MUSCLE PHYSIOLOGY

OBJECTIVES
Compare the duration of skeletal,
cardiac and smooth muscle
action potentials and describe
their underlying ionic
mechanisms.

HIGHLIGHTS
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 be
very prolonged (in the range of seconds).
Depolarization is brought by the influx of Na+ in skeletal and
some types of cardiac muscle fibers (i.e. conduction fibers,
atrial and ventricular fibers).
Depolarization is generated by the influx of Ca2+ in nodal cells
of cardiac tissue and in some smooth muscle fibers.
Repolarization is invariably brought about by the opening of
K+ 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 the
conductance of the major ions (Na+, K+, Ca2+) (gion) in the
configuration of the action potential for each muscle type.

Skeletal

Cardiac
Ventricular

2 ms

300 ms

Smooth

Pacemaker

200 ms

10 s

gNa+
gK+
gCa2+

gNa+ = sodium conductance

gK+ = potassium conductance, gCa2+ = calcium conductance

Compare the neural regulation of

muscle function for the three
major types of muscle.

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For skeletal muscle contraction, force is totally

dependent on neural stimulation through temporal and
spatial summations of motor units.
For cardiac muscle, the Autonomic Nervous System
does not initiate contraction but modulates the
frequency of activation, the velocity of conduction and
the force of contraction.
Smooth muscle contraction regulation is
heterogeneous. There are subtypes in which

MUSCLE PHYSIOLOGY
OBJECTIVES

HIGHLIGHTS
contractions are dependent on neural stimulation (i.e.
multiunit) while in others (i.e. unitary) contractions are
myogenic (independent of neural stimulation).

Describe the neuromuscular

junction (i.e. motor endplate)
found at skeletal muscles and
how acetylcholine (ACh) vesicles
are released here.

The motor end-plate is composed of (1) a pre-synaptic

element constituted by branches of the motor neuron axon
(2) a synaptic cleft or space between the pre and postsynaptic membranes (3) a post-synaptic element, formed by
the muscle cell membrane, organized in folds, immediately
beneath the axon terminal. In these folds are located many
nicotinic acetylcholine (ACh) receptors. Few or none ACh
receptors are located in the muscle membrane outside the
neuromuscular junction.

1
2
3

Identify the role of acetylcholine

(ACh) in the neuromuscular
junction.

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When a nerve action potential reaches the pre-synaptic

nerve terminal it opens Ca2+ channels through which
external calcium enters. The calcium is necessary for the
fusion of ACh vesicles found in the motor neuron terminal
to the endplate pre-synaptic membrane for the eventual
release of ACh into the synaptic cleft.
ACh interaction with its receptor (i.e.nicotinic) at the motorendplate (post-synaptic membrane) opens a cation agonist
operated-channel through which K+ moves out and Na+
moves in. This movement of ions in and out of the cell
generates an end-plate potential (at the post-synaptic
membrane only) which is the trigger (through depolarization)
that pushes adjacent skeletal muscle membrane to threshold
potential. When threshold potential is attained, voltagedependent Na+ channels in the muscle membrane open and
generate the skeletal muscle action potential.

MUSCLE PHYSIOLOGY
OBJECTIVES

HIGHLIGHTS

Identify the location of

acetylcholinesterase and what it
its role in the neuromuscular
process.

This enzyme is located in the post-synaptic membrane of

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

Recognize the importance of the

T tubule in striated (skeletal &
cardiac) muscle contraction.

The T tubule comprise a network of invaginations of the

surface membrane (sarcolemma) that runs deep into the
muscle fiber at the level of the junction between the A and
I bands of each sarcomere of mammalian striated muscles.
Their function is to spread action potentials to the cell
interior. This event is necessary to open ion channels
(dihydropiridine receptors, at the T-tubule) that permits
extracellular Ca2+ entry (in cardiac muscle) or to generate
conformational changes (in skeletal muscle) that results in
the opening of sarcoplasmic reticulum (SR) Ca2+ channels
(ryanodine receptors, for the release of stored calcium
into cytoplasm (in skeletal and cardiac muscles).

Identify the role of sarcoplasmic

reticulum (SR) in muscle
contraction.

In addition to serve as a storage and release site for

Ca2+, the sarcoplasmic reticulum functions as an uptake
site for these ions.
The membrane of SR contains, mainly in the non-junctional
surfaces, transport pumps- (Ca2+ATPases) that have a
higher affinity for Ca2+ than does troponin. The calcium
uptake is an energy requiring process since it must pump

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MUSCLE PHYSIOLOGY
OBJECTIVES

HIGHLIGHTS
Ca against a concentration gradient. ATP hydrolysis
provides the energy.
2+

Moreover, the calcium uptake rate is regulated by the cytosolic

Ca2+ concentration. In the resting muscle, when cytosolic Ca2+ is
low, 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 sarcoplasmic
reticular concentration of Ca2+ from perhaps 20 mM, if all were
free, to an estimated 1.0 mM. This action reduces the
concentration against which the pumps must act and reduces
energy expenditure.

