Lec-8
Dr. Twana A. Mustafa
Muscle Physiology
Skeletal Muscle Structure
Skeletal muscles generally are connected to the bones of the skeleton by tendons. The part of
the muscle generating the force is the body. The body contains bundles (fascicles) of muscle cells.
Muscle cells are called muscle fibers and are multinucleate. The plasma membrane is called
the sarcolemma.
The contractile component of muscle cells is contained within rod-like elements
called myofibrils. Myofibrils have overlapping thick and thin filaments myosin and actin,
respectively. The smooth endoplasmic reticulum surrounding the myofibrils is called sarcoplasmic
reticulum which is closely associated with inward extensions of the sarcolemma called transverse
tubules.
Skeletal muscle is striated muscle due to the orderly arrangement of thick and thin filaments
that run parallel to the long axis of the fiber. Myofibrils are also composed of repeating units
calledsarcomeres. Each sarcomere is bordered by Z lines that anchor the thin filaments. M
lines are in the center of the sarcomeres.
The sarcomere is banded with the following:
A band - appears dArk and is the length of the thick filaments
H zone - light region in the center of the A band
I band - lIght band where only thin filaments are located
Actin (thin) and myosin (thick) filaments are attached by cross bridges. Thin filaments are
composed of globular actin linked to form helical strands. Two regulatory proteins are associated
with actin.Tropomyosin extends over and covers binding sites on actin subunits. Troponin, a
complex of three proteins, uncovers binding sites when bound to calcium.
Each myosin molecule is composed of two parts (dimer) each part consisting of a tail twisted
around the other and a head. A thick filament consists of pairs of myosin molecules with each pair
attached by the ends of their tails. These pairs of myosin molecules are bundled together so that
their heads protrude in a helical pattern at either end with a bare zone in the centre. The head of
the myosin molecule has a site that binds to actin to form crossbridges, and an ATPase site
that hydrolyzes ATP.
Extending along the length of each thick filament from the M line to each Z line is an elastic
protein called titin. Titin gives the sarcomere elasticity so that when it is stretched it returns to its
original position when it is relaxed. Titin also anchors the thick filaments in the proper position.
Mechanism of Force Generation
Sliding-filament model
This model explains muscle contraction by the sliding of thick and thin filaments over one
another. This model best explains the changes that occur in the bands and the zones when a muscle
contracts.
Cross Bridge Cycle
1. Binding of myosin to actin
The myosin head is in its high-energy conformation. In this form the myosin head is bound
to ADP and Pi and binds to an actin subunit in the adjacent thin filament.
2. Power stroke
The binding of the myosin head to actin causes the release of ADP and Pi. During this release
the energy contained in the high-energy form is released as the myosin head pivots toward the
middle of the sarcomere and pulls the attached actin filament with it.
3. Rigor
The myosin head in its low-energy form and the actin subunit remain bound to one another
until the myosin head binds ATP.
4. Unbinding of myosin and actin
After ATP binds to the myosin head a conformational change occurs that causes the myosin
head to detach from actin.
5. Cocking of the myosin head
The ATP is soon hydrolyzed by the ATPase associated with the myosin head and the energy
that is released forces the myosin head into its high-energy conformation from where the cycle
can repeat itself.
Excitation-Contraction Coupling
Excitation-contraction coupling refers to the sequence of events that link the action potential
generated in a muscle cell by the motor neuron to contraction.
Role of Neuromuscular Junction
Each muscle fiber is innervated by only one motor neuron. An action potential in the motor
neuron causes acetylcholine to be released at the neuromuscular junction. Acetylcholine travels
across the synaptic cleft and attaches to receptors in the highly folded plasma membrane of
the motor end plate. The end plate potential that results is always followed by an action
potential in the muscle cell. The action potential travels along the sarcolemma and travels
through the T tubules. The change in potential of the membrane of the T tubule triggers
the release of calcium ion from the nearby sarcoplasmic reticulum. Calcium ion initiates the
crossbridge cycle.
Role of Calcium, Troponin and Tropomyosin
The calcium concentration in the sarcoplasmic reticulum is high due to the presence
of Ca++ pumps. Ca++ channels open to allow Ca++ to rush into the cytosol and initiate the
crossbridge cycle. Some of the Ca++ channels are voltage-gated in an unusual way.
