muscle physiology review 2015

7/21/2019 Muscle Physiology Review 2015

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MUSCLE PHYSIOLOGY 2015

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MUSCLE PHYSIOLOGYOBJECTIVES HIGHLIGHTS

Compare the duration of skeletal,cardiac and smooth muscleaction potentials and describe

their underlying ionicmechanisms.

Skeletal muscle action potentials duration is 2-5 ms,

Cardiac muscle action potentials duration is 200-400 ms,Smooth muscle action potentials duration is variable, can bevery prolonged (in the range of seconds).

Depolar izat ion is brought by the influx of Na+ in skeletal andsome types of cardiac muscle fibers (i.e. conduction fibers,atrial and ventricular fibers).Depolarization is generated by the influx of Ca2+ in nodal cellsof cardiac tissue and in some smooth muscle fibers.

Repolar izat ion is invariably brought about by the opening ofK+ channels in all types of muscles fibers.

Cardiac and smooth muscle action potentials are prolonged(last longer) due to the opening of calcium Ca2+channels.

The figure below identifies the contribution of changes in theconductance of the major ions (Na+, K+, Ca2+) (g ion) in theconfiguration of the action potential for each muscle type.

gNa+ = sodium conductancegK+ = potassium conductance, gCa2+ = calcium conductance

Compare the neural regulation ofmuscle function for the threemajor types of muscle.

For skeletal muscle contraction, force is totallydependent on neural stimulation through temporal andspatial summations of motor units.

For cardiac muscle, the Autonomic Nervous Systemdoes not initiate contraction but modulates thefrequency of activation, the velocity of conduction andthe force of contraction.

Smooth muscle contraction regulation isheterogeneous. There are subtypes in which

Ventricular Pacemaker

gNa+

gCa2+

gK+

2 ms2 ms2 ms 200 ms200 ms300 ms300 ms300 ms

10 s10 s

SmoothSmoothSkeletalSkeletal CardiacCardiac




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contractions are dependent on neural stimulation (i.e.mult iun i t ) while in others (i.e. uni tary ) contractions aremyogenic (independent of neural stimulation).

Describe the neuromuscular junction (i.e. motor endplate)found at skeletal muscles andhow acetylcholine (ACh) vesiclesare released here.

The motor end-plate is composed of (1) a pre-synapticelement constituted by branches of the motor neuron axon(2) a synaptic cleft or space between the pre and post-synaptic membranes (3) a post-synaptic element, formed bythe muscle cell membrane, organized in folds, immediatelybeneath the axon terminal. In these folds are located manynicotinic acetylcholine (ACh) receptors. Few or none AChreceptors are located in the muscle membrane outside theneuromuscular junction.

When a nerve action potential reaches the pre-synapticnerve terminal it opens Ca2+ channels through whichexternal calcium enters. The calcium is necessary for thefusion of ACh vesicles found in the motor neuron terminalto the endplate pre-synaptic membrane for the eventualrelease of ACh into the synaptic cleft.

Identify the role of acetylcholine(ACh) in the neuromuscular

junction.

ACh interaction with its receptor (i.e.nicotinic) at the motor -endplate (post-synaptic membrane) opens a cation agonistoperated-channel through which K+ moves out and Na+ moves in. This movement of ions in and out of the cellgenerates an end-plate potential (at the post-synapticmembrane only) which is the trigger (through depolarization)

that pushes adjacent skeletal muscle membrane to thresholdpotential. When threshold potential is attained, voltage-dependent Na+ channels in the muscle membrane open andgenerate the skeletal muscle action potential.

1

2

3




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Identify the location of

acetylcholinesterase and what itits role in the neuromuscularprocess.

This enzyme is located in the post-synaptic membrane of

the endplate and its role is to hydrolyze ACh, ending itsaction at the nicotinic receptor.

Recognize the importance of theT tubule in striated (skeletal &cardiac) muscle contraction.

The T tubule comprise a network of invaginations of thesurface membrane (sarcolemma) that runs deep into themuscle fiber at the level of the junction between the A andI bands of each sarcomere of mammalian striated musclesTheir function is to spread action potentials to the celinterior. This event is necessary to open ion channels(dihydropiridine receptors, at the T-tubule) that permits

extracellular Ca2+

entry (in cardiac muscle) or to generateconformational changes (in skeletal muscle) that results inthe opening of sarcoplasmic reticulum (SR) Ca2+ channels(ryanodine receptors, for the release of stored calciuminto cytoplasm (in skeletal and cardiac muscles).

Identify the role of sarcoplasmic

reticulum (SR) in musclecontraction.

In addition to serve as a storage and release site for

Ca

2+

, the sarcoplasmic reticulum functions as an uptakesite for these ions.

The membrane of SR contains, mainly in the non-junctionalsurfaces, transport pumps- (Ca2+ATPases) that have ahigher affinity for Ca2+ than does troponin. The calciumuptake is an energy requiring process since it must pump




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Ca2+ against a concentration gradient. ATP hydrolysisprovides the energy.

Moreover, the calcium uptake rate is regulated by the cytosolic

Ca

2+

concentration. In the resting muscle, when cytosolic Ca

2+

islow, the uptake rate decreases. However, as the cytosolic Ca2+ increases during excitation, the SR-uptake rate increases.

In addition, the SR interior contains a protein called calsequestrin that can weakly bind about 43 Ca2+ ions/molecule. Calsequestrin acts to reduce the sarcoplasmicreticular concentration of Ca2+ from perhaps 20 mM, if all werefree, to an estimated 1.0 mM. This action reduces theconcentration against which the pumps must act and reducesenergy expenditure.

