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Skeletal Muscle Physiology
General Education Program
Physiology 1
Presented by: Dr. Shaimaa Nasr Amin
Lecturer of Medical Physiology
Objectives
•Structure of skeletal muscles
•The motor unit
•Excitation contraction coupling
•Molecular events in muscle
contraction
STRUCTURE OF SKELETAL
MUSCLES
Introduction
• All activities that involve movement depend on
muscles
• 650 muscles in the human body
• Various purposes for muscles for:
• Locomotion
• Upright posture
• Balancing on two legs
• Support of internal organs
• Controlling valves and body openings
• Production of heat
• Movement of materials along internal tubes
Introduction • Three types of muscles in the human
body
• Skeletal
• Cardiac
• Smooth
Skeletal Muscle
• Skeletal muscles are
muscles which are
attached to the
skeleton.
• 40% of human body
mass
• Skeletal muscles are
mainly responsible for
locomotion, and
voluntary contraction
and relaxation.
NEUROMUSCUL
AR JUNCTION
NEUROMUSCULAR
JUNCTION is an area
of contact between a
muscle fibre and a
neuron.
Fig. An electron
micrographic sketch of
the junction between a
single axon terminal
and the muscle fiber
membrane.
Structure of Skeletal muscles
• Skeletal muscles are composed of clusters of
muscle cells.
• Muscle fibers
• Myofibers
• Myocytes
• A muscle consists of packages of muscle cells
called fascicles
• A muscle cell is long and spindle shaped
Structure of Skeletal muscles
• Cell structure • Muscles cells contain many nuclei
• The plasma membrane→ sarcolemma
• The cytoplasm→ sarcoplasm
• Length • ranges from 0.1cm to more the 30cm in length
• Diameter • ranges from 0.001cm to 0.01cm in diameter
• Myofibrils→ • elongated protein molecules
• aligned in parallel arrangements
• extend the full length of the cell.
Structure of Skeletal muscles
• The myofibril consists of protein chains
called myofilaments
• Myofilaments have a symmetrical,
alternating pattern of thick and thin
elements.
Skeletal Muscle Myosin • Thick myofilament
• consists of a large number of bundled myosin molecules aligned in overlapping arrays.
• hexameric proteins with two identical heavy chains and two pairs of different light chains.
• regulatory light chain (RLC)
• essential light chain (ELC)
Skeletal Muscle Actin
• The thin myofilament (F-actin, filamentous actin)
• made up of two helically intertwined chains of G-actin (globular actin) units.
• Other proteins that bind to the actin molecules:
• Tropomyosin
• The Troponin complex→ made up of three members
Muscle structure and function
NEUROMUSCULAR JUNCTION
A neuromuscular junction thus consists of:
• Presynaptic terminal (Nerve fibre) with vesicles
containing the NT
• A synaptic cleft (20-30 nm wide)
• A synaptic trough or gutter (Muscle fibre) which
has numerous folds called subneural clefts.
• Neuroreceptors for the NT.
MOTOR END-PLATE
Definition:
It is the specialized
portion of a muscle fibre
immediately under a
terminal nerve fibre. The
nerve fibre invaginates a
muscle fibre but lies
outside the muscle fibre
plasma membrane. The
entire structure is called
the motor end-plate.
NMJ
NEUROMUSCULAR JUNCTION
The NT at an NMJ is ACETYLCHOLINE (Ach).
The synaptic cleft contains the enzyme which
helps break down Ach and is called
Acetylcholinesterase.
Volage-gated Ca
channels
• The presynaptic membrane of the
neuron contains linear dense bars.
To each side of the dense bars are
protein particles penetrating the
neural membrane. These are the
voltage-gated calcium channels.
• When an action potential spreads
over the terminal, these channels
open and allow calcium ions to
diffuse from the synaptic space to
the interior of the nerve terminal.