Where T-tubules are in close contact with the sarcoplasmic reticulum, the Ca++ channels are
linked to proteins in the membrane of the T-tubule. The Ca++ channel of the sarcoplasmic
reticulum is called a ryanodine receptor (foot structure) and the protein in the T-tubule is called
a dihydropyridine receptor (DHP receptor). A depolarization in the membrane of the Ttubule causes the DHP receptor to open the Ca++ channel of the ryanodine receptor. The released
Ca++ then act as ligands when they bind to ligand-gated Ca++ channels also located in the
sarcoplasmic reticulum, releasing more Ca++.
When cytosolic calcium increases it binds to the troponin complex which undergoes a change in shape
that causes tropomyosin to shift and expose actin binding sites. Myosin binds to the active sites
onactin and enters the crossbridge cycle.
Muscle Cell Metabolism
A. several pathways supply ATP to muscle cells:
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ATP is the only energy source that is used directly for contractile activity
As soon as available ATP is hydrolyzed (4-6 seconds), it is regenerated by three pathways:
1. Transfer of high-energy phosphate from creatine phosphate to ADP, first energy
storehouse tapped at onset of contractile activity. Transfer of energy as a phosphate
group is moved from CP to ADP – the reaction is catalyzed by the enzyme creatine
kinase
Creatine phosphate + ADP → creatine + ATP
Stored ATP and CP provide energy for maximum muscle power for 10-15 seconds
2. Oxidative phosphorylation (citric acid cycle and electron transport system - takes
place within muscle mitochondria if sufficient O2 is present
-Glucose is broken down into pyruvic acide to yield 2 ATP
-When oxygen demand cannot be met, pyruvic acid is converted into lactic acid
-Lactic acid diffuses into the bloodstream – can be used as energy source by the liver,
kidneys, and heart
3. Glycolysis - supports anaerobic or high-intensity exercise,
Aerobic respiration occurs in mitochondria - requires O2
series of reactions breaks down glucose for high yield of ATP
• Glucose + O2 → CO2 + H2O + ATP
Muscle fatigue – the muscle is physiologically not able to contract
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•
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Occurs when oxygen is limited and ATP production fails to keep pace with ATP use
Lactic acid accumulation and ionic imbalances may also contribute to muscle fatigue
Depletion of energy stores – glycogen
•
When no ATP is available, contractures (continuous contraction) may result because cross
bridges are unable to detach
Oxygen debt – the extra amount of O2 needed for the above restorative processes
How Muscle Cell Metabolism Changes with Exercise Intensity
When the muscle is stimulated to contract the supply of ATP in the muscle may become
rapidly depleted under high exertion. The muscle cell gears up its ATP production to meet the
demand but for a few seconds energy is supplied by the creatine/creatine phosphate
system. Creatine phosphate in the resting cell can produce ATP by the reaction The
reaction is catalyzed by creatine kinase. There is enough creatine phosphate in the cell to
supply four to five times the quantity of preformed ATP.
Continuous muscle contraction at moderate rates is sustained by the ATP produced
by oxidative phosphorylation. After glycogen reserves are used up (first few
seconds) glucose and fatty acids are supplied by the blood stream. After 30 minutes fatty
acids become the dominant energy source.
During heavy exercise ATP is produced by glycolysis at a rate that pyruvate builds up too
rapidly to undergo oxidative phosphorylation. Excess pyruvate is converted to lactic acid.
The build-up of lactic acid is believed to be responsible for the burning sensation experienced
in the muscle.
Mechanisms of Skeletal Muscle Contraction
Muscle contraction is based on a twitch of the muscle fiber which is like an action potential in
being an all or nothing event. A twitch: is the mechanical response of an individual muscle fiber, an
individual motor unit, or a whole muscle to a single action potential. The motor unit consists of a
motor neuron and all the muscle fibers it innervates.
Phases of the Twitch
When a stimulus is applied and a fiber contracts the twitch can be divided into phases:
1. Latent period is the delay of a few milliseconds between an action potential and the start of a
contraction and reflects the time for excitation-contraction coupling.