Identify the normal restingintracellular calciumconcentration in a muscular cell,and its level upon activation.

Resting cytosolic Ca2+ :10-7M (0.1 M)

Cytosolic Ca2+ upon activation : 10 -6- to 10 -5M (1- 10 M)

Identify the significance ofextracellular calcium for theinitiation of skeletal, cardiac andsmooth muscle contraction.

Extracellular calcium is not needed for skeletal muscle contraction since abundant stores of Ca2+ are found in thelarge and developed SR. Therefore, for skeletal musclethe source of calcium for activation is intracellular (at the

SR).

Extracellular calcium is extremely important in bothcardiac and smooth muscle, because they exhibit thephenomenon of calcium-induced calcium release (CICR) in which extracellular calcium enters the cell andrelease calcium stored at the SR’s. SR’s of these types ofmuscles are not so well developed as in skeletal muscle.

SKELETAL CARDIAC SMOOTH

varicosityvaricosity

SR

SR

T-tubuleEnd-plate

Ryanodine

receptor

d ihydrop i r id ine

receptor

SR

T-tubule

SKELETAL CARDIAC SMOOTH

varicosityvaricosity

SR

SR

T-tubuleT-tubuleEnd-plate

Ryanodine

receptor


receptor

SR

T-tubuleEnd-plate

Ryanodine

receptor


receptor

SR

T-tubule

INTRA-

CELLULAR

EXCITATION-CONTRACTION COUPLING

EXTRA-CELLULARSource

of Ca2+

for

activation:

Ca2+-induced Ca2+ release

EXTRA-CELLULAR

Ca2+-induced Ca2+ release

Ca2+-store operated channel




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Identify the mechanisms throughwhich intracellular calcium

activates contractile proteins inskeletal, cardiac and smoothmuscle.

Ca2+ binds to regulatory proteins:

(1) troponin (in cardiac and skeletal muscles). This eventreleases the inhibition provided by tropomyosin, anotherregulatory component of the thin filament that is preventing theinteraction between actin and myosin when the muscle is atrest (i.e. when intracellular Ca2+ is low).

(2) calmodulin (smooth muscle) which activates myosin ATPase activity necessary to generate the sliding of actin andmyosin and the generation of force.

Identify the force generating stepin the cross-bridge cycle.

A to D show the crossbridge cycle. The swiveling ofmyosin head (90° to 45°) upon the release of ATPhydrolysis products (ADP and iP) (i.e. C to D) is the forcegenerating step.

Explain the mechanism for the r igor mort is in skeletal muscle.

When ATP levels are low, interaction between myosinand actin continues (the filaments cannot detach) and thecrossbridge-cycle stops in the contracted state. At thisstage the myosin head remains attached to the actinfilament at a 45° angle.




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Identify the organization ofprotein components in a striatedmuscle sarcomere.

Each sarcomere contains: a central dark A band,half of two lighter I bands delimited at both ends by a darklydark structure termed the Z line.

The A band arises from a particular arrangement between thickand thin filaments, while the I bands result from the arrangementof the thin filaments. The Z line is where adjacent sarcomerescome together.

Thick filaments are composed of myosin molecules.

Thin filaments are composed of G-actin, a globular protein thatpolymerizes to form a twisted two-stranded filament, F-actin; andtwo regulatory proteins, tropomyosin and troponin.

Describe the mechanism and theevidence for the sliding filamenttheory of muscle contraction.

Individual contractile fibers (thick and thin) do not change size,they overlap (slide) one past another. This has been supportedby the constancy of band A (mainly thick filaments) duringcontraction and relaxation. Only the I and H bands reduce insize with contraction.

Relaxed

Contracted

A band

A band




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Identify the energy sources formuscle contraction.

ATP is the immediate fuel for energy. ATP is generated fromthe hydrolysis of creatine phosphate which is used to re-phosphorylate ADP (fast source, but is found in limitedamounts). Glucose is the preferred source of musclecontraction. Anaerobic breakdown of glucose-glycolysis- also

yields ATP but in limited amounts. Oxidativephosphorylation of glucose provides the greatest amount of

ATP for contraction.

Distinguish between fast andslow skeletal muscle fibers.

Fast fibers (type IIb) fatigue easily, obtain energyanaerobically, do not possess much myoglobin (white fibers)and are part of large motor units that have high thresholds(i.e.do not respond easily) for their activation.

Slow fibers (type I) generate tension slowly, are fatigueresistant, possess great quantities of myoglobin (red fibers),depend mainly on aerobic reactions (i.e.oxidativephosphorylation) and are the first to be activated because oftheir low thresholds.




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Identify the concept of motor unit in skeletal musclephysiology

A motor unit is the motor neuron and the muscle fibers it innervates. Themotor unit is considered as the functional contractile unit because allthe cells within a motor unit contract synchronously (all-or none effect)when the motor neuron fires.

Types of motor units:

The SLOW MOTOR UNIT, also called the small motor unit (S), since itis innervated by small (slowly conducting) motoneurons and musclefibers belonging to type I classification (red fibers). This occurs inmuscles in which a high degree of control is exercised over finemovements; the motor axon will control only few muscle fibers. This

unit is recruited first and is the most frequently used unit.

The FAST FATIGABLE (FF) MOTOR UNIT, also called the large motor unit, innervated by large (rapidlyconducting) motor neurons. The innervated fibers are the white muscle fibers, type IIb. They contract andfatigue quickly since they generate ATP only by anaerobic glycolysis of glucose and glycogen. These areobserved in muscles that are specialized for large rapid movements with little fine control. Therefore, asingle motor axon will control a relatively large portion of the whole muscle. They are recruited for moreforceful movements.