• The vesicles then fuse with the
neural membrane and empty their
acetylcholine into the synaptic
space by the process of
exocytosis.
Acetylcholine
Receptor:
• Each Ach receptor complex has a
total molecular weight of 275,000.
• Each receptor complex is composed
of 5 subunits:
- 2 alpha
- 1 beta
- 1 gamma
- 1 delta.
• The channels remains closed unless
2 Ach molecules attach to the 2 alpha
subunits which open the gate.
• The opened acetylcholine channel
has a diameter of about 0.65
nanometer, which is large enough to
allow the important positive ions—
Na+, K+ and Ca++ —to move easily
through the opening.
The Steps in Neuromuscular Junction
An AP reaches the presynaptic terminal of the
NMJ.
The change in voltage causes the opening of the
voltage-gated calcium channels which cause
exocytosis of the Ach containing secretory
vesicles.
The NT Ach is secreted into the synaptic cleft.
The Steps in Neuromuscular Junction
Ach crosses the synaptic cleft to reach the
subneural clefts which contains the Ligand-gated
Ach channel.
The channels are activated and open allowing
the Na+ to move to the inside of the muscle fiber.
As long as the Ach is present in the synaptic cleft,
it keeps activating the Ach channels which remain
open.
The Steps in Neuromuscular Junction
The influx of Na+ into the muscle lead to the
initiation of the END PLATE POTENTIAL (EPP).
END-PLATE POTENTIAL
• At the motor end-plate, the large influx of the
Sodium ions leads to a large number of positive
charges pouring into the muscle.
• This creates a local positive potential change
inside the muscle fiber membrane, called the end
plate potential. It is usually about 50-75 mv.
• In turn, this end plate potential initiates an action
potential that spreads along the muscle
membrane and thus causes muscle contraction.
Degradation of Ach:
• The Ach present in the synaptic cleft is broken
down by the enzyme Acetylcholinesterase, into
Acetyl coA+ choline.
• Both the products are reuptaken by the
presynaptic terminal.
• The Ach is again synthesized by the nerve cell
body and then send by anterograde flow to the
presynaptic terminal for packaging into secretory
vesicles.
Remember:
• The Neurotransmitter at the NMJ is Acetylcholine.
• Acetylcholine is degraded by the
Acetylcholinestrase.
• End-plate potential is the name given to the
potential generated at the motor end-plate.
Safety Factor at NMJ: Fatigue
• Each impulse that arrives at the NMJ causes
about three times as much end plate potential as
that required to stimulate the muscle fiber.
Therefore, the normal neuromuscular junction is
said to have a high safety factor.
Safety Factor at NMJ: Fatigue
• However, stimulation of the nerve fiber at rates
greater than 100 times per second for several
minutes often diminishes the number of
acetylcholine vesicles so much that impulses fail
to pass into the muscle fiber. This is called fatigue
of the neuromuscular junction, and it is the same
effect that causes fatigue of synapses in the
central nervous system when the synapses are
overexcited.
Safety Factor at NMJ: Fatigue
• Under normal functioning conditions, measurable
fatigue of the neuromuscular junction occurs
rarely, and even then only at the most exhausting
levels of muscle activity.
Summary of events that occurs during neuromuscuiar transmission
Action potential in presynaptic motor axon terminals
↓
Increase in Ca2+ permeability and influx of Ca2+ into axon terminal
↓
Release of acetylcholine from synaptic vesicles into the synaptic cleft
↓
Diffusion of acetylcholine to postjunctional membrane
↓
Combination of acetylcholine with specific receptors on postjunctional
membrane
↓
Increase in permeability of postjunctional membrane to Na+ and K+ causes
EPP
↓
Depolarization of areas of muscle membrane adjacent to endplate and
initiation of an action potential
THE MOTOR UNIT
Without the Nervous System –
Muscles will not contract.