Identify the normal resting

intracellular calcium
concentration 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 of

extracellular calcium for the
initiation of skeletal, cardiac and
smooth muscle contraction.

Extracellular calcium is not needed for skeletal muscle

contraction since abundant stores of Ca2+ are found in the
large and developed SR. Therefore, for skeletal muscle
the source of calcium for activation is intracellular (at the
SR).
Extracellular calcium is extremely important in both
cardiac and smooth muscle, because they exhibit the
phenomenon of calcium-induced calcium release
(CICR) in which extracellular calcium enters the cell and
release calcium stored at the SRs. SRs of these types of
muscles are not so well developed as in skeletal muscle.
EXCITATION-CONTRACTION COUPLING
SKELETAL

CARDIAC

SMOOTH

varicosity

varicosity

End-plate

T-tubule

T-tubule

SR

SR
SR

Ryanodine
receptor

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dihydropiridine
receptor

Source
INTRAof Ca2+
CELLULAR
for
activation:

EXTRA-CELLULAR
Ca2+-induced

Ca2+

release

EXTRA-CELLULAR
Ca2+-induced Ca2+ release
Ca2+-store operated channel

MUSCLE PHYSIOLOGY
OBJECTIVES

Identify the mechanisms through

which intracellular calcium
activates contractile proteins in
skeletal, cardiac and smooth
muscle.

HIGHLIGHTS

Ca2+ binds to regulatory proteins:

(1) troponin (in cardiac and skeletal muscles). This event
releases the inhibition provided by tropomyosin, another
regulatory component of the thin filament that is preventing the
interaction between actin and myosin when the muscle is at
rest (i.e. when intracellular Ca2+ is low).
(2) calmodulin (smooth muscle) which activates myosin
ATPase activity necessary to generate the sliding of actin and
myosin and the generation of force.

Identify the force generating step

in the cross-bridge cycle.

A to D show the crossbridge cycle. The swiveling of

myosin head (90 to 45) upon the release of ATP
hydrolysis products (ADP and iP) (i.e. C to D) is the force
generating step.

Explain the mechanism for the

rigor mortis in skeletal muscle.

When ATP levels are low, interaction between myosin

and actin continues (the filaments cannot detach) and the
crossbridge-cycle stops in the contracted state. At this
stage the myosin head remains attached to the actin
filament at a 45 angle.

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MUSCLE PHYSIOLOGY
OBJECTIVES
Identify the organization of
protein components in a striated
muscle sarcomere.

HIGHLIGHTS
Each sarcomere contains:
a central dark A band,
half of two lighter I bands
delimited at both ends by a darkly
dark structure termed the Z line.
The A band arises from a particular arrangement between thick
and thin filaments, while the I bands result from the arrangement
of the thin filaments. The Z line is where adjacent sarcomeres
come together.
Thick filaments are composed of myosin molecules.
Thin filaments are composed of G-actin, a globular protein that
polymerizes to form a twisted two-stranded filament, F-actin; and
two regulatory proteins, tropomyosin and troponin.

Describe the mechanism and the

evidence for the sliding filament
theory of muscle contraction.

Individual contractile fibers (thick and thin) do not change size,

they overlap (slide) one past another. This has been supported
by the constancy of band A (mainly thick filaments) during
contraction and relaxation. Only the I and H bands reduce in
size with contraction.
A band

Relaxed

A band

Contracted

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MUSCLE PHYSIOLOGY
OBJECTIVES
Identify the energy sources for
muscle contraction.

Distinguish between fast and

slow skeletal muscle fibers.

HIGHLIGHTS
ATP is the immediate fuel for energy. ATP is generated from
the hydrolysis of creatine phosphate which is used to rephosphorylate ADP (fast source, but is found in limited
amounts). Glucose is the preferred source of muscle
contraction. Anaerobic breakdown of glucose-glycolysis- also
yields ATP but in limited amounts. Oxidative
phosphorylation of glucose provides the greatest amount of
ATP for contraction.

Fast fibers (type IIb) fatigue easily, obtain energy

anaerobically, 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 fatigue
resistant, possess great quantities of myoglobin (red fibers),
depend mainly on aerobic reactions (i.e.oxidative
phosphorylation) and are the first to be activated because of
their low thresholds.