THE FATIGUE RESISTANCE (FR) MOTORUNIT. This type of motor unit has properties thatare intermediate between the other two (i.e, FR

motor unit generates about twice the force of aslow unit.). The innervated muscle fibers aredenominated type IIa.

Recruitment of motor units follow a size princ iple ,motor units are recruited in order of increasing size(the small ones, first). When only a small amount offorce is required from a muscle with a mix of motorunit types, this force is provided exclusively by thesmall S units. As more force is required, FR and FFunits are progressively recruited, normally in aremarkably precise order based on the magnitudeof their force output. This minimizes thedevelopment of fatigue by using the most fatigue-resistant muscle fibers most often (holding morefatigable fibers in reserve until needed to achievehigher forces)




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Identify the meaning of a twitch. The twitch, is a single brief contraction produced by the arrival ofa single nerve action potential. Under constant conditions oftemperature, fiber length, the magnitude of the twitch is aconstant, all or none property, which means that once anappropriate stimulus activates a single fiber (or a single motor

unit), increasing the stimulus strength will cause no progressiveincrease in the strength of contraction. This is a result of the factthat a single skeletal action potential will release (from the SR)the same amount of Ca+2 regardless of the strength of thestimulus.

Define tetanus, and how isgenerated.

This is a sustained skeletal muscle contraction generatedupon the activation of muscle by repetitive (increase infrequency) stimulation of motor units.

This prolonged contraction with a force 3-5 fold greater than thetwitch is generated if the muscle fiber is re-stimulated before ithas relaxed completely, the second twitch will add its mechanicaleffect to the first, and the third stimuli add on to the mechanicaleffect of the first two stimuli and so on in a process calledtemporal summation.

Distinguish between a temporaland spatial summation duringthe activation of skeletal muscle.

In both, muscle force is greater than that observed during asingle twitch but for temporal summation the increase in forceis the result of an increase in the frequency of stimulation to aspecific motor unit while in the spatial summation the increasein force is the result of an increase in the number of motorunits (increase in # of total fibers) recruited. Spatialsummation is due to an increase in the intensity of stimuliwhich activate more motor units which have higher activationthresholds.

TEMPORAL SUMMATION SPATIAL SUMMATION




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Differentiate between preloadand afterload.

Preload is an external forcewhich stretches the muscleat rest and determines thesarcomere length before itsactivation. This event is

necessary to determine the# of actin-myosininteractions and thereforethe force magnitude thatwould generate uponactivation.

Afterload is an external force that opposes to musclecontraction upon its activation and will determine if themuscle can move the load or exert its maximal tension .

Differentiate between isotonicand isometric contraction.

During isotonic contraction, muscle will shorten and move theload with certain velocity and generate a constant tension tobalance the afterload (external weight).




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During isometric contraction the muscle does not shortenexternally (velocity is zero, there is no change in length) butthere is a gradual increase in tension (force) up to itsmaximum level. This happens when the afterload is heavierthan the maximal force that the muscle can develop.

Explain the mechanical propertyof muscles known as the length-tension relationship. Describeits structural basis and what ismeant by Lo.

This property is observed when an isolated muscle is arrangedexperimentally to record isometric contractions. It is based onthe observation that the length of a resting muscle (determinedby the preload) affects the force of its contraction uponactivation.

A relaxed isolated muscle does not have any resting tension. If theresting muscle is stretched, resting tension will increaseexponentially. The curve generated by such manipulationdescribes the passive tension curve.

When the experiment is repeated using muscle stretched atdifferent levels, but now stimulated with pulses of supramaximalintensity and tetanic frequency, another curve could be obtained.This curve is the total tension curve, which is the sum of passiveforce and the active force developed by crossbridge cycling ofcontractile fibers.

An active tension curve could be derived also by subtracting the passive from the total tension at each muscle length.




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The structural basis of the length-tension relationship is:

- The passive relationship is due to the elastic behavior of thecell membrane and of the connective tissue (parallel elasticelements) between the muscle cells. These structures resist the

forces applied to a resting muscle.

- The active relationship is due to the interaction between actinand myosin molecules within the sarcomere and depends uponthe degree of overlap of thick and thin filaments prior toactivation:

There is an optimal length (Lo)(i.e. 2.0 m) where the maximal number of interactions between actinand myosin is possible. At this resting sarcomere length muscle will generate a maximal force uponactivation.

Explain the mechanical propertyof muscles known as the force-velocity relationship.

This is the inverse relationship between the generated force and the magnitude of the velocity of contraction.

The larger the afterload a muscle has to balance or oppose,the smaller the shortening velocity it develops. On the otherhand, when afterload is zero (Y intercept, in the graph), themuscle exhibits its maximal velocity, Vmax.

When the afterload is too heavy to be moved, (V = 0, point A),the muscle exhibits its maximal force of contraction (Fmax, alsoknown as Po).

afterload

Vmax is a function of the myosin ATPase activity (i.e. the higherthe ATPase activity, the greater the velocity, fast fatigablefibers will exhibit higher Vmax than slow fibers).




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Identify functional similaritiesand differences between skeletaland cardiac muscle.

Similarities: In both muscles, contraction is actin-regulated. Sarcomeres slide. There is an optimal lengthat which force is maximal (Lo). Activation of myofibrils inboth depends on T tubule association with internal

sarcoplasmic reticulum calcium stores.

Differences:

All cardiac muscle fibers are activated in each heartbeat due to gap junctions (at the intercalated disks)which make this tissue a functional syncitium.

Cardiac action potentials are very long (300 ms), anevent that prevents tetanization, since muscle isrefractory to another stimulus while it is depolarized.