2. Contraction phase starts at the end of the latent period and ends when the muscle tension peaks
(tension = force expressed in grams). During this time cytosolic calcium levels are increasing as
released calcium exceeds uptake.
3. Relaxation phase is the time between peak tension and the end of the contraction when the tension
returns to zero. During this time cytosolic calcium is decreasing as reuptake exceeds release.
One feature of a muscle twitch is its reproducibility. Repetitive stimulation produces twitches of
the same magnitude and shape. (However, this will not be true when twitches follow one another
closely.) This results from its all or nothing character. Although muscle twitches are reproducible,
twitches may vary among muscles and muscle fibers. This is due to differences in the size of the
muscle fiber and differences in the speed of contraction among fibers.
Isometric Twitch
When the load (force opposing contraction) is greater than the force of contraction of the muscle,
the muscle creates tension when it contracts but does not shorten. This is an isometric (iso- same;
metric- length) twitch. An isometric twitch is measured by keeping the muscle immobile while
stimulating it and measuring the tension that develops during contraction. The rise and fall of tension
traces abell-shaped curve.
Isotonic Twitch
When the force of contraction of the muscle is at least equal to the load so that the
muscle shortens, the muscle is said to contract isotonically. An isotonic twitch is
measured by attaching the muscle to a moveable load. The tension curve for an
isotonic twitch shows a plateau during which the force or tension is constant (isosame; tonic- tension).
The tension curve resulting from an isotonic twitch will look different depending
upon the load placed on the muscle. The greater the load the higher the
plateau and the greater the time lag between stimuli and the start of muscle
shortening. When the load exceeds the amount of force the muscle can generate, an
isometric twitch results which is always of the same size and shape.
Factors Affecting the Force Generation of Individual Muscle Fibers
1. Frequency of Stimulation
When a muscle is stimulated at a frequency so that twitches follow one another closely,
the peak in tension rises in a step-wise fashion. This phenomenon is called treppe. Treppe
may occur because Ca++ released from previous twitches exceeds Ca++ reuptake and this
results in an increase in Ca++ concentration. This in turn increases the number of
crossbridges that form in the following contractions. Another possibility is that frequent
stimulation "warms up" the muscle and thereby increases the enzymatic rate.
Because a muscle twitch is fairly slow compared to an action potential many action
potentials can arrive before a single twitch is completed. This causes the twitches to bunch up
and results in the generation of a force that is greater than a single twitch. This process is
called summation.
When the frequency of stimulation is so high that Ca++ levels rise to peak levels,
summation results in the level of tension reaching a plateau called tetanus. When the
frequency of stimuli is high enough to cause tetanus but tension oscillates around an average
level, the tetanus is called incomplete or unfused. At greater frequencies of stimulus, levels
of Ca++ peak and cause a maximum number of crossbridges to cycle. At this point the tension
plateau smoothes out and tetanus is called complete or fused.
When the muscle is at maximum sustained tension it is said to have reached maximum
tetanic tension.
2. Fiber Diameter
Each muscle has a force generating capacity reflected by the maximum tetanic tension it
can generate in an isometric twitch. The number of cross bridges in each sarcomere and the
geometrical arrangement of the sarcomeres affect the force generating capacity. Also the
greater the number of sarcomeres arranged in parallel, the greater the force generating
capacity. The number of sarcomeres arranged in parallel correlates with a fiber's diameter.
The greater the cross-sectional area of a fiber, the more force it can generate.
3. Changes in Fiber Length
For each fiber the maximum force generating capacity occurs over a certain range of
lengths. The length-tension curve shown in the figure below illustrates this.
The sliding-filament model and the cross bridge cycle explains this curve. When the
muscle is at the optimum length the number of active cross bridges is the greatest. When
the muscle is stretched beyond this length the number of active cross bridges
decreases because the overlap between the actin and myosin fibers decrease. As the muscle
becomes shorter than the optimum length the thin filaments at opposite ends of the
sarcomere first begin to overlap one another and interfere with each other's movements. This
results in a slow decrease in tension as the sarcomeres get shorter.
