Muscles are effectors which enable movement to be carried out

• Muscles are responsible for all types of body movements – they contract or shorten and are the machine of the body

Muscle comprises the largest group of tissues in the body accounting for approximately half of the body’s weight.

Skeletal muscles __________ 40% of body weight

Cardiac and smooth muscle ____ 10% of body weight

3 types :Skeletal Muscles –

attached to skeleton

Cardiac Muscles – heart

Smooth Muscles – internal organs

The muscles have 4 important functions:

1. Production of movement-External and internal

2. Maintaining posture

3. Stabilizing joints

4. Generating heat

1. 1. ExcitabilityExcitabilitythe ability to receive and respond to stimuli for

e.g. Can respond to chemical neurotransmitters.

2. 2. ContractilityContractilityContracts when it is excited

3. 3. ExtensibilityExtensibilityThe ability of muscles to be stretched

4. 4. ElasticityElasticityThe ability of muscle to resume a resting

length after it has been stretched.

1. Depending upon striations: Striated: e.g. cardiac muscle and skeletal

muscle Non – striated: smooth muscle

2. Depending upon the control: Voluntary: Skeletal muscles Involuntary: Cardiac and smooth muscles

3. Depending upon situation: Cardiac: in heart Skeletal: attached to bones Smooth or visceral: present in visceras

Skeletal muscleSkeletal musclestriated with light & dark bands visible with

scope voluntary control of contraction & relaxationMakes up 40% of body weightResponsible for locomotion, facial

expressions, posture, respiratory movements, other types of body movement

Voluntary in action; controlled by somatic motor neurons

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Cardiac muscleCardiac musclestriated in appearanceinvoluntary controlAuto rhythmic because of built in

pacemaker (SA node)Innervated by autonomic nerves

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Smooth muscleSmooth musclenon-striated in appearanceInvoluntaryIn the walls of hollow organs, blood vessels,

eye, glands, uterus, skinSome functions: propel urine, mix food in

digestive tract, dilating/constricting pupils, regulating blood flow,

Controlled involuntarily by endocrine and autonomic nervous systems

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Connective tissue components of the muscle includeepimysium = surrounds the

whole muscle perimysium = surrounds

bundles (fascicles) of 10-100 muscle cells

endomysium = separates individual muscle cells

All these connective tissue layers extend beyond the muscle belly

to form the tendon 11

Muscle attachmentsMost skeletal

muscles run from one bone to another

One bone will move – other bone remains fixedOrigin – less

movable attach- ment

Insertion – more movable attach- ment

Composed of muscle cells (fibers), connective tissue, blood vessels, nerves

Fibers are long, cylindrical, and multinucleated and abundant mitochondria

Tend to be smaller diameter in small muscles and larger in large muscles. 1 mm- 4 cm in length

Develop from myoblasts; numbers remain constant

Striated appearance Nuclei are peripherally located Satellite cells are stem cells which

normally stay dormant but are activated when the muscle is injured

Cell membrane = sarcolemma

Cytoplasm = sarcoplasmSER = sarcoplasmic reticulum

Deep structures of a sceletal muscle

Microscopic Anatomy of Skeletal Muscle fiber

The predominant structural feature of a skeletal muscle fiber is numerous Myofibrils

(80% of volume of muscle fiber)

Myofibrils are aligned to

give distinct bands

I band = light band

A band = dark band

Myofibrils are densely packed, rod like cylindrical contractile elements

They make up most of the muscle volume (80%)

Each muscle fiber has several hundred to several thousand myofibrils.

The arrangement of myofibrils within a fiber is such that a perfectly aligned repeating series of dark A bands and light I bands is evident

MyofibrilEach myofibril is composed of 1500 adjacent myosin filaments and 3000 actin filaments which are large polymerized protein molecules made up of polymerization of proteins myosin and actin molecules respectively that are responsible for the actual muscle contraction.