At normal resting state (diastole) sarcomere length(i.e.preload) in cardiac muscle does not yield maximal

tension. Changes in active tension for cardiac muscle can

be generated by changes in the amount ofcytoplasmic calcium available. Calcium enters fromthe extracellular fluid. Norepinephrine facilitatescalcium entry and increases the force of contraction.

Passive tension (generated by elastic elements) at restfor cardiac muscle is higher than that observed forskeletal muscle.

Contrast the major differences

between cardiac and skeletalmuscle length- tensionrelationship

Passive Tension Curve: Although isometric force is

altered by changes in resting muscle length, (as in skeletamuscle) quantitatively, cardiac muscle exhibits greaterpassive force at all sarcomere lengths. At Lo (optimalength), skeletal muscle exhibits almost no passive forcewhereas for cardiac muscle at Lo, passive force is 15-20% of total force This passive tension, which risessteeply beyond the optimal length, represents a safetyfeature that serves to prevent over-extension of thecardiac muscle in the event of excessive filling.

Active Tension Curve: The subtraction of the PassiveTension Curve observed during each resting length fromthe Total Tension Curve (obtained upon stimulation of themuscle preparation) yields an Active Tension Curve, verymuch like that of skeletal muscle. Little active tension isdeveloped at very short or very long resting lengthsActive tension is maximal at an intermediate length - Lo.




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However, contrary to skeletal muscle, in which its boneattachments set the resting length at Lo, unstressedcardiac muscle fibers normally operate at lengths welbelow Lo. Therefore, for cardiac muscle, increasing

sarcomere length (from 2.0 to 2.3 µ) increases the tensiondeveloped during an isometric contraction. Themechanism that explains the length-tension relationshiplike in the skeletal muscle, is based on the extent of overlapof the thick and thin filaments in the sarcomere at rest.

Identify the effect of changes inpreload in the force-velocityrelationship of cardiac muscle

Similar to skeletal muscle the velocity of contraction, at anyinitial length, is altered by the afterload. Increasing theafterload will cause a greater amount of the total contractileenergy to be utilized during the isometric phase of thecontraction to develop tension and less will be available for lifting(shortening) the weight at some rate.

Contrary to skeletal muscle (in which resting length is set by itsattachments to bone) velocity of contraction of an afterloadedcardiac muscle is also altered by its resting length.

When the resting length (preload) is increased, the tensionis augmented according to the length-tension relationship

There is an increase in P0, which is the measure of thenumber of active cross-bridge interactions (or maximaforce) and

There is a change in the velocity of shortening at all

loads except at a zero load. Or in other words, themaximum rate of force development (Vmax) does not changewith variations in resting length.




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The Vmax of cardiac muscle under unstressed conditions ismuch lower than that observed in skeletal muscle. Such

observation is consistent with a lower rate of cardiac myosin ATPase and the concomitantly slower rate of cross-bridgeturnover.

Define refractory period Refractory period is a feature of excitable tissue and itsduration parallels the duration of the action potential. Therefractory period refers to the time a cell is unable torespond to a stimulus and generate another action potential.

Identify the timing of refractoryperiods in cardiac muscle.

In the first part of this period- the effective refractory period(ERP) - a stimulus cannot activate the cell because of theinactivation of fast Na+ channels and the cell is totally

unexcitable. For cardiac fibers developing fast action potentiathis period extends to the half of phase 3.




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The second part- the relative refractory period- begins asmembrane voltage becomes more negative and lasts from themiddle of phase 3 to the restoration of normal resting potential(phase 4). During this period the cell will require a strongerthan normal stimulus to evoke a response and the action

potentials generated are of smaller amplitude and duration

Identify the importance of longrefractory periods in cardiacmuscle.

The figure shows that the time relationship between theelectrical and mechanical responses is different focardiac muscle when compared to skeletal muscleSkeletal action potential and refractory period are of shortduration (2 ms). Therefore, mechanical responses can besummed.




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As illustrated in the figure below the duration of cardiacaction potential is as long as the contractile response.Thus, the cardiac muscle relaxes before it is possible tostimulate it again because of its long refractory period.

It is impossible to generate tetanus (or temporalsummation) in cardiac muscle as it happens in skeletalmuscle.

Distinguish betweenheterometric and homometricregulation of cardiac musclecontraction.

The mechanisms that regulate force in cardiac muscle are based on the discussed intrinsic mechanicalproperties of cardiac muscle and can be classified aseither:

Heterometric- those that involve changes in restingsarcomere length. Or in other words those whichdepend on the length-tension relationship discussed

before.

Homeometric-those which do not involve changes inresting sarcomere length. In other words those whichdepends on changes in contractility.

Define the cardiac muscleproperty known as contractility

Contractility may be defined as a certain level offunctional capability (measured by a quantity such as forceshortening velocity) when it is measured at a constantmuscle length.

Skeletal muscle has a fixed contractility since peak forcedepends of resting muscle length, which does not changefrom contraction to contraction. On the contrary, cardiacmuscle exhibits variable contractility, which representsone of the mechanisms for the modulation of force in theheart. Any factor, intrinsic and extrinsic, that affects cardiaccontractility is called an inotropic agent.




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A factor which increases contractility is said to be a positiveinotropic agent. Conversely, those that decrease heartcontractility are negative inotropic agents.

Identify the effect of changes incardiac muscle contractility inthe force-velocity relationship.

In Force-Velocity Curves contractility changes will beexpressed as shifts in the Vmax but will not affect theP0 value. For example, this indeed is what happensduring tachycardia which temporarily increasescontractility.

Identify the effect of changes incardiac muscle contractility inthe isometric twitchdevelopment.