Regulation of Force Generated by Whole Muscles
The whole muscle can generate greater force by increasing the number of individual
fibers that contract in a process called recruitment.
Recruitment
The nervous system exerts most of its control over muscle force by varying the number
of active motor units. Recruitment is the term used to describe an increase in the number of
active motor units. Motor units themselves vary in the number of fibers they stimulate and
in the size of the fibers within each unit.
Size Principle
According to the size principle when a muscle is called upon to generate small
forces only smaller motor units are stimulated. When larger forces are
needed larger motor units are recruited. This enables fine movements to be
controlled by the smaller increments of force generated by the smaller motor units.
When greater force is required, the larger increments come from the larger motor
units.
Velocity of Shortening
The speed with which a muscle contracts is also important in movement. When a
muscle contracts isotonically under increasing loads the contractions display the
following effects:
1. The latent period (time lag between stimulation and shortening) increases.
2. The duration of shortening decreases.
3. The velocity of shortening decreases.
When the velocity of shortening is plotted as a function of load, as the load
increases the velocity of shortening gradually decreases.
Types of Fibers
Speed of Contraction
Under isometric contraction muscles vary in the speed they reach maximum
tension. This is because there are fast-twitch and slow-twitch fibers. Certain
muscles (e.g. soleus) contain mostly slow twitch fibers and will contract slowly.
Some contain predominantly fast-twitch fibers (e.g. extraocular) and contract
quickly. Fast-twitch fibers also have higher maximum shortening
velocities compared to slow-twitch.
The difference between fast-twitch and slow-twitch depends on the type of
myosin. Fast myosin hydrolyzes ATP at a faster rate and this leads to more cross
bridge cycles per second compared to slow myosin.
Primary Mode of ATP Production:
Glycolytic fibers have a high cytosolic concentration of glycolytic
enzymes and few mitochondria. They produce ATP rapidly by glycolysis but have
a lower capacity for producing ATP by oxidative phosphorylation. These fibers
are bigger and have fewer capillaries.
Oxidative fibers are rich in mitochondria and have a high capacity to produce
ATP by oxidative phosphorylation. These fibers are smaller and have more
capillaries. These fibers also have an oxygen binding protein
called myoglobin. This molecule reversibly binds with oxygen like hemoglobin and
serves as an oxygen buffer. It supplies oxygen to oxidative fibers when oxygen is
temporarily cut off. Myoglobin gives the muscle fibers a reddish-brown color. These
fibers are often referred to as red muscle while glycolytic fibers are called white
muscle.
Glycolytic fibers produce ATP less efficiently by glycolysis but can function
with little oxygen. Pyruvate builds up in these fibers and is converted to lactic acid.
Oxidative fibers have a greater need for oxygen but are more resistant to
fatigue than glycolytic fibers.
Three Types of Skeletal Muscle Fibers
1. Slow oxidative fibers contain slow myosin and produce most of their ATP
by oxidative phosphorylation. These fibers also tend to be small in diameter and
generate less force.
2. Fast oxidative fibers also have a high oxidative capacity but have fast myosin. In
size and force generation these fibers are intermediate.
3. Fast glycolytic fibers contain fast myosin and have a high glycolytic capacity.
These fibers tend to be the largest and to generate the most force.
All muscles have all three types but in different proportions.
Size of Motor Unit and Order of Recruitment
The three fiber types are segregated into separate motor units.
1. The slow oxidative fibers have smaller fibers and are associated with
the smaller motor units that tend to be recruited first for movements
requiring a small force.
2. The fast glycolytic fibers have larger fibers and are associated with
the larger motor units that tend to be recruited last for movement requiring
greater force.
3. The fast oxidative fibers are intermediate between the two.
Resistance to Fatigue
Muscles differ in their ability to resist fatigue. Fatigue occurs when muscles are
stimulated at higher frequencies and when larger forces are generated.
High Intensity Exercise (e.g. weight lifting, sprinting)
Fast glycolytic fibers are recruited which tend to build up lactic acid because of
low oxidative capacity. Strong contractions constrict blood vessels decreasing
oxygen delivery and increase dependence on glycolysis. Lactic acids build up and
lowers the pH.