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MUSCLE PHYSIOLOGY
OBJECTIVES

HIGHLIGHTS

Identify the concept of motor unit in skeletal muscle

physiology
A motor unit is the motor neuron and the muscle fibers it innervates. The
motor unit is considered as the functional contractile unit because all
the 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 it
is innervated by small (slowly conducting) motoneurons and muscle
fibers belonging to type I classification (red fibers). This occurs in
muscles in which a high degree of control is exercised over fine
movements; 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 (rapidly
conducting) motor neurons. The innervated fibers are the white muscle fibers, type IIb. They contract and
fatigue quickly since they generate ATP only by anaerobic glycolysis of glucose and glycogen. These are
observed in muscles that are specialized for large rapid movements with little fine control. Therefore, a
single motor axon will control a relatively large portion of the whole muscle. They are recruited for more
forceful movements.

THE FATIGUE RESISTANCE (FR) MOTOR

UNIT. This type of motor unit has properties that
are intermediate between the other two (i.e, FR
motor unit generates about twice the force of a
slow unit.). The innervated muscle fibers are
denominated type IIa.

Recruitment of motor units follow a size principle,

motor units are recruited in order of increasing size
(the small ones, first). When only a small amount of
force is required from a muscle with a mix of motor
unit types, this force is provided exclusively by the
small S units. As more force is required, FR and FF
units are progressively recruited, normally in a
remarkably precise order based on the magnitude
of their force output. This minimizes the
development of fatigue by using the most fatigueresistant muscle fibers most often (holding more
fatigable fibers in reserve until needed to achieve
higher forces)

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MUSCLE PHYSIOLOGY
OBJECTIVES
Identify the meaning of a twitch.

Define tetanus, and how is

generated.

HIGHLIGHTS
The twitch, is a single brief contraction produced by the arrival of
a single nerve action potential. Under constant conditions of
temperature, fiber length, the magnitude of the twitch is a
constant, all or none property, which means that once an
appropriate stimulus activates a single fiber (or a single motor
unit), increasing the stimulus strength will cause no progressive
increase in the strength of contraction. This is a result of the fact
that a single skeletal action potential will release (from the SR)
the same amount of Ca+2 regardless of the strength of the
stimulus.
This is a sustained skeletal muscle contraction generated
upon the activation of muscle by repetitive (increase in
frequency) stimulation of motor units.
This prolonged contraction with a force 3-5 fold greater than the
twitch is generated if the muscle fiber is re-stimulated before it
has relaxed completely, the second twitch will add its mechanical
effect to the first, and the third stimuli add on to the mechanical
effect of the first two stimuli and so on in a process called
temporal summation.

Distinguish between a temporal

and spatial summation during
the activation of skeletal muscle.

In both, muscle force is greater than that observed during a

single twitch but for temporal summation the increase in force
is the result of an increase in the frequency of stimulation to a
specific motor unit while in the spatial summation the increase
in force is the result of an increase in the number of motor
units (increase in # of total fibers) recruited. Spatial
summation is due to an increase in the intensity of stimuli
which activate more motor units which have higher activation
thresholds.

TEMPORAL SUMMATION

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SPATIAL SUMMATION

MUSCLE PHYSIOLOGY
OBJECTIVES
Differentiate between preload
and afterload.

HIGHLIGHTS
Preload is an external force
which stretches the muscle
at rest and determines the
sarcomere length before its
activation. This event is
necessary to determine the
# of actin-myosin
interactions and therefore
the force magnitude that
would generate upon
activation.
Afterload is an external force that opposes to muscle
contraction upon its activation and will determine if the
muscle can move the load or exert its maximal tension.

Differentiate between isotonic

and isometric contraction.

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During isotonic contraction, muscle will shorten and move the

load with certain velocity and generate a constant tension to
balance the afterload (external weight).

MUSCLE PHYSIOLOGY
OBJECTIVES

HIGHLIGHTS
During isometric contraction the muscle does not shorten
externally (velocity is zero, there is no change in length) but
there is a gradual increase in tension (force) up to its
maximum level. This happens when the afterload is heavier
than the maximal force that the muscle can develop.

Explain the mechanical property

of muscles known as the lengthtension relationship. Describe
its structural basis and what is
meant by Lo.

This property is observed when an isolated muscle is arranged

experimentally to record isometric contractions. It is based on
the observation that the length of a resting muscle (determined
by the preload) affects the force of its contraction upon
activation.

A relaxed isolated muscle does not have any resting tension. If the
resting muscle is stretched, resting tension will increase
exponentially. The curve generated by such manipulation
describes the passive tension curve.
When the experiment is repeated using muscle stretched at
different levels, but now stimulated with pulses of supramaximal
intensity and tetanic frequency, another curve could be obtained.
This curve is the total tension curve, which is the sum of passive
force and the active force developed by crossbridge cycling of
contractile 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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MUSCLE PHYSIOLOGY
OBJECTIVES

HIGHLIGHTS
The structural basis of the length-tension relationship is:
- The passive relationship is due to the elastic behavior of the
cell membrane and of the connective tissue (parallel elastic
elements) between the muscle cells. These structures resist the
forces applied to a resting muscle.
- The active relationship is due to the interaction between actin
and myosin molecules within the sarcomere and depends upon
the degree of overlap of thick and thin filaments prior to
activation:

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

Explain the mechanical property

of muscles known as the forcevelocity 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 other
hand, when afterload is zero (Y intercept, in the graph), the
muscle 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, also
known as Po).

afterload

Vmax is a function of the myosin ATPase activity (i.e. the higher

the ATPase activity, the greater the velocity, fast fatigable
fibers will exhibit higher Vmax than slow fibers).