Nerve-Muscle Interaction
• Skeletal muscle activation is initiated through neural
activation
• The Nervous system can be divided into central (CNS)
and peripheral (PNS)
Nerve-Muscle Interaction
• It can also be divided in terms of function: motor and
sensory activity
• Sensory: collects info from the various sensors located
throughout the body and transmits the info to the brain
• Motor: conducts signals to activate muscle contraction
Activation of motor unit and its innervation systems
.1Spinal cord 2. Cytosome 3. Spinal nerve
4. Motor nerve 5. Sensory nerve 6. Muscle with muscle fibres
Motor Unit
• Motor nerves extend from the spinal cord to the
muscle fibres
• Each fibre is activated through impulses
delivered via motor end plate
• Motor unit: a group of fibres activated via the
same nerve
• All muscle fibres of one particular motor unit
are always of the same fibre type
Motor Unit
• Muscles needed to perform precise movements
generally consist of a large number of motor
units and few muscle fibres
• Less precise movements are carried out by
muscles composed of fewer motor units with
many fibres per unit
All-or-none Principle
• Whether or not a motor unit activates upon the
arrival of an impulse depends upon the so called
all-or-none principle
• An impulse of a certain magnitude (or strength)
is required to cause the innervated fibres to
contract
• Every motor unit has a specific threshold that
must be reached for such activation to occur
Intra-muscle Coordination
• The capacity to apply motor units
simultaneously is known as intra-muscle
coordination
• Many highly trained power athletes, such as
weightlifters, wrestlers, and shot putters, are
able to activate up to 85% of their available
muscle fibres simultaneously (untrained: 60%)
Intra-muscle Coordination
• Force deficit: the difference between assisted
and voluntarily generated maximal force
(trained: 10%, untrained: 20-35%)
Intra-muscle Coordination cont.
• Trained athletes have not only a larger muscle
mass than untrained individuals, but can also
exploit a larger number of muscle fibres
• Athletes are more restricted in further developing
strength by improving intra-muscular coordination
• Trained individuals can further increase strength
only by increasing muscle diameter
Inter-muscle Coordination • The interplay between muscles that generate
movement through contraction (agonists) and
muscles responsible for opposing movement
(antagonists) is called inter-muscle coordination
• The greater the participation of muscles and
muscle groups, the higher the importance of
inter-muscle coordination
Inter-muscle Coordination
• To benefit from strength training the individual muscle groups can be trained in relative isolation
• Difficulties may occur if the athlete fails to develop all the relevant muscles in a balanced manner
Inter-muscle Coordination cont.
• High-level inter-muscle coordination greatly
improves strength performance and also
enhances the flow, rhythm, and precision of
movement
• Trained athlete is able to translate strength
potential to enhance inter-muscle coordination
Muscle’s Adaptation to Strength Training
• Individual’s performance improvements occur
through a process of biological adaptation,
which is reflected in the body’s increased
strength
• Adaptation process proceeds at different time
rates for different functional systems and
physiological processes
Muscle’s Adaptation to Strength Training
• Adaptation depends on intensity levels used in
training and on athlete’s unique biological
make-up
• Enzymes adapt within hours, cardiovascular
adaptation within 10 to 14 days
Electromyography
• Activation of motor units in man can be studied by
electromyography.
• Electromyography is a record of the electrical
activity of the muscle using a cathode ray
ossiloscops. The electrical activity is picked up by
metal disc electrode placed on the skin overlying
the muscle or by hypodermic needle electrodes
inserted in the muscle itself. The record obtained
is called electromyogram (EMC).
EMG
EXCITATION CONTRACTION
COUPLING
• The process by which depolarization of the
muscle fiber initiates muscle contraction is
called EXCITATION-CONTRACTION
COUPLING
Contraction of Skeletal Muscle
The thick and thin filaments, along with their
associated myofibril proteins, are responsible
for muscle contraction.
Contraction of Skeletal Muscle
• How does muscle contraction work?