During isometric twitch development, changes in the leveof inotropic state are reflected not only by changes in thepeak tension but also, occur in the rate of tensiondevelopment and the rate of relaxation associated withchanges in the duration of contraction).

For example, a positive inotropic stimuli (such asNorepinephrine & Digitalis,( i.e. curve A ) produces anincrease in peak isometric tension, decreased time to peak

tension and shortening of the duration of contraction.




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Identify the molecular basisexplaining changes in cardiaccontractility.

The inotropic state is determined directly by subcellularprocesses that regulate the concentration of cytosoliccalcium during activation of cardiac muscle.

Under normal conditions the contractile filaments of cardiacmuscle are only partly activated. This is because, unlike thesituation in skeletal muscle, not enough calcium is released tooccupy all of the troponin molecules, and not all potentiallyavailable crossbridges can attach the thin filament and cycle. An increase in the availability of calcium would increase thenumber of crossbridges activated. Therefore, contractility ismodulated by factors that affect intracellular calciumavailability.

Define the importance offrequency of heart beats in thedetermination of cardiac muscleforce.

Several examples of this relationship, also known as the force-

frequency relationship has been described.

The Staircase or Treppe Phenomenon in which a rapidincrease in heart rate causes gradual increases in force overthe next several beats.

Rest-Potentiation- A rest period between beats augmentsthe force of the following few beats.

Post-extrasystolic potentiation- A pause after anextrasystole will be followed by a stronger contraction.

The above responses are intrinsic to cardiac muscle and areprobably due to temporary alterations in cardiac musclecontractility due to a time-induced alteration in Ca2+ availability to the muscle cell.




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Compare smooth muscle actionpotentials with skeletal muscleaction potential.

Although different types of smooth muscle differ only slightly inresting membrane potential, they differ markedly in the types ofmembrane potentials exhibited when they are excited. Actionpotentials are usually seen in unitary (visceral) smoothmuscle. The smooth muscle cell membrane has far more

voltage-gated calcium channels than skeletal muscle. Flow ofextracellular calcium ions to the interior of the fiber is mainlyresponsible for the action potentials. Since calcium channelsopen and close more slowly than sodium channels, thisaccount for the slower upstroke and longer duration (up to

100 ms) than do skeletal muscle action potentials ( 2 ms). Some of the calcium channels are activated by a ligand(receptor-activated) or the stretch of the plasma membrane.Moreover, action potentials do not occur in all cells that areactivated by ligand-receptor interaction or stretch. In these cells,calcium influx may be matched by an efflux of potassium,resulting in small or no changes in membrane potential.

Action potentials leading

to a twitch or summedmechanical response

Slow waves triggeringaction potentials.

Contractions associatedwith burst of action potentials.

Tone contractile activityrelated to membrane potential changesin the absence of action

potentials.

Changes in force produced bythe addition or removalof hormones in the absence

of membrane potential changes.




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Identify the mechanism throughwhich calcium regulatescontraction in smooth muscle.

Calcium binds to calmodulin which in turn activates themyosin light chain kinase (MLCK) which phosphorylatesmyosin light chains in the thick filaments. Thephosphorylation is crucial for myosin binding to actin.

Relaxation occurs when calcium levels decrease anddoes not support the activation of MLCK kinase tophosphorylate MLC. This will shift the equilibrium todeposphorylated myosin that has low affinity for actin,therefore producing relaxation. There is always a MLCphosphatase activity (an enzyme that catalizes thedephosphorylation of MLC) even during contraction.

Relaxation can also be produced by agonist stimulation:The neurotransmitter norepinephrine, upon activation of

their -receptors can stimulate the production of cAMPthat activates a cAMP-Protein kinase responsible forenahncing Ca2+ uptake by the SR. This kinase can alsoreduce the activity of MCLK.

Another agent that induces relaxation in smooth muscle isNitric oxide (NO). NO through the stimulation of cGMPlevels will activate a cGMP dependent Protein kinase, thatpromotes Ca2+ uptake by the SR.

Describe the autonomic nerve(ANS) influence over smoothmuscle.

There are no structured neuromuscular junctions.Functionally however, they are comparable since there arecorresponding pre-synaptic release of transmitter, diffusionacross the junction and combination with a post-synapticreceptor. The muscle membrane itself is not specializednear the "junction". One autonomic nerve will produceseveral varicosities, or swellings abundant in neuro-transmitter vesicles. Each varicosity will be near a sectionof the muscle's cell membrane and in conjunction they willform the neuromuscular junction.

This is a slow process since neurotransmitter mustdiffuse out from varicosities to individual muscle fibers.Nerve stimulation is mainly to modulate spontaneousactivity.




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Distinguish between theanatomical distribution ofneuromuscular junctions atmultiunit and unitary smooth

muscle

In smooth muscle, neuromuscular junctions are notstructurally defined and specialized as in skeletal muscleThe distance varies from one type of muscle to another:

Multiunit Varicosities located 6 to 20 nm from celmembrane. Few gap junctions between cells

Single unit Varicosities at 80 to 120 nm from celmembrane limiting responses to neuraactivity.

Compared to skeletal muscle, the neurotransmission insmooth muscle is slower and in many types this influencemainly works to modify spontaneous activity.

Define the concept “slow waves” in smooth muscleelectrophysiology.

Refers to the periodical variation in the resting potentiavalue. Slow wave potentials are due to a gradual cycling betweena relatively depolarized and polarized state that are postulated tobe caused by automatic cyclical changes in the rate at whichsodium ions are actively transported across the membrane.

The slow waves themselves cannot cause musclecontraction, but when the potential of the slow wave rises above

the threshold, action potentials (spikes) develop and spread ovethe muscle mass.