With an electron microscope , a myofibril displays alternating dark bands (A band) and light band (I band) . The bands of all the myofibrils lined up parallel to one another collectively producing the striated appearance of skeletal muscle fibers visible under light microscope

Alternate stacked sets of thick and thin filaments that slightly overlap one another are responsible for the A and I band

A microscopic photo and a scheme of

Different polarization characteristics throughout

A bands: a dark band; full length of thick filament & the portions of thin filaments that overlaps on both ends of the thick filaments

H zone - thick but NO thin filaments

M line –system of supporting proteins which hold the thick filaments together vertically within each stack (protein to which myosins attach)

Having like properties in all directions (singly refractive)

I bands: a light band; it is the remaining of the actin filament that do not project into A band

Thin but NO thick filaments

In the middle of I band is a Z lineThe area b/w 2 Z lines is called sarcomere

which is the functional unit of the skeletal muscle

Z disk: filamentous network of protein. Serves as attachment for actin filaments of the two adjoining sarcomeres

So I band extends from A band of one sarcomere to A band of the next sarcomere

Figure 9.3c,d

The distance between two successive Z lines is called sarcomere which is the functional unit of the skeletal muscle. Each relaxed sarcomere is 2.5 μm in width and consists of one whole A band and half of each of the two I bands located on either side. About 10,000 sarcomeres per myofibril

Thick filaments(myosin)

Thin filaments(actin)

Mline

Zline

Zline

proteins in the Z line

justthin

filament

overlap zone- both

thick & thinfilaments

justthick

filament

myosinbare zone

- nocross bridges

proteins in the M line

Titin filaments: single strand of giant, elastic protein called titin extend in both direction from the M line along the length of the thick filament to the Z lines it is the largest protein in the body with 30,000 amino acids

1. Along with M line proteins titin helps stabilize the position of the thick filaments.

2. By acting like a spring , it greatly augments a muscles elasticity

3. Gets stiffer as it is stretched (uncoiled) which keeps sarcomeres from overstretching.

These are small projections from the sides of the myosin filaments towards the surrounding thin filaments in the areas where the thick and thin filaments overlap.

Each thick filament is surrounded by six thin filaments and each thin filament is surrounded by 3 thick filaments

Myosin forms the thick or myosin filamentEach thick filament is formed by the

polymerization of 200 or more myosin molecules

It is a protein containing 2 identical subunits , each shaped like a golf club. The tails or 2 heavy chains of myosin molecules wound together to form a rod portion lying parallel to the myosin filament and two heads or 4 light chains projecting out at one end so it is a (hexamer)

The tails of the myosin molecules bundled together to form the body of myosin filament while heads of the molecules hang outward to the sides of the body

Mirror image of each other

Also part of the body of each myosin molecule hangs to the side along with the head thus providing an arm

The protruding arm and heads are called cross bridges.

There are no cross bridge heads in the centre of myosin filament

Each cross bridge is flexible at 2 points called hinges

1. Hinged Arms: it is present where arm leaves the body of the myosin filament . It allows the head either to be extended far outward from the body of the myosin filament or to be brought close to the body

Hinged heads: This hinge is present where head attaches to the arm. The hinge heads in turn participate in the actual contraction process.

1. Actin binding site : Can bind to active sites on the actin molecules

2. Have ATPase activity: activity that breaks down adenosine triphosphate (ATP), releasing energy.

Actin filament

Thin filaments = actin filaments

Composed of 3 proteins

Thin filaments are chiefly composed of the protein actin (back bone of thin filament)

Each actin molecule is a helical polymer of globular or spherical subunits called G actin which are linked to create the F actin filaments

The subunits contain the active sites to which myosin cross bridge attach during contraction

Tropomyosin (“stiffener and blockade”) and troponin (TnI, TnT, TnC) are regulatory subunits bound to actin

TnI – bound to the actin fiber and is inhibitory, by blocking the binding site

TnT – bound to the tropomyosin fiber holding it in place

TnC – will bind to Ca++ ions to cause a position shift that exposes the actin binding site so that cross-bridging can occur, resulting in contraction

In a relaxed muscle contraction does not take place; actin cannot bind with cross bridge because of the way the troponin and tropomyosin are positioned within the thin filament.

When no Ca bound to troponin , it stabilizes tropomyosin in its blocking position over active sites of actin filament.

But when Ca binds to troponin, the shape of this protein is changed in such a way that tropomyosin slips away from its blocking position so now actin and myosin filament can bind with each other and result in muscle contraction.