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MUSCLE PHYSIOLOGY
OBJECTIVES
Identify functional similarities
and differences between skeletal
and cardiac muscle.

HIGHLIGHTS
Similarities: In both muscles, contraction is actinregulated. Sarcomeres slide. There is an optimal length
at which force is maximal (Lo). Activation of myofibrils in
both depends on T tubule association with internal
sarcoplasmic reticulum calcium stores.
Differences:
All cardiac muscle fibers are activated in each heart
beat due to gap junctions (at the intercalated disks)
which make this tissue a functional syncitium.
Cardiac action potentials are very long (300 ms), an
event that prevents tetanization, since muscle is
refractory 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 of
cytoplasmic calcium available. Calcium enters from
the extracellular fluid. Norepinephrine facilitates
calcium entry and increases the force of contraction.
Passive tension (generated by elastic elements) at rest
for cardiac muscle is higher than that observed for
skeletal muscle.

Contrast the major differences

between cardiac and skeletal
muscle length- tension
relationship

Passive Tension Curve: Although isometric force is

altered by changes in resting muscle length, (as in skeletal
muscle) quantitatively, cardiac muscle exhibits greater
passive force at all sarcomere lengths. At Lo (optimal
length), skeletal muscle exhibits almost no passive force
whereas for cardiac muscle at Lo, passive force is 1520% of total force This passive tension, which rises
steeply beyond the optimal length, represents a safety
feature that serves to prevent over-extension of the
cardiac muscle in the event of excessive filling.

Active Tension Curve: The subtraction of the Passive

Tension Curve observed during each resting length from
the Total Tension Curve (obtained upon stimulation of the
muscle preparation) yields an Active Tension Curve, very
much like that of skeletal muscle. Little active tension is
developed at very short or very long resting lengths.
Active tension is maximal at an intermediate length - Lo.

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MUSCLE PHYSIOLOGY
OBJECTIVES

Identify the effect of changes in

preload in the force-velocity
relationship of cardiac muscle

HIGHLIGHTS
However, contrary to skeletal muscle, in which its bone
attachments set the resting length at Lo, unstressed
cardiac muscle fibers normally operate at lengths well
below Lo. Therefore, for cardiac muscle, increasing
sarcomere length (from 2.0 to 2.3 ) increases the tension
developed during an isometric contraction. The
mechanism that explains the length-tension relationship,
like in the skeletal muscle, is based on the extent of overlap
of the thick and thin filaments in the sarcomere at rest.
Similar to skeletal muscle the velocity of contraction, at any
initial length, is altered by the afterload. Increasing the
afterload will cause a greater amount of the total contractile
energy to be utilized during the isometric phase of the
contraction 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 its
attachments to bone) velocity of contraction of an afterloaded
cardiac muscle is also altered by its resting length.
When the resting length (preload) is increased, the tension
is augmented according to the length-tension relationship
There is an increase in P0, which is the measure of the
number of active cross-bridge interactions (or maximal
force) and

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There is a change in the velocity of shortening at all

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

MUSCLE PHYSIOLOGY
OBJECTIVES

HIGHLIGHTS

The Vmax of cardiac muscle under unstressed conditions is

much 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-bridge
turnover.

Define refractory period

Refractory period is a feature of excitable tissue and its

duration parallels the duration of the action potential. The
refractory period refers to the time a cell is unable to
respond to a stimulus and generate another action potential.

Identify the timing of refractory

periods in cardiac muscle.

In the first part of this period- the effective refractory period

(ERP) - a stimulus cannot activate the cell because of the
inactivation of fast Na+ channels and the cell is totally
unexcitable. For cardiac fibers developing fast action potential
this period extends to the half of phase 3.

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MUSCLE PHYSIOLOGY
OBJECTIVES

HIGHLIGHTS
The second part- the relative refractory period- begins as
membrane voltage becomes more negative and lasts from the
middle of phase 3 to the restoration of normal resting potential
(phase 4). During this period the cell will require a stronger
than normal stimulus to evoke a response and the action
potentials generated are of smaller amplitude and duration

Identify the importance of long

refractory periods in cardiac
muscle.