Slow waves

spikes




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Describe the major types ofsmooth muscle contraction.

(1) Phasic activity, which refers to rapid contractions followedby relaxations. Mainly considered the result of neuralinfluence.

(2) Tonus in which muscle remains with active tension for

long periods. Mainly considered the result of muscleactivation by hormonal, metabolic factors.

Compare excitation contractioncoupling mechanisms in smoothmuscle with that observed inskeletal muscle.

As in striated muscle, contraction and relaxation of smoothmuscle are regulated by changes in the amount of cytosoliccalcium. However, contrary to skeletal muscle, in addition tostimuli that increases in cytosolic calcium, smooth muscle cellscan respond actively to stimuli that cause a lowering of cytosolicCa2+ inducing relaxation or reduction of tone. Since smoothmuscles are functionally diverse and generate various types omechanical activity there are also a variety of mechanisms thatinteract to determine the cytosolic calcium in smooth muscle.

Coupling between activation and contraction in smooth musclecontrary to skeletal situation, may be of two types:

Electromechanical co upl ing in which the contraction ispreceded by a depolarization of the cell membrane.Calcium enters from the extracellular space through eithervoltage gated channels or through receptor operatedchannels and depolarizes the cell. The influx of calcium canactivate contractile proteins directly or can induce morecalcium release from sarcoplasmic reticulum.

Pharmacomechanical coupl ing in which an agent (i.e.hormone, drug, and neurotransmitters) initiates contractionthrough the activation of G-protein coupled receptors. The activation of these receptors leads to formation ofsecond messengers such like IP3 and diacylgylcerol. IP3 willeventually induce the release of intracellular Ca2+ from




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internal stores. In this case, elicited contractions are notassociated with changes in membrane potential.

Identify similarities and differences on the length tension relationship of smooth musclewith that observed in striated muscles.

The force-length relationship curves for skeletal and smooth muscles are qualitatively similar. The passiveforce-length curve demonstrates that relaxed smooth muscle, due to a large amount of connective tissuecan withstand high distending forces. Also, like in striated muscle, the active force developed onstimulation depends on tissue length. These observations have been taken as evidence to suggest thaa sliding filament mechanism also explain contraction in this type of muscle.

Smooth muscle howeveris capable of shorteninga far greater % of its

length than can skeletalmuscle while maintainingalmost full force ofcontraction. Skeletalmuscle has a usefuldistance of contraction ofonly about 1/4 to 1/3 of itsstretched length, whereassmooth muscle can oftencontract quite effectivelymore than 2/3 of itsstretched length.

The enhanced shortening ability has been related to the irregular arrangement of contractile filamentsWith less myosin available, smooth muscle can generate active forces comparable and sometimes greaterthan skeletal muscle.

Compare the force-velocityrelationship of smooth musclewith that observed in striated

The velocity-force curves determined for smooth muscleexhibit the characteristic hyperbolic fall in velocity withload. Graphically, this produces a curve similar to that offast and slow skeletal muscle but very differentquantitatively. Contraction velocities are much slower insmooth muscle.

Most smooth muscles therefore require several seconds todevelop maximal isometric force. In fact, the specificATPase activity of phosphorylated smooth muscle myosinis more than 100 fold lower than the fast skeletal myosinisoenzyme. The low activity is reflected in the low energycost of tension maintenance.




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muscles

.

Moreover, another important difference between smoothand skeletal muscle is that smooth muscle appears toposses mechanisms for regulating the rate of cross-bridge cycle as well as the number of activated bridges.

The following figure illustrates that the force-velocity curveschange with the percentage phosphorylation of myosin

crossbridges.

Describe the long term effects ofexercise on skeletal muscle.

The effects of exercise on muscles varies with the type andduration of the activity. Aerobic exercise is typical ofactivities requiring endurance and sustained musclecontractions. Such activities rely mainly on Type I (slow-

twitch muscles) which sustain contraction for extensiveperiods of time. This use of slow-twitch muscle, and theavailability of O2, prevents the buildup of lactic acid andtypically does not result in substantial muscle fatigue in theshort-term. Sustained aerobic respiration tends to shift themetabolic pathways of muscle to favor the use of fat as theprimary source of ATP and glycogen is generally avoided.

The major long term effect of exercise includes:Hypertrophy of fibers (more actin and myosin, same # ofcells)

Increase in tendon strength. Increased capillary networks.

Increase in myoglobin stores.

Increase # of mitochondria.

Increase storage of glycogen and fat.

Increase tolerance to lactic acid.




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Describe the effects of aging onskeletal muscle.

Reduced muscular mass which reduces strength. Lostmuscle tissue may be replace by tough fibrous tissue.Reduced flexibility.Muscle may lose tone

Increase risk of injuries.Reduced activity tolerance and reduced reflexes. Appearance of involuntary movements (tremor &fasciculation) and abnormal sensations (paresthesias).

FEATURE SKELETAL CARDIAC SMOOTH

fiber structure long, multinucleatedstriated appearanceunder the lightmicroscope

short, thin,mononucleated,striated appearanceunder the lightmicroscope

short,mononucleated,homogeneous(smooth) structureunder the lightmicroscope

cellarrangement

parallel series Both parallel and inseries

Origin ofcontraction

neurogenic myogenic myogenic, neurogeniand humoral

Filamentsrelaxationmechanism

due to Ca2+ uptake bySR. State of inhibitionby regulatory proteinsreturns as Ca2+ ionsare captured by SRCa2+ ATPase(SERCA).

due Ca2+ uptake bySR. State ofinhibition byregulatory proteinsreturns as Ca2+ ionsare captured by SRCa2+ ATPase.

