neuromuscular

The Motor Unit of Skeletal Muscle

Somatic Motor Neurons

  • All skeletal muscles are under voluntary or reflex control by motor neurons of the somatic motor system.

  • Somatic motor neurons are efferent neurons.

  • Their cell bodies are located in the central nervous system (CNS).

  • For spinal nerves, the cell body resides in the ventral horn of the spinal cord.

Pathway of a Motor Neuron

1. Cell Body

  • Located in the ventral horn of the spinal cord.

2. Axon Leaves the Spinal Cord

  • The motor neuron sends out an axon toward the skeletal muscle.

3. Axon Branches

  • Near its termination, the axon typically branches.

  • These branches innervate a few or many individual muscle fibers.

A single muscle fiber responds to only one motor neuron.

Motor Unit

Definition

A motor unit =

  • one motor neuron

  • all the muscle fibers innervated by its branches

So:

  • one neuron → many muscle fibers

  • all of them together = one motor unit.

Motor Neuron Pool

  • A muscle does not receive input from only one motor neuron.

  • A typical skeletal muscle receives innervation from ~100 somatic motor neurons.

  • The collection of many motor neurons supplying one muscle is called a motor neuron unit.

The Innervation Ratio of the Skeletal Muscle

Whole Muscle Function

A whole muscle can produce:

  • a wide range of forces

  • a graded range of shortening

by varying the number of motor units excited within the muscle.

Innervation Ratio

Definition

The innervation ratio of a whole skeletal muscle is defined as:

the number of muscle fibers innervated by a single motor neuron

Small Innervation Ratio

Function

Muscles with a small innervation ratio control:

  • fine movements

  • small forces

Example

Fine, high precision movements of the extraocular muscles that control positioning movements of the eye are achieved through an innervation ratio of:

  • ~3 muscle fibers per neuron

Large Innervation Ratio

Function

Muscles with a large innervation ratio control:

  • rough movement

  • development of large forces

Examples

Soleus Muscle

Postural control by the soleus muscle uses an innervation ratio of:

  • ~200

Gastrocnemius Muscle

The gastrocnemius muscle, which is capable of developing large forces required in athletic activities such as jumping, has innervation ratios that vary from:

  • ~100 to ~1000

Neuromuscular Junction / Motor End-Plate

Motor Neuron Pathway

  • motor neuron (spinal cord)
    → one axon
    → branches into axon processes near the point of contact with the target muscle

Axon Branch

  • one axon branch innervate an individual muscular fiber

through:

Terminal Arborizations

  • a small tree-like patch of unmyelinated nerve processes

Nerve Endings

  • ending into bulb-shaped terminals called boutons

Schwann Cells

  • Schwann cells intimately associate with the nerve terminal

  • form a cap over the face of the nerve membrane

Synaptic Transmission at the Neuromuscular Junction – Motor End-Plate

Presynaptic Boutons

  • presynaptic boutons contain ACh vesicles

  • 6000–10000 ACh molecules / vesicle = quantum

  • → quantum release into the synaptic cleft

After Each AP

  • within a few sec. after each AP, “coated pits” appear in the presynaptic membrane

  • caused by clathrin = contractile proteins in the nerve endings

  • within ~20 sec. the proteins contract and cause the pits to break away to the interior of the membrane

  • thus forming new vesicles

Vesicle Reloading

  • bouton reloads its discharged synaptic vesicles by resynthesizing ACh

  • transport it into the vesicles through an ACh-H+ exchanger

  • working on a vacuolar H+-pump expense

AChE

AChE = acetylcholinesterase, in the synaptic cleft

Breakdown of ACh

AChE + ACh
↓
acetyl-AChE
↓
acetate + AChE

Products

  • choline

  • acetate

Neuromuscular Junction

Synaptic Cleft

  • synaptic cleft is ~50 nm wide

  • filled with a meshwork of proteins and proteoglycans

  • part of the extracellular matrix

Muscle Basement Membrane

Synaptic Basal Lamina

Contains Proteins

  • collagen

  • laminin

Functions

  • mediate adhesion of the neuromuscular junction

  • play important roles in:

    • synapse development

    • regeneration

Acetylcholinesterase (AChE)

  • synaptic basal lamina contains a high concentration of acetylcholinesterase (AChE)

  • terminates synaptic transmission

  • rapidly hydrolyzing free ACh to:

    • choline

    • acetate

Postsynaptic Membrane

  • postsynaptic membrane of the skeletal muscle fiber (motor end-plate)

  • lying directly under the nerve terminal

  • characterized by extensive invaginations/infoldings
    = post-junctional folds

Function

  • increase postsynaptic surface

Postsynaptic Receptors

  • postsynaptic nicotinic ACh receptors

  • ionotropic receptors

→ end-plate potential (EPP)
= excitatory postsynaptic potential (EPSP)

Neuromuscular Junction

Action Potential (AP)

AP spreads over the presynaptic terminal
↓
voltage-gated Ca channels open
↓
Ca2+ influx
↓
ACh vesicles draw to the presynaptic membrane
↓
vesicles fuse with the presynaptic membrane
↓
ACh emptied into the synaptic space by exocytosis

Removal of ACh

ACh is removed rapidly (few msec) by:

1. Acetylcholinesterase

  • attached mainly to the spongy layer of fine connective tissue in the synaptic space

2. Diffusion

  • diffusion out of the synaptic space

  • a smaller amount

ACh Nicotinic Receptors

  • ACh nicotinic receptors in the muscle fiber membrane are ion channels

  • diameter ~0.65 nm

Allow

  • positive ions:

    • Na+

    • K+

to move easily

Cl-

  • repelled by the negative charge of the channel pore

End-Plate Potential (EPP)

Na+ influx creates a local positive potential change of 50–75 mV inside the muscle fiber membrane

= end-plate potential (EPP)

↓

initiates a regenerating AP

↓

AP spreads along the muscle membrane

↓

muscle contraction

Synaptic Facilitation

  • short-lived enhancement of the EPP in response to:

    • a brief increase in the frequency of nerve stimulation

    • a transient increase in the mean number of quanta/nerve stimulus

Synaptic Potentiation

(or post-tetanic potentiation)

  • long-lived and pronounced increase in ACh release

  • occurs after a long period of high-frequency nerve stimulation

  • can last for minutes after the conditioning stimulus

  • may be caused by a period of intense nerve firing

    • increases [Ca2+]i in the presynaptic terminal

    • thus increases the probability of exocytosis

Synaptic Depression

  • transient decrease in the efficiency of transmitter release
    → reduction in the EPP in response to a period of frequent nerve stimulation

  • may result from temporary depletion of transmitter-loaded vesicles from the presynaptic terminal
    → reduction in the number of available quanta.

Pharmacology of the Vertebrate Neuromuscular Junction (NMJ)

Presynaptic

Neuronal Na+ Channel

Prevent Depolarization

  • Tetrodotoxin

  • Saxitoxin

Ca2+ Channel

  • ω-Conotoxin

K+ Channel

Inhibit Repolarization

  • Dendrotoxin

ACh Release

  • Tetanus toxin

  • Botulinum toxin

Postsynaptic

Muscle Na+ Channel

  • Tetrodotoxin

  • Saxitoxin

  • μ-Conotoxin

AChR Channel

Agonists (+)

  • Acetylcholine

  • Nicotine

Antagonists (−)

  • d-Tubocurarine

  • α-Bungarotoxin

Acetylcholinesterase

  • Physostigmine

  • DFP

Notes

  • many proteins involved in synaptic transmission at the mammalian neuromuscular junction are targets of naturally occurring or synthetic drugs

  • antagonists are shown as minus signs highlighted in red

  • agonists are shown as plus signs highlighted in green

Drugs that Enhance or Block Transmission at the Neuromuscular Junction

Drugs that Stimulate the Muscle Fiber by Acetylcholine-Like Action

Drugs

  • methacholine

  • carbachol

  • nicotine

Characteristics

  • ACh agonists

  • not destroyed by cholinesterase
    or

  • destroyed so slowly that their action persists for many minutes to several hours

Effects

  • cause localized areas of depolarization of motor end plate

  • every time the muscle fiber recovers from a previous contraction, these depolarized areas, by virtue of leaking ions, initiate a new AP

→ muscle spasm

Drugs that Stimulate the Neuromuscular Junction by Inactivating Acetylcholinesterase

