Muscle Structure and Function (1)

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The human body is comprised of 324 muscles Muscle makes up 30-35% (in women) and 42-47% (in

men) of body mass. 40% of body is skeletal muscle and another 10% smooth

and cardiac muscles.

Types of Muscle

Skeletal muscle Cardiac muscle

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Smooth muscle

A. Skeletal (Striated) Muscle

Composed of numerous muscle fibers (10-80 micrometer).

Each fiber extends entire length of muscle

Each muscle fiber is innervated by only one nerve ending (except 2% fibers)

Biomechanics: assessment of movement and the

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Biomechanics: assessment of movement and the sequential pattern of muscle activation that move body segments

Sarcolemma: cell membrane of muscle fiber with outer thin layer of polysaccharide material containing collagen fibrils. Fuses with tendon fiber (collect to form muscle tendons).

B. Smooth Muscle

Located in the blood vessels, the respiratory

tract, the iris of the eye, the gastro-intestinal

tract

The contractions are slow and uniform

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The contractions are slow and uniform

Functions to alter the activity of various

body parts to meet the needs of the body at

that time

Is fatigue resistant

Activation is involuntary

C. Cardiac Muscle

Has characteristics of both skeletal and

smooth muscle

Functions to provide the contractile

activity of the heart

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activity of the heart

Contractile activity can be graded (like

skeletal muscle)

Is very fatigue resistant

Activation of cardiac muscle is

involuntary (like smooth muscle)

The term "excitation-contraction coupling" refers to the mechanism bywhich the action potential causes the myofibrils of muscle to contract

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surrounding the myofibrils of each muscle fiber is an extensive reticulumcalled the sarcoplasmic reticulum .

This reticulum has a special organization that is extremely important incontrolling muscle contraction

Transverse Tubules and the Sarcoplasmic Reticulum

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The transverse (T) tubules are an extensive network of muscle cellmembrane (sarcolemmal membrane) that invaginates deep into themuscle fiber. The T tubules are responsible for carrying depolarizationfrom action potentials at the muscle cell surface to the interior of thefiber

The sarcoplasmic reticulum is an internal tubular structure, which isthe site of storage and release of Ca2+ or excitation-contractioncoupling

Each muscle fiber contains several hunderdsto several thousands myofibrils. Each myofibril is composed of 1500 myosin filaments and 3000 actin filaments.

Light bands contain

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Light bands contain only actin filaments- I bands (isotropic).Dark bands contain myosin as well as ends of actin filament A bands (anisotropic).Bands give striated appearance.

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The sarcomere is the basic contractile unit, and it is delineated by the Z disks. Each sarcomere (2m) contains a full A band in the center and one half of two I bands on either side of the A ban.

Titin filamentous molecules make myosin and actin filaments in placeOne of largest protein molecule (3,000,000D) in body.Very springy (act as framework that lines up the myosin and actin filaments to make contractile machinery of the sarcomere work). Itself act as template for initial formation of portions

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Itself act as template for initial formation of portions of contractile filaments of sarcomere mainly myosin.

Sarcoplasm: intracellular matrixlarge quantity of K+, Mg++, PO4- and multiple enzymes numerous mitochondria (parralel to myofibrils) extensive ER (sarcoplasmic reticulum)

Myosin filamentMade of 200 or more individual myosin mol.Six polypeptide chains (Mwt. 480,000): two heavy chains (200,000) and 4 light chains (20,000each). Myosin head has ATPase activity

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Actin filament:Three protein components: actin, tropomyosin, troponin.

F-actin: 1m longBack bone

Tropomyosin moleculeTropomyosin (70,000), 40nm

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oBack boneoPolymerised G-actin molecules (wt 42,000), 13 molecules per revolution of each strand.oOne ADP (active sites) attached to each G-actin molecule.

Tropomyosin (70,000), 40nmWrapped around F-actin, lie upon top of actin strand in resting stage.