Occurs when MLC Phosphatase activitpredominates overMLC kinase activitymyosin isdephosphorylated andetaches from actin.

myofilaments thin and thick (2:1) thin and thick (2:1) Thin and thick (15:1)

myosin content (1/3-1/5 of skeletal muscle

thin filamentsattachment

at Z lines at Z lines To the dense bodies




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T tubules Located at the junctionof A and I bands

at the Z lines none (caveoli ?)

sarcoplasmicreticulum

Abundant Less developed not so abundant

structuralarrangement offibers

Sarcomere sarcomere unknown

fiber to fiber

communication

None Many, through

intercalated disks

In single unit type:

many and variable(gap junctions),In multinunit type:none

contractilemodel

sliding of filaments sliding of filaments sliding of filaments

regulation ofcontraction

Neurogenic (somaticmotor neurons)

Intrinsic: Force-Length

Extrinsic: AutonomicNervous System(ANS), hormonalchanging contractility

Neurogenic (ANS,intrinsic nerves)

pharmacogenic(hormones,metabolites),stretch

control offilamentsactivation

actin-linked :Ca2+ binding totroponin removestropomyosin inhibitionof actin-myosin

interaction.

actin-linked :Ca2+ binding totroponin removestropomyosininhibition of actin-

myosin interaction.

myosin-linked :Ca2+ binds tocalmodulin andactivates MLCK whicphosphorylates and

activate myosinfilament.

restingmembranepotential

stable (-90 mV), due topermeability to K+

Unstable inpacemaker cells,

multiunit: stable (-50mV)




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Stable in Purkinje,ventricular, atrialfibers.

single unit: variable(expressed as slowwaves)

ionic basis foraction potential

Opening of voltage-activated channels forNa+ and K+

Opening of voltage-activated channelsfor Na+, Ca2+and K+

Opening of voltage-activated andagonist-activated Cachannels.

neuromuscular junction

end-plate formed bya pre-synapticcomponent- branchesof motor axon;post-synaptic

component -specialized folds insarcolemma.

ANS nerve axondevelops swellings – varicosities nearbycardiac cells, nospecial structure in

cardiac cell plasmamembrane.

ANS nerve axondevelops swellings -varicosities- nearbysmooth membranecells, no special

structure in smoothcell plasmamembrane.

Restingcystoliccalciumconcentration

10-7M (0.1µM) 10-7M (0.1 µM) 10-7 (0.1 µM)

Cytosolic

calciumduringcontraction

10 -6 to 10 -5M 10 -6- to 10 -5M 10-6 to 10 -5M

Calciumsources forcontraction

intracellular-sarcoplasmic reticulum

Both extracellular(primarily) andintracellular -sarcoplasmicreticulum

Both extracellular(primarily) andintracellular -sarcoplasmicreticulum

Excitationcontractioncoupling

Mechanical coupling (conformation)between T tubule(DHP receptor) andsarcoplasmic(ryanodine receptor)calcium channels

Ca2+

inducedcalcium release:calcium enteringCa2+ channel in Ttubule activatesarcoplasmic

Ca2+

induced calciurelease, IP3 mediateCa2+ release from SRCa2+ entry throughvoltage-gatedchannels, Ca2+ entry




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reticulum (SR)calcium channels

through store-operated channels.

Calcium

receptor forexcitation-contractioncoupling

Troponin Troponin Calmodulin

Duration ofaction potential

2 ms 300 ms 10 ms to 1 s

Mechanism for

variation inforce

Temporal summation

in a single motor unitand spatialsummation of motorunits.

Length –tension

andContractility changes (variationsin intracellular Ca2+)

Variations in

intracellular Ca2+ ,Balance between MLphosphorylation anddephosphorylation.

Duration ofcontraction

rapid and slow < 1 sec prolonged (tonic)fast (phasic)

Receptor(s)activated for

contraction

Acetylcholine NE- Modulatesmyogenic contraction

increasescontraction,

Depends on muscletype: neurotransmitte

(ACh, NE, ATP),neuropeptides (NPY,BDK, serotonin),hormones (AII,estrogen), stretch

Receptor(s)activated forrelaxation

none ACh- Modulatesmyogeniccontraction:decreases

contraction

Depends on muscletype:ACh, NE, HIST,autacoids (nitricoxide), metabolites

(adenosine).

ATPexpenditure forcontraction

fast fiber (highest)slow fiber (less thanin fast fibers)

intermediate lowest (due to lowmyosin ATPaseactivities)




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Majormetabolicmachinery

fast fibers: glycolyticslow fibers: oxidative

oxidative oxidative

STUDY QUESTIONS

SKELETAL MUSCLE

1. Which is the ATP generating pathway used most by fast fatigable muscle fibers?

2. Which biochemical property enables SR to function as a Ca+2 storage site during the restingstate?

3. Which type of muscle possess predominantly large motor units ?

4. Describe the myosin affinity for actin when crossbridges are perpendicular (90°) to the thickfilament.

5. Which is the event (regulated by Ca+2 ions) that constitutes the final link between excitation andcontraction.

6. How you differentiate between a preload and afterload?

7. Which biochemical event promotes the conformational changes in the myosin crossbridge?

8. Which generates the highest intracellular free Ca+2

concentration, twitch or tetanus?

9. Describe the experimental setup that permits an isometric contraction.

10. Which is the predominant type of fibers in a muscle involved in maintaining posture?

11. Why the total tension curve for skeletal muscle exhibits a plateau when sarcomere length

fluctuates from 2 to 2.2 m?

12. Which is the currently accepted hypothesis explaining calcium release channel opening at thesarcoplasmic reticulum during skeletal muscle activation?