So troponin and tropomyosin are called regulatory proteins because they cover or expose the binding sites for cross bridge interaction b/w actin and myosin filament

Troponin•T, tropomyosin binding site•C, calcium binding site•I, inhibitory site

Myosin cross bridgespull on thin filaments

Thin filaments slide inward

Z Discs come toward each other

Sarcomeres shorten.The muscle fiber shortens. The muscle shortens

Notice :Thick & thin filaments do not change in length 51

Moves Actin closer to the M-LineCloses the distance between Z-DiscsShortens the muscle fiber

The above micrographs show that the sarcomere gets shorter when the muscle contracts

The light (I) bands become shorterThe dark bands (A) bands stay the same

length

Relaxedm uscle

Contractedm uscle

relaxed sarcom ere

contracted sarcom ere

So, when the muscle contracts, sarcomeres become smaller

However the filaments do not change in length.

Instead they slide past each other (overlap)So actin filaments slide between myosin

filamentsand the zone of overlap is larger

In order to contract, a skeletal muscle must:Be stimulated by a nerve endingPropagate an electrical current, or action potential, along its sarcolemma

Have a rise in intracellular Ca2+ levels, the final trigger for contraction

The skeletal muscle fibers are innervated by large myelinated nerve fibers that originate from large motor neurons in the anterior horn of spinal cord

Each nerve ending makes a junction called neuromuscular junction with the muscle fiber near its mid point

AP initiated in the muscle fiber by the nerve signal travels in both the direction towards the muscle fiber length

There is one such junction per muscle fiber

Axons of these motor neurons travel in nerves to muscle cells

Axons of motor neurons branch profusely as they enter muscles called axon terminal

Each axon terminal forms a neuromuscular junction with a single muscle fiber

The motor end plate of a muscle, which is a specific part of the sarcolemma that contains receptors and helps form the neuromuscular junction

The axon terminal is enlarged into a knob like structure the terminal button which fits into the shallow groove or depression in the underlying muscle fiber.

This structure is called motor end plate

Synaptic gutter or trough: the invaginated membrane of muscle cell

Synaptic cleft or synaptic space: the space b/w axon terminal and fiber membrane

Subneural clefts: at the bottom of gutter are numerous folds of cell membrane to increase the surface area at which neurotransmitter acts

Numerous mitochondria which provide energy for synthesis of neurotransmitter which excite the muscle membrane

Secretory vesicles store neurotransmitter (300,000)

Since the space b/w two structures is too large to permit electrical transmission of an impulse b/w them

Action potentialat the pre-synaptic membrane activatesvoltage-gatedCa channels – Ca2+ influx – vesicles with neurotransmitter Acetylcholine (ACh) - the only transmitter here –releases this AChinto the synaptic cleft.

Motor fibers (axons of motoneurons) within the motor nerves conduct action potentials to the neuro-muscular junction.

The vesicles are formed by the Golgi apparatus in the cell body of the motor neuron in the spinal cord. Then they are transported to the tips of nerve fibers.

For continued function of NMJ these vesicles must be replenished

Acetylcholine binds with receptors on

postsynaptic (motor end-plate) membrane of

muscle cell – activation chemically gated

channels in the end plate – depolarization =

End plate potential when reaches a threshold

action potential is fired which spread in both

direction along the muscle membrane . Once

initiated, the action potential is unstoppable, and

ultimately results in the contraction of a muscle

Small amount of acetylcholine are released from axon terminals even when the motor nerve fiber and muscle are apparently and completely at rest . This small amount of acetylcholine give rise to small degree of depolarization of the post synaptic membrane called miniature end plate potential

If volley of AP arises greater depolarization called end plate potential occurs and if reaches the threshold AP is fired.

ACh bound to ACh receptors is quickly destroyed by the enzyme acetylcholinesterase

This destruction prevents continued muscle fiber contraction in the absence of additional stimuli

And if sustained contraction is needed for desired movement another motor neuron action potential leads to release of more acetylcholine so keeping contractile process going.

Each impulse that arises at NMJ causes 3 times as much end plate potential as that required to stimulate the muscle fiber.