• Influx of calcium ions in the cell
• as a result of nerve impulses
• troponin complex pulls tropomyosin molecules away from the G-actin subunits
• Exposure of the myosin binding sites.
• The heads of the myosin molecules can bind to the actin subunits, forming cross bridges.
• active site in each myosin head disrupts the high-energy bond of ATP molecules
• release of energy moves the myosin head towards the F- actin,
• when contact is made with the actin subunits, the F-actin is pulled along, causing the myofilament to contract.
Contraction of Skeletal Muscle
• The coordinated contraction of all the
myofilaments of all the muscle cells of a
muscle, causes the entire muscle to
contract.
T-Tubule & the
Sarcoplasmic
Reticulum
The t-tubules have the DHP
receptors in their
membranes…The DHP is
Dihydropyridine Receptor.
When this receptor is
activated because of an AP, it
causes the opening of the
voltage gated foot proteins/
Ryanodine channel/ Ca
release channel. These
channels are present in the
cisterns of the Sarcoplasmic
Reticulum.
The opening of these
channels leads to the release
of Ca into the Sarcoplasm.
Excitation –Contraction Coupling
Steps in contraction:
1. Discharge of motor neuron.
2. Release of NT (Ach) at motor end-plate.
3. Binding of Ach to Ach receptors on the motor end plate.
4. ↑ Na & K conductance in end-plate membrane.
5. Generation of end-plate potential EPP).
6. Remember the Safety Factor!
7. EPP leading to generation of Action Potential (AP).
8. Inward spread of depolarization (as AP) along T tubules
9. Release of Ca2+ from terminal cisterns of SR
10. Binding of Ca2+ to Troponin C
11. Troponin C pulls the tropomyosin off the actin uncovering binding sites on actin.
12. Formation of cross-linkages between actin & myosin.
13. Sliding of thin on thick filaments, producing contraction.
EXCITATION-CONTRACTION COUPLING
Steps in relaxation:
Ca2+ pumped back into Sarcoplasmic
Reticulum (SR) by the ATP-dependant Ca2+
pump in SR membrane.
Release of Ca2+ from troponin C.
A new ATP binds to the myosin head
↓
interaction between actin and myosin STOPS and
RELAXATION of the muscle fiber takes place.
IMPORTANT TERMS
• The Triad: name given to the structure formed by a single
t-tubule and 2 cisterns of SR on its each side.
• Calsequestrin: the protein present in the SR to which is
attached the Calcium.
• ATPase dependant Calcium Pump: the pump which
helps pump the Calcium back into the SR once the
contraction is over.
• DHP: is also called the Dihyropyridine receptor which is
present is the membranes of the t-tubule & opens in
response to an AP.
• Ryanodine channel: which is present in the membranes
of the cisterns of SR & which open in response to
activation of DHP receptor.
MOLECULAR EVENTS IN
MUSCLE CONTRACTION
Sarcomere: Organization of Fibers
Important:
3-dimensionally, thin filaments are arranged hexagonally around thick filaments and the cross-bridges project from each thick filament in all 6 directions towards the surrounding thin filaments……each thin filament is surrounded by 3 thick filaments.
What are Cross-bridges?
• With an electron microscope, fine cross
bridges can be seen extending from each
thick filament to the thin filament. These are
formed by the arm and head of the myosin
molecules projecting outward from the tail,
and pointing towards the thin filaments.
SLIDING FILAMENT THEORY
Definition:
When a muscle cell contracts, the thin filaments
slide past the thick filaments, and the sarcomere
shortens. This process comprised of several steps
is called the Sliding Filament Theory. It is also
called the Walk Along Theory or the Ratchet
Theory.
After the ATP has bound to the myosin head, the
binding of Myosin to Actin molecule takes place:
Once the actin active sites are uncovered,
the myosin binds to it:
Power Stroke
POWER STROKE
SLIDING FILAMENT THEORY
• It has the following steps:
• Before contraction begins, An ATP molecule
binds to the myosin head of the cross-bridges.