13. Which biochemical event diminishes myosin affinity for actin?

14. Why a skeletal muscle fiber cannot attain maximal force during a twitch?

15. Which is the intracellular (cytosolic) free calcium level in a resting muscle fiber, during peaktension development?

16. What conditions predispose to r igor mort is?

17. Which motor units are activated first, the large or the small motor units? Why?




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18. If the afterload of a muscle is increased 50%, what will happen to the velocity of contraction?

19. Which of the ATP regenerating pathways predominates in red muscles? white muscles? Why?

20. Which type of skeletal muscle fibers exhibits the fastest rate of ATP hydrolysis?

21. What is the basis for the classification of the motor endplate as a chemical synapse?

22. Identify the location of ATPase activity in a sarcomere.

23. Which is the fastest pathway for ATP regeneration during muscle activation?

24. Which event takes the skeletal muscle membrane potential to threshold to generate an actionpotential?

25. In the resting state, what prevents actin from binding myosin crossbridges?

26. Which is the most efficient (quantitatively) pathway for regenerating ATP during musclecontraction?

27. Which components in the sarcomere are called the regulatory proteins of muscle contraction?

28. Describe the structural evidence that supports the sliding filament theory for musclecontraction.

29. Which is the approximate length of skeletal muscle sarcomeres at rest in vivo?

30. Which is the most efficient substrate from which skeletal muscle obtains a high yield of ATP?

31. What is the importance of acetylcholinesterase?

32. What is a crossbridge, where it is localized, and what is its importance?

33. Which is the structural basis for the passive curve of the length-tension relationship?

34. Which type of muscle fibers are dound in a fast motor unit?

35. Differentiate between temporal and spatial summation.

36. Where are the acetylcholine receptors in a nerve-muscle preparation? What is their importance?

37. Enumerate the similarities between the nerve and skeletal muscle action potentials.

38. Which experimental setup is used to observe the force-velocity relationship?

39. What is the functional role of T tubules?

40. Which sarcomere band shortens during a contraction? Which band never shortens?




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CARDIAC MUSCLE

1. Describe the different stages of excitability for a cardiac fiber that generates fast actionpotentials.

2. Identify the temporal span of the relative refractory period in a fast action potential.

3. Which is the ionic basis for phase 3 of the cardiac action potential?

4. Which is the ionic basis for phase 0 of a fast action potential?

5. What structural characteristic permits heart to work as a functional syncytium?

6. Explain why the removal of Ca2+ from the external bath solution of cardiac cells is detrimentalto its function.

7. Describe the differences observed between the excitation-contraction event at skeletal muscle

and those, which occur at the cardiac muscle.

8. Why a long refractory period is important for cardiac muscle function?

9. Are contractility changes an expression of the Frank-Starling Law? Explain.

10. What is the major difference between the sarcomere active-passive tension relationship asobserved for skeletal and cardiac muscle?

11. What is the safety factor that protects the cardiac muscle from a large external stretch?

12. What is the basis for the Treppe phenomenon?

13. Theoretically, what type of elastic elements prevents the damage of resting contractile elementswhen the cardiac muscle is subjected to an external stretch?

14. What biochemical events are important for returning the intracellular concentration of Ca2+ toits normal range in between contractions?

15. Define an inotropic agent.

16. Mention a major biochemical difference between the excitation-contraction process in thecardiac and skeletal muscle.

SMOOTH MUSCLE

1. Why the resting membrane potential of smooth muscle is less negative than those observed forskeletal muscle or nerve tissue?

2. Which ionic current explains the upstroke of smooth muscle action potentials?

3. What is the structural relationship between autonomic nerve terminals and smooth musclecells?




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4. Identify the source of calcium ions needed to activate contractile fibers in smooth muscle cells.

5. Identify the types of excitation-contraction observed in smooth muscle cells.

6. Which molecule in smooth muscle exerts the role that troponin does in striated muscle?

7. Why smooth muscle contraction is said to be a thick filament regulated event?

8. Which are the most important features of unitary smooth muscle?

9. What determines the slow kinetics of a smooth muscle action potential?

10. Which is the type of smooth muscle found in blood vessels, uterus and intestines?

11. What event is necessary in order for relaxation to take place in smooth muscle cells?

12. Identify the concentration of intracellular calcium in a smooth muscle cell when it is activated.

13. Why smooth muscle does not show a striated pattern under the microscope?

14. What is the relative proportion of thin to thick filaments in smooth muscle cells ? How it

compares to striated muscle?

15. What types of nerves modulate smooth muscle contraction?

16. Do nerve terminals initiate or modulate smooth muscle contraction?

17. What is the suggested role of caveolae in smooth muscle cells?

18. Compared to skeletal muscle, what is the degree of development of sarcoplasmic reticulum insmooth muscle cells?

19. Which type of smooth muscle cell acts as a syncitium, unit or multiunit?

20. In which situation contraction is independent of membrane potential changes for a smoothmuscle cell?

21. What is the source and role of IP3 in a smooth muscle cell?

22. For the smooth muscle situation describe the characteristic features of the mechanical responseknown as tonus.

23. Compare the shortening ability of smooth muscle with that observed in striated muscle.

24. Compare smooth muscle myosin ATPase activity with that observed in skeletal muscle.

25. What is the most probable mechanism for regulating crossbridge cycling in smooth musclecell?

26. Compare the smooth muscle cell force-length and force velocity curves with those recordedfor striated muscle, qualitatively and quantitatively.

27. Describe the role of calmodulin in smooth muscle contraction.

28. Compare the expenditure of ATP during smooth muscle contraction with that observed forskeletal muscle.

muscle physiology review 2015

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