Low Intensity Exercise (e.g. walking)
Recruits mostly oxidative fibers that produce little lactic acid. Fatigue develops
more slowly and is probably due to depletion of energy reserves.
Very High Intensity Exercise
May induce neuromuscular fatigue due to a depletion of acetylcholine at
synaptic terminals.
Complex psychological factors are also involved with fatigue.
Long Term Responses of Muscle to Exercise
Aerobic exercise (low intensity; long duration) converts some fast glycolytic
fibers to fast oxidative fibers. This is associated with an increase in the number of
mitochondria, capillaries and a decrease in fiber diameter. High intensity
exercise (e.g. weight lifting) converts a portion of the fast oxidative fibers into fast
glycolytic fibers. There is a decrease in mitochondria, an increase in glycolytic
enzymes and an increase in fiber diameter.
Muscle growth is due to an increase in fiber diameter due to an increase in the
myofibrils in the muscle fiber.
Smooth Muscle
Smooth muscle has thick and thin filaments but they are not arranged in
myofibrils. The filaments are arranged in parallel but bundles of them run obliquely
in various directions. Dense bodies connect these groups of filaments and connect
them to the cell's exterior.
Excitation-Contraction Coupling
Smooth muscles contract when voltage-gated calcium channels cause
calcium to enter the cytosol from sarcoplasmic reticulum and from outside the
cell. Calcium binds reversibly with calmodulin and the calcium-calmodulin
complex activates the enzyme myosin light chain kinase. This enzyme
catalyzes the phosphorylation of myosin crossbridges and starts crossbridge
cycle activity. The activity of another enzyme phosphatase removes
phosphate groups from myosin and inactivates myosin.
In comparison to skeletal muscle, smooth muscle contraction takes longer to
initiate and terminate.
Neural Regulation of Contraction
Smooth muscles are innervated by autonomic neurons. The neurons can be
sympathetic, parasympathetic or both. Autonomic neurons may excite or
inhibit smooth muscle cells. Sympathetic and parasympathetic neurons affect
smooth muscle in opposite ways. The smooth muscle may also relax or contract in
response to the same type of autonomic neuron depending upon differences in
neurotransmitter receptors in different locations.
Autonomic neurons do not form synapses with specific cells but with groups of
cells. Neurotransmitter is released at varicosities (swellings) found along the length
of the axon. This causes a neighboring group of cells to contract together. Smooth
muscle cells contract in groups also because of gap junctions between cells that
allow electrical signals to spread from one cell to another.
Smooth muscle cells may respond to an action potential with a slow-twitch-like
contraction. But most smooth muscle cells respond to neural stimulation in a graded
fashion with either increasing or decreasing tension depending upon whether the
neural stimulation is excitatory or inhibitory.
Some smooth muscles display a resting degree of tension or tone even in the
absence of neural stimulation. Smooth muscle may also respond to the presence
of hormones and mechanical stretch.
Organization and Innervation of Smooth Muscle Tissue
Multi-Unit Smooth Muscle
In this organization the smooth muscle cells are mostly separate and richly
supplied with neurons. These are found in places where fine control of
contraction is needed such as respiratory airways and large arteries.
Single-Unit Smooth Muscle
In this organization the smooth muscle cells are connected by gap junctions and
there are fewer neurons. This organization is present in the wall of the
gastrointestinal tract and the uterus.
Pacemaker Activity
Some smooth muscle cells in single-unit smooth
as pacemakers by depolarizing on a regular basis to
potentials. These pacemaker potentials cause smooth muscle
unison. Pacemaker potential occur spontaneously but may be
input.
muscle may serve
produce pacemaker
cells to contract in
regulated by neural
Cardiac Muscle
Cardiac muscle has a sarcomere structure and a troponin/tropomyosin
system for regulating contractions. Cardiac muscle cells are extensively connected
by gap junctions that allow action potentials to spread rapidly. Cardiac action
potentials are broad and last for hundreds of milliseconds. This prevents summation
and allows cardiac muscle to relax between contractions.
Some cardiac muscle cells located in the sinoatrial and atrioventricular
nodes show pacemaker activity. This enables the heart to beat by itself without
neural input. The autonomic nervous system regulates the frequency and force of
muscle contraction.