) In cardiac and smooth muscle, the contractions are intrinsic due to action potentials
   that are passed to neighboring cells by gap junctions. Smooth muscle can also be
   stimulated to contract by neural and hormonal methods (more information later).

Neuromuscular (muscle) spindles are stretch receptor organs within skeletal muscle
1) Muscle spindles are specialized receptor units that are responsible for the regulation
   of muscle tone via a spinal stretch reflex.
2) These specialized receptor units are particularly numerous in muscles involved in
   fine, precision movements (intrinsic muscles of hand or extraocular muscles of eye).
3) Muscle spindles are encapsulated, lymph filled, fusiform structures that contain
   modified skeletal muscle fibers called intrafusal fibers, which are much smaller than
   skeletal muscle fibers proper (extrafusal fibers).
4) The two recognized intrafusal fibers, nuclear bag and nuclear chain fibers, have a
   central non-striated area in which their nuclei tend to be concentrated. In nuclear
   bag fibers, the central nuclear area is dilated. In nuclear chain fibers, there is no
   dilatation and the nuclei are arranged in a single row.
5) Associated with these intrafusal fibers are two sensory receptors, the annulospiral
   endings, which wrap around the non-striated middle portion of the intrafusal fibers,
   and the flower-spray endings, which are smaller, myelinated sensory fibers located
   on the peripheral, striated portions of the intrafusal fibers.
6) When the muscle is stretched, the activity in these neurons increases substantially.
   Conversely, when the muscle is contracted, the tonic activity decreases.
7) Muscle spindles are only present in skeletal muscle.

Characteristics of Smooth Muscle
1) Smooth muscle is found in intrinsic, visceral musculature of blood vessels,
   alimentary canal, respiratory tract, and other hollow, tubular organs. Smooth muscle
   is also associated with the hair follicles, the dartos of the scrotum, and the iris and
   ciliary body of the eye.
2) This type of muscle has no regular cross-banding or striation pattern, and therefore, it
   stains evenly with eosin in routine H&E sections due to the irregular arrangement of
   myofilaments.
3) Smooth muscle often occurs as bundles (or sheets) of elongated, fusiform shaped
   fibers, and each fiber (cell) has one centrally-located, spindle-shaped nucleus.
4) Smooth muscle fibers are much shorter than their skeletal muscle counterparts.
5) Like cardiac muscle, smooth muscle fibers may branch. This branching is not seen in
   skeletal muscle.
6) In smooth muscle cut in cross-section, nuclei are only included when fibers are cut
   through their widest diameter. To distinguish between cardiac muscle, note the
   paucity of connective tissue and capillaries in between the muscle fibers. The nuclei
   of smooth muscle are also more rounded.
7) Smooth muscle has a high rate of regeneration, which is not seen cardiac and skeletal
   muscle.
8) Smooth muscle has bundles of contractile proteins that criss-cross the cell and insert
   into focal densities in the plasma membrane called dense bodies. The presence of
   these contractile proteins allows for cell motility.



                                             7
Smooth Muscle is unique in its mechanism of contraction and innervation
1) Smooth muscle exhibits slow, prolonged contractions following intrinsic, neural, or
   hormonal stimuli.
           a) intrinsic contractions - action potentials that are passed to neighboring
               cells by gap junctions
           b) hormonal contractions - an example of this type of stimulation would
               include myoepithelial cells of the mammary gland and smooth muscle
               fibers of the uterus contracting following hormonal excitation generated
               by oxytocin.
           c) neural stimulation - postganglionic autonomic neurons can pass over the
               smooth muscle surface, but their nerve terminals do not directly contact
               the smooth muscle cells. Varicosities from these autonomic neurons
               release neurotransmitters (Ach or norepinephrine), which diffuse toward
               and bind to receptors on the sarcolemma. No NMJ are present (as in
               skeletal muscle).
2) Due to a basal level of calcium within the sarcoplasm, smooth muscle is usually in a
   state of contraction, called muscle tone.
3) Troponin is not associated with calcium binding in smooth muscle as this protein is
   not present. Calmodulin binds calcium ions intracellularly and caldesmon may
   regulate cross-bridge cycle in smooth muscle.
4) There is also NO T-tubule system, but there are voltage-gated ion channels present in
   the sarcolemma of smooth muscle that lead to depolarization.
5) Contraction response is much slower, but smooth muscle can maintain high force
   contraction with very little ATP usage for long periods of time.
6) Calcium-calmodulin complex activates an enzyme called myosin light-chain kinase
   (MLCK), which phosphorylates myosin and permits “cross-bridge” cycling.
7) Smooth muscle cells have numerous invaginations of the cell membrane called
   caveolae (equivalent to T tubules).

Characteristics of Cardiac Muscle
1) This type of muscle is only found in the heart and pulmonary veins.
2) Cardiac muscle consists of long, branching fibers with individual mononucleated
   muscle cells forming the fibers. The nuclei are centrally-located.
3) In between the muscle fibers, a delicate collagenous tissue supports a rich capillary
   network that surrounds each cell.
4) The ends of cardiac myocytes have interdigitating cell surfaces that are attached to
   specialized junctions called intercalated disks, which consist of a fascia adherens,
   desmosomes, and gap junctions. Intercalated disks have a transverse and lateral
   component.
           a) transverse component - located at the Z-line, and it is composed
              primarily of fasciae adherentes, where actin filaments insert and thereby
              transmit contractile forces from cell to cell, and desmosomes (maculae



                                            8
                 adherentes), which provide anchorage for intermediate filaments of the
                 cytoskeleton and exist less frequently.
             b) lateral component - where gap junctions are usually present, and they are
                 sites of low electrical resistance through which excitation passes from cell
                 to cell.
5)   At high magnification, the juxtanuclear region of cardiac muscle is rich in
     mitochondria, Golgi apparati, as well as glycogen and lipofuscin granules.
6)   The arrangement of contractile proteins in cardiac muscle is very similar to skeletal
     muscle; however, the sarcomeres are not arranged in single columns. Their
     arrangement is more staggered like steps on a staircase.
7)   At the light microscopy level, it is often hard to visualize striations of cardiac muscle
     due to irregular branching shape of the fibers and their myofilaments. Therefore,
     cardiac muscle is not referred to as “striated muscle” (a term reserved for skeletal
     muscle), even though it does exhibit striations due to the organization of its
     myofilaments.
8)   Mature cardiac myocytes do not divide. The absence of blood perfusion leads to
     myocardial infarction, which causes the formation of fibrous CT (scar tissue) and loss
     of cardiac function.

Cardiac muscle: contraction and stimulation
1) Contractions of cardiac muscle are involuntary, vigorous, and rhythmic.
2) Cardiac muscle contracts through intrinsic action potentials that are passed to
   neighboring cells via gap junctions. Gap junctions permit extremely rapid spread of
   contractile stimuli from one cell to another. Thus, adjacent fibers contract almost
   simultaneously acting as a functional syncytium.
3) The sarcoplasmic reticulum of cardiac muscle do not form terminal cisternae.
   Remember, diads (T-tubule and the small terminals of the sarcoplasmic reticulum) are
   located in the vicinity of the Z disk.




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