Troponin: complex of three loosely bound protein subs. : Troponin I- strong affinity to actinTroponin T- for tropomyosinTroponin C- Calcium ions

General mechanism of muscle contraction1. action potential along a motor nerve to muscle fibers

2. acetylcholine

3. open multiple "acetylcholine-gated" cation channels through protein molecules floating in the membrane

4. large quantities of sodium ions diffuse to the interior of the muscle fiber membrane-local depolarization -opening of voltage-gated sodium channels- an action potential at the membrane.

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sodium channels- an action potential at the membrane.

5. The action potential depolarizes the muscle membrane-sarcoplasmic reticulum to release large quantities of calcium ions that have been stored within this reticulum.

6. attractive forces between the actin and myosin filaments-slide alongside each other.

7. After a fraction of a second, the calcium ions pumped back by a Ca ++membrane pump- muscle contraction to cease.

Molecular mechanism of muscle contraction

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Sliding filament mechanism

Walk along theory or rachet theory of contraction

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Action potential- Ca++ from sarcoplasmic reticulum- inactivation of inhibitory effect of troponin-tropomyosin complex- (4 Ca++ bind with one TroponinC- conformational change- uncover active sites in actin).

The head attaches to an active site, this causes forces between the head and arm of its cross-bridge. this causes the head to tilt toward the arm and to drag the actin filament along with it.

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Fen effect: greaterthe work performedby muscle, greateramount of ATP iscleaved

The Amount of Actin and Myosin Filament Overlap Determines Tension Developed by the Contracting Muscle

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Effect of Muscle Length on Force of Contraction in the Whole Intact Muscle


Relation of Velocity of Contraction to Load

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when the load has been increased to equal the maximum force that the muscle can exert, the velocity of contraction becomes zero and no contraction results, despite activation of the muscle fiber .

Muscle contraction is said to be isometric when the muscle does not shorten during contraction and isotonic when it does shorten but the tension on the muscle remains constant throughout the contraction

Isotonic contraction

Isometric contraction

Shortening yes No

Increase in tension

no Yes

Amt of heat generated

greater Less

Work done yes No

example Lifting a bucket off the floor

Pushing against a wall

21Characteristics of Isometric Twitches Recorded from Different Muscles

Motor Unit-

All the Muscle Fibers Innervated by a Single Nerve Fiber

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Force Summation

Summation means the adding together of individual twitch contractions to increase the intensity of overall muscle contraction

Summation occurs in two ways:

(1)by increasing the number of motor units contracting simultaneously, which is called multiple fiber summation , and

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simultaneously, which is called multiple fiber summation , and

(2)by increasing the frequency of contraction, which is called frequency summation and can lead to tetanization .

Multiple Fiber Summation

When the central nervous system sends a weak signal to contract a muscle, the smaller motor units of the muscle may be stimulated in preference to the larger motor units. Then, as the strength of the signal increases, larger and larger motor units begin to be excited as well ,

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This is called the size principle

Frequency Summation and Tetanization

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as the frequency increases, there comes a point where each new contractionoccurs before the preceding one is over. As a result, the second contraction isadded partially to the first, so the total strength of contraction risesprogressively with increasing frequency. When the frequency reaches acritical level, the successive contractions eventually become so rapid thatthey fuse together and the whole muscle contraction appears to be completelysmooth and continuous. This is called tetanization .

if the muscle is stimulated repeatedly, there is insufficient time for thesarcoplasmic reticulum to reaccumulate Ca+2 , and the intracellular Ca 2+ concentration never returns to the low levels that exist during relaxation.Instead, the level of intracellular Ca+2 concentration remains high, resultingin continued binding of Ca 2+ to troponin C and continued cross-bridgecycling. In this state, there is a sustained contraction called tetanus, ratherthan just a single twitch .

MECHANISM OF TETANUS

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than just a single twitch .

Skeletal Muscle Tone

Even when muscles are at rest, a certain amount of tautness usually remains.

This is called muscle tone .

Because normal skeletal muscle fibers do not contract without an actionpotential to stimulate the fibers, skeletal muscle tone results entirely from alow rate of nerve impulses coming from the spinal cord

Neuromuscular junction

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Diameter of acetylcholine-gated channel is 0.65nm

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End plate potential

It is a local positive potential onthe postsynaptic membraneresulting from the entry ofsodium via the acetylcholinereceptor channel.