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The figure shows that the time relationship between the

electrical and mechanical responses is different for
cardiac muscle when compared to skeletal muscle.
Skeletal action potential and refractory period are of short
duration (2 ms). Therefore, mechanical responses can be
summed.

MUSCLE PHYSIOLOGY
OBJECTIVES

Distinguish between
heterometric and homometric
regulation of cardiac muscle
contraction.

Define the cardiac muscle

property known as contractility

HIGHLIGHTS
As illustrated in the figure below the duration of cardiac
action potential is as long as the contractile response.
Thus, the cardiac muscle relaxes before it is possible to
stimulate it again because of its long refractory period.
It is impossible to generate tetanus (or temporal
summation) in cardiac muscle as it happens in skeletal
muscle.

The mechanisms that regulate force in cardiac muscle

are based on the discussed intrinsic mechanical
properties of cardiac muscle and can be classified as
either:

Heterometric- those that involve changes in resting

sarcomere length. Or in other words those which
depend on the length-tension relationship discussed
before.

Homeometric-those which do not involve changes in

resting sarcomere length. In other words those which
depends on changes in contractility.

Contractility may be defined as a certain level of

functional capability (measured by a quantity such as force,
shortening velocity) when it is measured at a constant
muscle length.
Skeletal muscle has a fixed contractility since peak force
depends of resting muscle length, which does not change
from contraction to contraction. On the contrary, cardiac
muscle exhibits variable contractility, which represents
one of the mechanisms for the modulation of force in the
heart. Any factor, intrinsic and extrinsic, that affects cardiac
contractility is called an inotropic agent.

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MUSCLE PHYSIOLOGY
OBJECTIVES

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

Identify the effect of changes in

cardiac muscle contractility in
the force-velocity relationship.

In Force-Velocity Curves contractility changes will be

expressed as shifts in the Vmax but will not affect the
P0 value. For example, this indeed is what happens
during tachycardia which temporarily increases
contractility.

Identify the effect of changes in

cardiac muscle contractility in
the isometric twitch
development.

During isometric twitch development, changes in the level

of inotropic state are reflected not only by changes in the
peak tension but also, occur in the rate of tension
development and the rate of relaxation associated with
changes in the duration of contraction).
For example, a positive inotropic stimuli (such as
Norepinephrine & Digitalis,( i.e. curve A) produces an
increase in peak isometric tension, decreased time to peak
tension and shortening of the duration of contraction.

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MUSCLE PHYSIOLOGY
OBJECTIVES
Identify the molecular basis
explaining changes in cardiac
contractility.

HIGHLIGHTS
The inotropic state is determined directly by subcellular
processes that regulate the concentration of cytosolic
calcium during activation of cardiac muscle.
Under normal conditions the contractile filaments of cardiac
muscle are only partly activated. This is because, unlike the
situation in skeletal muscle, not enough calcium is released to
occupy all of the troponin molecules, and not all potentially
available crossbridges can attach the thin filament and cycle.
An increase in the availability of calcium would increase the
number of crossbridges activated. Therefore, contractility is
modulated by factors that affect intracellular calcium
availability.

Define the importance of

frequency of heart beats in the
determination of cardiac muscle
force.

Several examples of this relationship, also known as the forcefrequency relationship has been described.

The Staircase or Treppe Phenomenon in which a rapid

increase in heart rate causes gradual increases in force over
the next several beats.
Rest-Potentiation- A rest period between beats augments
the force of the following few beats.
Post-extrasystolic potentiation- A pause after an
extrasystole will be followed by a stronger contraction.

The above responses are intrinsic to cardiac muscle and are

probably due to temporary alterations in cardiac muscle
contractility due to a time-induced alteration in Ca2+
availability to the muscle cell.

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MUSCLE PHYSIOLOGY
OBJECTIVES
Compare smooth muscle action
potentials with skeletal muscle
action potential.

HIGHLIGHTS
Although different types of smooth muscle differ only slightly in
resting membrane potential, they differ markedly in the types of
membrane potentials exhibited when they are excited. Action
potentials are usually seen in unitary (visceral) smooth
muscle. The smooth muscle cell membrane has far more
voltage-gated calcium channels than skeletal muscle. Flow of
extracellular calcium ions to the interior of the fiber is mainly
responsible for the action potentials. Since calcium channels
open and close more slowly than sodium channels, this
account 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 are
activated 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 summed
mechanical response

Slow waves triggering

action potentials.
Contractions associated
with burst of action potentials.

Tone contractile activity

related to membrane potential changes
in the absence of action
potentials.

Changes in force produced by

the addition or removal
of hormones in the absence
of membrane potential changes.

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MUSCLE PHYSIOLOGY
OBJECTIVES
Identify the mechanism through
which calcium regulates
contraction in smooth muscle.