• The ATPase activity of the myosin head
immediately cleaves the ATP molecule but the
products (ADP+P) remains bound to the head.
Now the myosin head is in a high energy state
and ready to bind to the actin molecule.
SLIDING FILAMENT THEORY
• When the troponin-tropomyosin complex binds
with calcium ions that come from the
sarcoplasmic reticulum, it pulls the tropomyosin
so that the active sites on the actin filaments for
the attachment of the myosin molecule are
uncovered.
• Myosin head binds to the active site on the actin
molecule.
SLIDING FILAMENT THEORY (cont)
• The bond b/w the head of the cross
bridges(myosin) & the actin filaments causes a
the bridge to change shape bending 45° inwards
as if it was on a hinge, stroking towards the
centre of the sarcomere, like the stroking of a
boat oar. This is called a POWER STROKE.
• This power stroke pulls the thin filament inward
only a small distance.
SLIDING FILAMENT THEORY (cont)
• Once the head tilts, this allows release of ADP &
phosphate ions.
• At the site of release of ADP, a new ATP binds.
This binding causes the detachment of the
myosin head from the actin.
SLIDING FILAMENT THEORY (cont)
• A new cycle of attachment-detachment-
attachment begins.
• Repeated cycles of cross-bridge binding, bending
and detachment complete the shortening and
contraction of the muscle.
Important
• Through the attachment-detachment-
attachment cycle, the myosin heads or cross
bridges “walk” along an actin filament to pull it
inward relative to the stationary thick filament.
Important
• Because of the way the myosin molecules are
oriented within a thick filament, all the cross-
bridges stroke towards the center of the
sarcomere.
Important
• At any time during contraction, part of the
cross bridges are attached to the thin
filaments and are stroking, while others are
returning to their original conformation in
preparation for binding with another actin
molecule.
Important
• Thus, some cross-bridges ―hold on‖ while
others ―let go‖. Otherwise, the thin filaments
would slip back to their resting position b/w
strokes.
Important
• Through the attachment-detachment-attachment
cycle, the myosin heads or cross bridges “walk”
along an actin filament to pull it inward relative to the
stationary thick filament.
• Because of the way the myosin molecules are
oriented within a thick filament, all the cross-bridges
stroke towards the center of the sarcomere.
Important
• At any time during contraction, part of the cross
bridges are attached to the thin filaments and are
stroking, while others are returning to their original
conformation in preparation for binding with another
actin molecule. Thus, some cross-bridges ―hold on‖
while others ―let go‖. Otherwise, the thin filaments
would slip back to their resting position b/w strokes.
Important
• The detachment of the myosin head from the actin
cannot take place until and unless a new ATP does
not attach to the myosin head. This is important
when death occurs, no more ATP is available and
thus, rigor mortis occurs.
Shortening of the
Muscle:
• The thick and thin filaments DO NOT shorten.
• Contraction is accomplished by the thin filaments from opposite sides of each sarcomere sliding closer together or overlapping the thick filaments further.
• The H-zone becomes smaller as the thin filaments approach each other.
• The I band becomes smaller as the thin filaments further overlap the thick filaments.
• The width of the A band remains unchanged as it depends on the thick filaments and the thick filaments do not change length.
½ I ½ I
When muscle contracts, the
sarcomere shortens. The I band
and H Zone also shorten. But
the length of the A band remains
the same.
Mechanism of muscle contraction:
• Width of sarcomere decreases from 2.2 to 2 or
less
• Length of thick and thin filament remain the same
• Power stroke pull the Z discs towards the center
of the sarcomere
Mechanism of muscle contraction:
• Results in app. Of the Z discs
• Cyclic attachment-detachment-attachment of
myosin head to actin, till there is complete
overlap of thick & thin filaments
• Decrease in I-band and H-band, A-band stays the
same