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Nerve action potential

Muscle action potential

Resting membrane potential -70 mV -80 to -90mV

Duration of action potential 0.2-0.3 msec 1-5 msec

Velocity of conduction 70-120 m/sec 3-5 m/sec

Formation and release of Ach

Small vesicles (40nm) formed at Golgi body of cell body of motonurons of spinal cord.Axoplasm to tip of peripheral nerve. 300,000 vesicles at end plate.Acetylcholine synthesized at cytosol of nerve fiber terminal and stored in vesicles (10, 000 molecules per vesicle)


and stored in vesicles (10, 000 molecules per vesicle)Action potential- opening of Ca++ channel- Ca++ entry (100 fold)- fusion of vesicles (10,000 fold)- exocyosis. About 125 vesicles rupture with each action potential.After a few milliseconds Ach is split in to acetate and choline. Choline is absorbed actively

Acetylecholine is split by actetyle choline esterase- acetateion and choline. Choline is reabsorbed actively in terminal.Botilinum toxin- prevent release of AchCholinomimetic drugs: methacholine, carbachol and nicotine(acetylcholine like action). Not destructed by cholinesterase,action persists for many minutes to several hours.Neostigmine, physostigmine, and diisopropylfluorophosphate- inactivate actelylecholinesterase musclespasm.

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spasm.Curariform drugs block action of acetlylecholine on theAch receptorMyasthenia gravis (an autoimmune disease)- antibodiesagainst Ach receptors.Lambert-Eaton syndrome- Antibodies to voltage gateCalcium ion channels in presynaptic terminals- inhibit releaseof ACh molecules Cobra venom toxin- competitive blockage of nicotinicAChR in skeletal muscle motor end plate

Excitation-contraction coupling

1. Motor neuron releases Ach onto the surface of the skeletal muscle fiber. The fibers nicotinic receptors are activated, opening K+ and Na+ channels. The cell membrane is depolarized.

2. The action potential moves away from the motor end plate in all directions, including down the t-tubule system.

3. Receptors in the t-tubules called dihydropyridine receptors (DHP) are activated by the change in voltage. They are connected to the ryanodine receptors in the lateral sacks of the sarcoplasmic reticulum (SR).

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4. The ryanodine receptors are opened by the change in conformation of the DHP receptors and Ca2+ is released from the SR.

5. Ca2+ diffuses across the myofilaments.

6. The Ca2+ binds to troponin C, causing it to change conformation, pulling on troponin I, which in turn pulls on tropomyosin. With the altered conformation in tropomyosin, the myosin binding sites on g-actin molecules are exposed.

7. Myosin heads can now bind to g-actin molecules and cross-bridge cycling begins, shortening the sarcomere by pulling on the actin filaments and drawing the z disks closer together

Rigor Mortis

Rigor= rigidity; Mortis= deathIt is a postmortem stiffening of voluntary and involuntary muscles of the body which develop at variable period after death and succeeds the state of primary muscle flaccidity. In RM ATP is not generated and actin-myosin complex is not dissociated. Indicates molecular death and time since death indicates position and attitude of body at the time of death. may give idea about cause and nature of death Does not start in all muscles simultaneously (Nystens rule), starts from

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Does not start in all muscles simultaneously (Nystens rule), starts from head towards tail. Helpful in determining the time of death. disappears after decomposition (enzymes released from lysosomes).Appearance and disappearance: 1st in involuntary muscles i.e. heart

in voluntary muscles it appears and disappears in same sequence, eye lid- back of neck-lower jaw-front of neck-face-chest-upper extremity- abdomen.Fast appearance- fast disappearanceFaster at high temp.

RM is not related with Nervous system& blood supply,If Brocken it does not develop again (if fully devd.)