HIGHLIGHTS
Calcium binds to calmodulin which in turn activates the
myosin light chain kinase (MLCK) which phosphorylates
myosin light chains in the thick filaments. The
phosphorylation is crucial for myosin binding to actin.
Relaxation occurs when calcium levels decrease and
does not support the activation of MLCK kinase to
phosphorylate MLC. This will shift the equilibrium to
deposphorylated myosin that has low affinity for actin,
therefore producing relaxation. There is always a MLC
phosphatase activity (an enzyme that catalizes the
dephosphorylation 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 cAMP
that activates a cAMP-Protein kinase responsible for
enahncing Ca2+ uptake by the SR. This kinase can also
reduce the activity of MCLK.
Another agent that induces relaxation in smooth muscle is
Nitric oxide (NO). NO through the stimulation of cGMP
levels will activate a cGMP dependent Protein kinase, that
promotes Ca2+ uptake by the SR.

Describe the autonomic nerve

(ANS) influence over smooth
muscle.

There are no structured neuromuscular junctions.

Functionally however, they are comparable since there are
corresponding pre-synaptic release of transmitter, diffusion
across the junction and combination with a post-synaptic
receptor. The muscle membrane itself is not specialized
near the "junction". One autonomic nerve will produce
several varicosities, or swellings abundant in neurotransmitter vesicles. Each varicosity will be near a section
of the muscle's cell membrane and in conjunction they will
form the neuromuscular junction.
This is a slow process since neurotransmitter must
diffuse out from varicosities to individual muscle fibers.
Nerve stimulation is mainly to modulate spontaneous
activity.

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MUSCLE PHYSIOLOGY
OBJECTIVES
Distinguish between the
anatomical distribution of
neuromuscular junctions at
multiunit and unitary smooth
muscle

HIGHLIGHTS
In smooth muscle, neuromuscular junctions are not
structurally defined and specialized as in skeletal muscle.
The distance varies from one type of muscle to another:
Multiunit

Varicosities located 6 to 20 nm from cell

membrane. Few gap junctions between cells.

Single unit

Varicosities at 80 to 120 nm from cell

membrane limiting responses to neural
activity.

Compared to skeletal muscle, the neurotransmission in

smooth muscle is slower and in many types this influence
mainly works to modify spontaneous activity.

Define the concept slow waves

in smooth muscle
electrophysiology.

Refers to the periodical variation in the resting potential

value. Slow wave potentials are due to a gradual cycling between
a relatively depolarized and polarized state that are postulated to
be caused by automatic cyclical changes in the rate at which
sodium ions are actively transported across the membrane.
The slow waves themselves cannot cause muscle
contraction, but when the potential of the slow wave rises above
the threshold, action potentials (spikes) develop and spread over
the muscle mass.
spikes

Slow waves
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MUSCLE PHYSIOLOGY
OBJECTIVES
Describe the major types of
smooth muscle contraction.

HIGHLIGHTS
(1) Phasic activity, which refers to rapid contractions followed
by relaxations. Mainly considered the result of neural
influence.
(2) Tonus in which muscle remains with active tension for
long periods. Mainly considered the result of muscle
activation by hormonal, metabolic factors.

Compare excitation contraction

coupling mechanisms in smooth
muscle with that observed in
skeletal muscle.

As in striated muscle, contraction and relaxation of smooth

muscle are regulated by changes in the amount of cytosolic
calcium. However, contrary to skeletal muscle, in addition to
stimuli that increases in cytosolic calcium, smooth muscle cells
can respond actively to stimuli that cause a lowering of cytosolic
Ca2+ inducing relaxation or reduction of tone. Since smooth
muscles are functionally diverse and generate various types of
mechanical activity there are also a variety of mechanisms that
interact to determine the cytosolic calcium in smooth muscle.
Coupling between activation and contraction in smooth muscle,
contrary to skeletal situation, may be of two types:

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Electromechanical coupling in which the contraction is

preceded by a depolarization of the cell membrane.
Calcium enters from the extracellular space through either
voltage gated channels or through receptor operated
channels and depolarizes the cell. The influx of calcium can
activate contractile proteins directly or can induce more
calcium release from sarcoplasmic reticulum.

Pharmacomechanical coupling in which an agent (i.e.

hormone, drug, and neurotransmitters) initiates contraction
through the activation of G-protein coupled receptors.
The activation of these receptors leads to formation of
second messengers such like IP3 and diacylgylcerol. IP3 will
eventually induce the release of intracellular Ca2+ from

MUSCLE PHYSIOLOGY
OBJECTIVES

HIGHLIGHTS
internal stores. In this case, elicited contractions are not
associated with changes in membrane potential.