So normal NMJ is said to have high safety factor

However stimulation of the nerve fiber at rates greater than 100 times per second for several minutes often diminishes the no. of acetylcholine vesicles so much that impulses fail to pass into the muscle fiber and finally muscle will not contract at all. This is called fatigue of NMJ.

Cause: inability of the synthesis of acetylcholine to keep pace with its release and hydrolysis.

In intact organism it is unlikely to be the site of fatigue.

Drugs that stimulate muscle fiber by acetylcholine like action:

1.Methacholine2.Carbachol3.Nicotine

Same effect as acetylcholine. But not destroyed by enzyme acetyl cholinesterase leading to continuous state of muscle contraction called muscle spasm

It causes explosive release of Ach from storage vesicles.

So prolonged depolarizationRespiratory failure

Neostigmine and pysostigmine inactivates acetylcholinesterase in the synapse

So Ach is not hydrolyzed so it accumulates leading to muscle spasm

Death due to respiratory muscle spasm

Inhibits release of Ach from the terminal button in response to a motor neuron AP.

It’s a type of food poisioning (botulism) resulting from improperly canned food contaminated with clostridial botulini bacteria which release a toxin inhibiting release of Ach from the nerve terminal

Muscle does not respond Death due to respiratory failure

Curariform drugs: these drugs block the effect of released Ach which binds reversibly to Ach receptors on motor end plate. So when they bind Ach cannot bind to receptors so channels do not open so no AP occurs. So muscle paralysis can occurs . If high dose given death due to respiratory paralysis.

They irreversibly inhibit acetylcholinesterase preventing the inactivation of released acetylcholine . Death from respiratory failure because the diaphragm cannot repolarize and returns to resting state(present in pesticides) so death due to muscle spasm

NeostigminePhysostigmine

They inactivate acetylcholinesterase in the synapse so that it no longer hydrolyze acetylcholine so it accumulates leading to muscle spasm. And can cause death leading to laryngeal spasm

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Progressive autoimmune disorder that blocks the ACh receptors at the neuromuscular junction

The more receptors are damaged the weaker the muscle. More common in women 20 to 40Begins with double vision & swallowing difficulties &

progresses to paralysis of respiratory muscles Treatment includes steroids that reduce antibodies that

bind to ACh receptors and inhibitors of acetylcholinesterase e.g. neostigmine which by inhibiting acetyl cholinesterase temporarily prolongs the action of Ach at the NMJ . The resultant end plate potential is of sufficient magnitude to initiate an AP and subsequent contraction in muscle fiber as it normally would

The skeletal muscle fiber is so large that APs spreading along its surface membrane cause almost no current flow deep within the muscle fiber

To cause maximum muscle contraction , current must penetrate deeply into the muscle fiber to the vicinity of separate myofibrils

This is achieved by transmission of APs along transverse tubules (T Tubules) that penetrate all the way thru the muscle fiber from one side of the fiber to the other

The T – tubule APs cause release of Ca ++ ions inside the muscle fiber in the immediate vicinity of the myofibrils and these Ca ++ then cause muscle contraction

This process is called excitation contraction coupling

Linking the electrical signal to the contraction is excitation-contraction coupling

Two membranous structures within the muscle fiber play an important role in linking the excitation to contraction .

These are :1.T tubules2.Sarcoplasmic reticulum

At each junction of A and I band the sarcolemma invaginate into the muscle fiber to form T tubule running perpendicular from one end of muscle fiber to other end.

These tubules contains ECF in them as they are internal extensions of the cell membrane

Therefore when an AP spreads over a muscle fiber membrane , a potential change also spread along the T tubules to the deep interior of the muscle fiber.

Action potential travels along sarcolemma, down T-tubule

This causes calcium to be released from sarcoplasmic reticulum

Adjacent to each T-tubule is a sarcoplasmic reticulum.

It is modified smooth ER consists of fine network of interconnected compartments surrounding each myofibril like a mesh sleeve

Lateral sacs or terminal cisternae: that lie adjacent to the T – Tubules it stores Ca ions

Longitudinal tubules: that surrounds all surfaces of the actual contracting myofibrils

The sarcoplasmic reticulum surrounds the myofibrils and holdsa reserve of the Ca2+ ions. A transverse T - tubules are the pathway for the action potential to signal the sarcoplasmic reticulum.