4 phases1st phase: muscle remain normal for some time after somatic death, but rapid onset occur in vigorous exercise prior to death like epilepsy, tetanus, electrocution, strychnine etc.2nd phase: ATP fall bellow critical level (

Contraction of smooth muscles

Six types:VascularRespiratoryurinaryreproductive Gastrointestinal

Two types:Phasic: poorly maintain tone, have relatively high shortening velocity, capable of generating regenerative action potential e.g. taenia coli of intestine, portal vein, antrum of stomach

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Gastrointestinalocular

Intracellular free Ca++ in smooth muscles is a major determinant of smooth muscle contractility.

stomach Tonic: do not generally display action potential or regenerative electrical activity. Slower shortening velocity but more effectively maintain tone. E.g. aorta, trachea, GIT,

Contraction of Smooth Muscle

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the same attractive forces between myosin and actin filaments cause contraction in smooth muscle as in skeletal muscle, but the internal physical arrangement of smooth muscle fibers is different.

Dense bodies serve same role as Z disc in skeletal musclesMyosin filaments are sidepolar cross bridges (contract about 80% contrast 30 % in Sk. Mu. ) Actin has no troponin or tropomyosin

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Actin has no troponin or tropomyosincomponents1/10 to 1/300 as much energy required copmp. to sk. Mu. For same tone. slow cycling (1/10 to 1/300)- cross bridge heads have less ATPase activity slow onset of contraction and relaxation. smooth muscles have far more voltage-gated Calcium channels and few Na- gated channels than sk. Mu. Ca++ gated channels are slow in opening.

Source of Calcium Ions That Cause Contraction Through the Cell Membrane and from the Sarcoplasmic Reticulum

Role of the Smooth Muscle Sarcoplasmic Reticulum(less developed)

Caveoli

Flask-shaped (120nm length, 30-90nm wide) invaginations of sarcolema

Often closely associated with SR

Caveolin a specific protein

analogue of T- tubule system

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analogue of T- tubule system

Extracellular Ca++ : if falls to a low level smooth muscle contraction ceases. Not affected in sk. Mu.

Calcium pump- removal of Ca++ from intracellular fluid to extracellular fluid. But slow acting than sarcoplasmic reticulum pump

Comparison of Smooth Muscle Contraction and Skeletal Muscle Contraction

Although most skeletal muscles contract and relax rapidly, most smooth muscle contraction is prolonged tonic contraction, sometimes lasting hours or even days.

Slow Cycling of the Myosin Cross-Bridges

Low Energy Requirement to Sustain Smooth Muscle Contraction

Slowness of Onset of Contraction and Relaxation of the Total Smooth

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Slowness of Onset of Contraction and Relaxation of the Total Smooth Muscle Tissue

Maximum Force of Contraction is Often Greater in Smooth Muscle than in Skeletal Muscle

"Latch" Mechanism Facilitates Prolonged Holding of Contractions of Smooth Muscle (once smooth muscle has developed full contraction, the degree of activation of the muscle usually can be reduced to far less than the initial level and yet the muscle maintains full force of contraction.)

The phenomenon of Ca++ dependent force maintenancewithout detectable elevation in phosphorylation was termedlatch by Dillon et al.(1981) to indicate mechanical similaritywith moluscan catch muscle. Key in the latch phenomenon isthe decreased rates of cross-bridge cycling and ATP utilizationreminiscent of the ability of catch muscles to maintain closureof the shell with negligible energy consumption.

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Caldesmon (CaD) is a thin filament-associated, actin and CaM-binding protein that is found in appreciable quantity in a variety of smooth muscles.Calponin (CaP) is an actin binding protein that inhibits myosin ATPase activity.

Regulation of Contraction by Calcium Ions

smooth muscle does not contain troponin

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smooth muscle can be stimulated to contract by multiple types of signals: by nervous signals, by hormonal stimulation, by stretch of the muscle, and in several other ways.

The principal reason for the difference is that the smooth muscle membrane contains many types of receptor proteins that can initiate the contractile process.

Still other receptor proteins inhibit smooth muscle contraction, which is another difference from skeletal muscle .

*Myosin light chain kinase (MLCK)

Probably half of all smooth muscle contraction is initiated by stimulatory factorsacting directly on the smooth muscle contractile machinery and without actionpotentials.