Identify similarities and differences on the length tension relationship of smooth muscle
with that observed in striated muscles.
The force-length relationship curves for skeletal and smooth muscles are qualitatively similar. The passive
force-length curve demonstrates that relaxed smooth muscle, due to a large amount of connective tissue,
can withstand high distending forces. Also, like in striated muscle, the active force developed on
stimulation depends on tissue length. These observations have been taken as evidence to suggest that
a sliding filament mechanism also explain contraction in this type of muscle.
Smooth muscle however
is capable of shortening
a far greater % of its
length than can skeletal
muscle while maintaining
almost full force of
contraction.
Skeletal
muscle has a useful
distance of contraction of
only about 1/4 to 1/3 of its
stretched length, whereas
smooth muscle can often
contract quite effectively
more than 2/3 of its
stretched length.

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

Compare the force-velocity

relationship of smooth muscle
with that observed in striated

The velocity-force curves determined for smooth muscle

exhibit the characteristic hyperbolic fall in velocity with
load. Graphically, this produces a curve similar to that of
fast and slow skeletal muscle but very different
quantitatively. Contraction velocities are much slower in
smooth muscle.
Most smooth muscles therefore require several seconds to
develop maximal isometric force. In fact, the specific
ATPase activity of phosphorylated smooth muscle myosin
is more than 100 fold lower than the fast skeletal myosin
isoenzyme. The low activity is reflected in the low energy
cost of tension maintenance.

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MUSCLE PHYSIOLOGY
OBJECTIVES
muscles

HIGHLIGHTS
Moreover, another important difference between smooth
and skeletal muscle is that smooth muscle appears to
posses mechanisms for regulating the rate of crossbridge cycle as well as the number of activated bridges.
The following figure illustrates that the force-velocity curves
change with the percentage phosphorylation of myosin
crossbridges.

Describe the long term effects of

exercise on skeletal muscle.

The effects of exercise on muscles varies with the type and

duration of the activity. Aerobic exercise is typical of
activities requiring endurance and sustained muscle
contractions. Such activities rely mainly on Type I (slowtwitch muscles) which sustain contraction for extensive
periods of time. This use of slow-twitch muscle, and the
availability of O2, prevents the buildup of lactic acid and
typically does not result in substantial muscle fatigue in the
short-term. Sustained aerobic respiration tends to shift the
metabolic pathways of muscle to favor the use of fat as the
primary source of ATP and glycogen is generally avoided.
The major long term effect of exercise includes:
Hypertrophy of fibers (more actin and myosin, same # of
cells)
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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MUSCLE PHYSIOLOGY
OBJECTIVES
Describe the effects of aging on
skeletal muscle.

FEATURE

HIGHLIGHTS
Reduced muscular mass which reduces strength. Lost
muscle 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).

SKELETAL

CARDIAC

SMOOTH

fiber structure

long, multinucleated
striated appearance
under the light
microscope

short, thin,
mononucleated,
striated appearance
under the light
microscope

short,
mononucleated,
homogeneous
(smooth) structure
under the light
microscope

cell
arrangement

parallel

series

Both parallel and in

series

Origin of
contraction

neurogenic

myogenic

myogenic, neurogenic
and humoral

Filaments
relaxation
mechanism

due to Ca2+ uptake by

SR. State of inhibition
by regulatory proteins
returns as Ca2+ ions
are captured by SR
Ca2+ ATPase
(SERCA).

due Ca2+ uptake by

SR. State of
inhibition by
regulatory proteins
returns as Ca2+ ions
are captured by SR
Ca2+ ATPase.

Occurs when MLC

Phosphatase activity
predominates over
MLC kinase activity,
myosin is
dephosphorylated and
detaches from actin.

myofilaments

thin and thick (2:1)

thin and thick (2:1)

Thin and thick (15:1)

myosin content (1/31/5 of skeletal muscle)

thin filaments
attachment

at Z lines

at Z lines

To the dense bodies

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FEATURE
T tubules

SKELETAL
Located at the junction
of A and I bands

CARDIAC
at the Z lines

SMOOTH
none (caveoli ?)

sarcoplasmic
reticulum

Abundant

Less developed

not so abundant

structural
arrangement of
fibers

Sarcomere

sarcomere

unknown

Many, through
intercalated disks

In single unit type:

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

None
fiber to fiber
communication

contractile
model

sliding of filaments

sliding of filaments

sliding of filaments

regulation of
contraction

Neurogenic (somatic
motor neurons)

Intrinsic: ForceLength
Extrinsic: Autonomic
Nervous System
(ANS), hormonal
changing contractility

Neurogenic (ANS,
intrinsic nerves)
pharmacogenic
(hormones,
metabolites),
stretch

control of
filaments
activation

actin-linked :
Ca2+ binding to
troponin removes
tropomyosin inhibition
of actin-myosin
interaction.

actin-linked :
Ca2+ binding to
troponin removes
tropomyosin
inhibition of actinmyosin interaction.

myosin-linked :
Ca2+ binds to
calmodulin and
activates MLCK which
phosphorylates and
activate myosin
filament.

resting
membrane
potential

stable (-90 mV), due to Unstable in

permeability to K+
pacemaker cells,

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multiunit: stable (-50

mV)

FEATURE

SKELETAL

Opening of voltageionic basis for

action potential activated channels for
Na+ and K+

CARDIAC
Stable in Purkinje,
ventricular, atrial
fibers.

