physiology 1 skeletal muscle physiology files/physiology 1/part 1 muscle... · 2018. 7. 2. ·...

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