Two types of non-nervous and non action potential stimulating factors often involved are

(1) local tissue chemical factors and

(2) various hormones

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Cardiac muscles

Three major types of muscles:Atrial muscles, ventricular muscles (contract in much same way as sk. Mu. Except that duration of contraction is much longer)and specialized excitatory and conductive muscle fibers (contract feebly exhibit rhythmicity and varying rate of conduction)Cardiac muscle is a syncytium of many heart muscle cells (intercalated discs) Potential from atria to ventricle is conducted by A-V bundle.

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Action potential105 mV (-85mV to + 20 mV)Depolarisation in atria: 0.2 secVentricular muscles: 0.3 sec.Plateau by abrupt repolarizationContraction lasts for 15 times as sk. Mu.Act.pot. Caused by fast sodium channels and slow calcium.

MyoglobinGlobular protein containing heme group that carries oxygen to muscles


FrankStarling law: an increase in the end-diastolic volume of the left ventricle leads to an increase in ventricular stroke volume during systole.


during systole.

Contraction of cardiac muscle

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The strength of contraction of cardiac muscle depends to a great extent on the concentration of calcium ions in the extracellular fluids.

In fact, a heart placed in a calcium-free solution will quickly stop beating .

The events causing heart muscle contraction differ slightly from those of skeletal muscle

Cardiac muscle just as skeletal muscle- require calcium to allow actin to bind to myosin which is the main component of the sliding filament model of muscle contraction.

All the calcium required for skeletal muscle contraction is located on the inside of the skeletal muscle cell in the sarcoplasmicreticulum however cardiac muscle requires some calcium to enter

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reticulum however cardiac muscle requires some calcium to enter from outside of the muscle cell.

in cardiac muscle some (10 -20%) extracellular calcium is required for contraction. This calcium enters through voltage dependent calcium channels known as L channels or sometimes referred to as slow calcium channels. In fact the 10 -20% of calcium coming from the outside of the cell not only goes to troponin C to assist directly with contraction but it also assists in the opening of the calcium release channels in the cardiac muscle cell sarcoplasmicreticulum for the other 80 90% to be released.

This influx of calcium from the outside of the cell occurs during the cardiac muscle action potential part of the mechanism of the action potential especially in the plateau phase. Thus even though the calcium enters as part of the action potential mechanismit is also important for the contraction action.

The entering calcium is important for excitation and contraction.

Since (1) the amount of calcium available to troponin C is important to the strength of contraction in both skeletal muscle and cardiac muscle and (2) some of the calcium for

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muscle and cardiac muscle and (2) some of the calcium for cardiac muscle contraction must come from the extracellular fluid the blood (extracellular fluid) calcium level is more important to cardiac muscle than skeletal muscle.

Since cardiac muscle has functional L calcium channels and skeletal muscle cells do not a calcium channel blocker drug will affect cardiac muscle and not skeletal muscle (example Verapamil) . The medication will decrease the force of contractility (inotropic effect).

NO TETANY The heart muscle should never go into tetany. A

heart muscle cell should do one muscle twitch then relax for a while before it embarks on another twitch.

A heart chamber only fills with blood when it is relaxed (diastole) thus tetany would cause a heart chamber to have a sustained contraction-

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heart chamber to have a sustained contraction-not relax and be unable to fill with blood.

If the heart chamber cannot fill it has no blood to empty into the next chamber or into the next blood vessels.

If heart muscle goes into tetany that is what is called cardiac flutter and fibrillation. Fibrillation can lead to death.

Prevention of Cardiac muscle tetany Since one initiated action potential can

cause one muscle contraction (muscle twitch) and a rapid succession of action potentials on a muscle cell can cause tetany then make the action potentials get further apart so they cannot summate as easily.

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apart so they cannot summate as easily.

How can this be done?

Prolong the absolute refractory period.

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The plateau phase of the cardiac muscle action potential provides a longer absolute refractory period thus disallowing cardiac muscle action potentials from coming to close together thus disallowing cardiac muscle tetany.

In addition to the fact that the cardiac muscle action potentials cannot come to close together there is another fact of interest the absolute refractory period lasts over 200 msec which is almost the entire time of one cardiac muscle twitch (one contraction). Thus by the time the action potential is fully over so is the muscle contraction thus no tetany.