Action potential on T - tubules & sarcoplasmic reticulum activates voltage-gated Ca channels on cisternae and logitudinal tubules - Ca2+ released into intracellular space of muscle fiberCa2+ – isan initiatorof muscle contraction

the triad is a diagnostic feature of skeletal muscle

It is composed of two lateral cisternae on either side of a T-tubule.

It is not found in cardiac or smooth muscle

SR stores Ca++ when muscle not contracting When stimulated, calcium released into sarcoplasm

Muscle contraction continues as long as the Ca ions remains in high concentration

SR membrane has Ca++ pumps that function to pump Ca++ out of the sarcoplasm back into the SR after contraction

Inside the SR a protein called calsequestrin is present that can bind Ca ++ ions.

The normal resting state concentration of Ca++ in the cytosol is too little to elicit contraction.

But full excitation of T – Tubules and SR system causes enough release of Ca ions to increase the concentration about 500 times more which is 10 times the level required to cause maximum contraction . This is called Ca pulse.

So during Ca pulse muscle contraction occurs Immediately then Ca pump depletes the Ca ions

again

Same as in nerve fiber but following differences

RMP= -80 to -90mvsDuration of AP: 1-5 ms

( 5 times as long as in large myelinated nerve fibers)

Velocity of conduction: 3-5 m/s (1/3 of velocity in large myelinated nerve fibers)

As soon as the actin filament becomes activated by the Ca ions the heads of cross bridges from the myosin filaments become attracted to the active sites of the actin filament and cause muscle contraction by walk along theory or rachet theory of muscle contraction

When a muscle contracts work is performed and energy is required. Large amount of ATP is cleaved to form ADP during contraction process

Greater the amount of work performed by the muscle , the greater the amount of ATP that is cleaved.

This is called fenn effect

Before cross bridge ever links with the actin molecule that is before contraction begins the heads of the cross bridges binds with ATP .

The ATPase activity of myosin head immediately cleaves the ATP but leaves the cleavage product ADP and Pi remain tightly bound to the myosin head

And the generated energy is stored within the cross bridge to produce high energy form of myosin

Cross bridge is cocked like a gun & ready to be fired when the trigger is pulled

When the muscle fiber is excited Ca pulls the troponin tropomyosin complex out of its blocking position so that energized myosin cross bridge can bind with an actin filament.

This contact b/w actin and myosin filament pulls the trigger

The bond b/w head and active site causes a conformation change in the head prompting the head to tilt towards the arm of the cross bridge this provides the power stroke for pulling the actin filament towards the M line

During the power stroke the inorganic Pi is released and ADP after power stroke

So when both are released the myosin ATPase site is free for attachment of another ATP molecule.

The actin and myosin remain linked at the cross bridge until a fresh molecule of ATP attaches to myosin at the end of power stroke

Attachment of new ATP permits detachment of cross bridge which returns to its unbent form ready to start another cycle pulling actin inward towards M line

One ATP molecule is split by each cross bridge in each cycle

However the cross bridges are all out of synchronous so there are always many cross bridges attached at any one time to maintain force otherwise the thin filament would slip back towards their resting position b/w strokes.

Greater the number of cross bridges in contact with the actin filament at any given time the greater the force of contraction

1. Action potential generated and propagated along sarcomere to T-tubules

2. Action potential triggers Ca2+ release

3. Ca++ bind to troponin; blocking action of tropomyosin released

4. contraction via crossbridge formation; ATP hyrdolysis

5. Removal of Ca+2 by active transport

6. tropomyosin blockage restored; contraction ends

Figure 9.10

Fresh ATP must attach to myosin to permit the cross bridge link b/w myosin and actins to break at the end of the cycle.

So this phenomenon is seen in rigor mortisIt is generalized locking of the skeletal muscles

that begins 3-4 hours after death and completes in about 12 hours.

This rigidity of muscles results from loss of all the ATP which is required to cause separation of the cross bridges from the actin filament . With the lack of oxygen and circulation, ATP production quickly stops.

The muscle remains in rigor until the muscle protein deteriorate about 15-25 hours later from autolysis from lysosomal enzymes . All these events occur m ore rapidly at higher temperature