SMOOTH
single unit: variable
(expressed as slow
waves)

Opening of voltageactivated channels

for Na+, Ca2+and K+

Opening of voltageactivated and

agonist-activated Ca2+
channels.
ANS nerve axon
develops swellings varicosities- nearby
smooth membrane
cells, no special
structure in smooth
cell plasma
membrane.

neuromuscular
junction

end-plate formed by
a pre-synaptic
component- branches
of motor axon;
post-synaptic
component specialized folds in
sarcolemma.

ANS nerve axon

develops swellings
varicosities nearby
cardiac cells, no
special structure in
cardiac cell plasma
membrane.

Resting
cystolic
calcium
concentration

10-7M (0.1M)

10-7M (0.1 M)

10-7 (0.1 M)

Cytosolic
calcium
during
contraction

10 -6

10 -6- to 10 -5M

10-6 to 10 -5M

Calcium
sources for
contraction

intracellularBoth extracellular
sarcoplasmic reticulum (primarily) and
intracellular sarcoplasmic
reticulum

Excitation
contraction
coupling

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

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to

10 -5M

Ca2+ induced
calcium release:
calcium entering
Ca2+ channel in T
tubule activate
sarcoplasmic

Both extracellular
(primarily) and
intracellular sarcoplasmic
reticulum
Ca2+ induced calcium
release, IP3 mediated
Ca2+ release from SR,
Ca2+ entry through
voltage-gated
channels, Ca2+ entry

FEATURE

CARDIAC
reticulum (SR)
calcium channels

SMOOTH
through storeoperated channels.

Troponin

Calmodulin

2 ms
Duration of
action potential

300 ms

10 ms to 1 s

Mechanism for
variation in
force

Temporal summation
in a single motor unit
and spatial
summation of motor
units.

Length tension
and
Contractility
changes (variations
in intracellular Ca2+)

Variations in
intracellular Ca2+ ,
Balance between MLC
phosphorylation and
dephosphorylation.

Duration of
contraction

rapid and slow

< 1 sec

prolonged (tonic)
fast (phasic)

Receptor(s)
activated for
contraction

Acetylcholine

NE- Modulates
myogenic contraction
increases
contraction,

Depends on muscle
type: neurotransmitters
(ACh, NE, ATP),
neuropeptides (NPY,
BDK, serotonin),
hormones (AII,
estrogen), stretch

Receptor(s)
activated for
relaxation

none

ACh- Modulates
myogenic
contraction:
decreases
contraction

Depends on muscle
type:ACh, NE, HIST,
autacoids (nitric
oxide), metabolites
(adenosine).

ATP
expenditure for
contraction

fast fiber (highest)

slow fiber (less than
in fast fibers)

intermediate

lowest (due to low

myosin ATPase
activities)

Calcium
receptor for
excitationcontraction
coupling

SKELETAL

Troponin

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FEATURE
Major
metabolic
machinery

SKELETAL
fast fibers: glycolytic
slow fibers: oxidative

CARDIAC
oxidative

SMOOTH
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 resting
state?
3. Which type of muscle possess predominantly large motor units ?
4. Describe the myosin affinity for actin when crossbridges are perpendicular (90) to the thick
filament.
5. Which is the event (regulated by Ca+2 ions) that constitutes the final link between excitation and
contraction.
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 the
sarcoplasmic 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 peak
tension development?
16. What conditions predispose to rigor mortis?
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 action
potential?
25. In the resting state, what prevents actin from binding myosin crossbridges?
26. Which is the most efficient (quantitatively) pathway for regenerating ATP during muscle
contraction?
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 muscle
contraction.
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 action
potentials.
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 detrimental
to 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 as
observed 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 elements
when the cardiac muscle is subjected to an external stretch?
14. What biochemical events are important for returning the intracellular concentration of Ca2+ to
its normal range in between contractions?
15. Define an inotropic agent.
16. Mention a major biochemical difference between the excitation-contraction process in the
cardiac and skeletal muscle.

SMOOTH MUSCLE
1.

Why the resting membrane potential of smooth muscle is less negative than those observed for
skeletal 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 muscle
cells?

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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 in

smooth 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 smooth

muscle 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 response
known 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 muscle
cell?

26.

Compare the smooth muscle cell force-length and force velocity curves with those recorded
for 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 for
skeletal muscle.

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