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Events in the Cardiac Muscle Action Potential

small transient down-shoot

plateau phase

rapid repolarization

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rapid depolarization

usual Resting Membrane Potential (Na/K)

Events of the Pacemaker Action PotentialThe rate at which the pacemaker potential reaches threshold is the key to understanding the differences in the rate of firing of the different pacemakers.

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Pacemaker cells The pacemaker cells have automatic rhythm they

spontaneously in and of themselves can fire action potentials.

Each pacemaker structure has a different automatic firing rate.

SA node:60 80 natural pacemaker of the heart because it has the fastest firing frequency

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because it has the fastest firing frequency

AV node:40 60 spontaneous action potentials per minute

Bundle of HIS : 20 40 action potentials per minute

Bundle Branches:10 20 action potentials per minute

It is the pacemaker cells that cause the adjacent cardiac muscle cells to reach threshold voltage thus initiating the cardiac muscle cell action potential

Muscle Teamwork

Agonist (prime mover):

- the muscle or group of muscles producing a desired effect

Antagonist:

- the muscle or group of muscles opposing the action

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- the muscle or group of muscles opposing the action

Synergist:

- the muscles surrounding the joint being moved

Fixators:

- the muscle or group of muscles that steady joints closer to the body axis so that the desired action can occur

High microscope magnification of sarcomeres within a myofibril

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Contractile Machinery:

Optimal muscle length and optimal joint angle

The distance between sarcomeres is dependent on the stretch of

the muscle and the position of the joint

Maximal muscle force occurs at optimal muscle length (lo)

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Maximal muscle force occurs at optimal muscle length (lo)

Maximal muscle force occurs at optimal joint angle

Optimal joint angle occurs at optimal muscle length

Contractile Machinery:

Tendons, origin, insertion

In order for muscles to contract, they must be attached to the bones to create movement

Tendons: strong fibrous tissues at the ends of each muscle that attach muscle to bone

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Tendons: strong fibrous tissues at the ends of each muscle that attach muscle to bone

Origin: the end of the muscle attached to the bone that does not move

Insertion: the point of attachment of the muscle on the bone that moves

Muscle Fibre Types

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Slow twitch fibres:

Slow Oxidative (Type I)

Fast twitch fibres:Fast Glycolytic (Type IIb) Fast Oxidative Glyc. (Type IIb)

1) Smaller fibers.

2) innervated by smaller nerve fibers.

3) More extensive blood vessel system and capillaries to supply extra amounts of oxygen.

Slow Fibers (Type 1, Red Muscle)

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4) Greatly increased numbers of mitochondria, also to support high levels of oxidative metabolism.

5) Fibers contain large amounts of myoglobin, an iron-containing protein similar to hemoglobin in red blood cells. Myoglobincombines with oxygen and stores it until needed; this also greatly speeds oxygen transport to the mitochondria. The myoglobin gives the slow muscle a reddish appearance and the name red muscle .

Fast Fibers (Type II, White Muscle )

(1)Large fibers for great strength of contraction.

(2)Extensive sarcoplasmic reticulum for rapid release of calcium ions to initiate contraction.

(3)Large amounts of glycolytic enzymes for rapid release of energy

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(3)Large amounts of glycolytic enzymes for rapid release of energy by the glycolytic process.

(4)Less extensive blood supply because oxidative metabolism is of secondary importance.

(5)Fewer mitochondria, also because oxidative metabolism is secondary. A deficit of red myoglobin in fast muscle gives it the name white muscle .

The Histochemistry

The biopsy samples are first sectioned (8-10 m thickness)

Sections are processed for myosin ATPase:

Fast twitch fibres rich in myosin ATPase (alkaline labile)

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Fast twitch fibres rich in myosin ATPase (alkaline labile)

Slow twitch fibres low in myosin ATPase (acid labile)

Sections are processed for other metabolic characteristics
Types of MuscleB. Smooth MuscleGeneral mechanism of muscle contractionPacemaker cells

Muscle Structure and Function (1)

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