Drugs

  • neostigmine

  • physostigmine

  • pyridostigmine

  • diisopropyl fluorophosphate

Mechanism

  • inactivate AChE

  • with each successive AP, additional ACh accumulates

  • stimulates the muscle fiber repetitively

→ muscle spasm caused by minimum stimulation

  • can also cause death due to laryngeal spasm

Neostigmine and Physostigmine

  • combine with AChE

  • reversibly inactivate the AChE

  • for up to several hours

Pyridostigmine

  • used in myasthenia gravis treatment

Diisopropyl Fluorophosphate

  • powerful “nerve” gas poison

  • inactivates AChE for weeks

  • particularly lethal poison

Drugs that Inhibit the Postsynaptic Transmission at the Neuromuscular Junction

Curariform Drugs

  • prevent passage of impulses from the nerve ending into the muscle

  • by competing for the ACh receptor sites

Example

D-tubocurarine

  • blocks the action of ACh on the muscle fiber ACh receptors

  • prevents sufficient increase in permeability of the muscle membrane channels

  • prevents initiation of an action potential

Myasthenia Gravis

= muscle weakness
(from the Greek mys and asthenia)

Disorder

  • acquired autoimmune disorder

  • spontaneous production of anti-ACh receptor (AChR) antibodies

Effects

  • progressive loss of muscle AChRs

  • degeneration of post-junctional folds

Antibody Target

  • most common target:

    • region of the AChR α subunit

    • called MIR (main immunogenic region)

Clinical

  • fatigue

  • weakness of skeletal muscle

Severe Cases

  • paralysis of the respiratory muscles
    → death

Treatment

1. Reduce the Potency of the Immunological Attack

Immuno-suppressants

  • corticosteroids

Plasmapheresis

  • removal of antibodies from the patient’s serum

2. Enhance Cholinergic Activity Within the Synapse

AChE Inhibitors

  • pyridostigmine

Important

  • dosage must be carefully monitored

  • to prevent overexposure of the remaining AChRs to ACh

Overstimulation Effects

  • overstimulation of the postsynaptic receptors

  • prolonged depolarization of the postsynaptic membrane

  • inactivation of neighboring Na+ channels

  • synaptic blockade

3. Thymoma Removal

  • some patients with myasthenia gravis have a thymus gland tumor

  • removal of the thymoma leads to clinical improvement in nearly 75% of the cases

Muscle Fiber Cell / Myofiber

  • smallest contractile unit of skeletal muscle

  • multinucleated

  • elongated cell

Endomysium

  • single muscle fibers are surrounded by a sheath called the endomysium

Sarcolemma

  • beneath the endomysium surrounding each muscle fiber is sarcolemma

  • plasma membrane of the muscle cell

Fascicle

  • a bundle of linearly aligned muscle fibers forms a fascicle

  • enveloped by a sheath called the perimysium

Muscle

  • bundles of fascicles form a muscle

  • covered by epimysium

  • extends towards tendons

Myofibrils

  • an individual skeletal muscle cell contains a densely arranged parallel array of cylindrical elements called myofibrils

Sarcomeres

  • myofibrils
    = an end-to-end chain of regular repeating units
    = sarcomeres

Myofilaments

  • sarcomeres consist of smaller interdigitating filaments
    = myofilaments

Types

  • actin

  • myosin

Tropomyosin ( thin filament )

  • two identical α-helices

  • coil around each other

  • sit near the two grooves formed by the two helical actin strands

Head-to-Tail Contact

  • head-to-tail contact between neighboring tropomyosin molecules

  • results in two nearly continuous helical filaments

  • shadow the actin double helix

Role of Tropomyosin

  • regulate the binding of myosin head groups to actin

Troponin

  • heterotrimer consisting of:

1. Troponin T (TnT or TNNT)

  • binds to a single molecule of tropomyosin

2. Troponin C (TnC or TNNC)

  • binds Ca2+

  • related to another Ca2+-binding protein:

    • calmodulin

3. Troponin I (TnI or TNNI)

  • binds to actin

  • inhibits contraction

Coordinated Interaction

  • coordinated interaction among:

    • troponin

    • tropomyosin

    • actin

allows:

  • actin-myosin interactions to be regulated by changes in [Ca2+]i

Thick Filaments

  • 10 nm in diameter

  • 1.6 micrometers in length

Myosin

  • bipolar assembly of multiple myosin II molecules

Structure of Myosin

Heavy Chains

  • 2 intertwined heavy chains

  • contain:

    • tail

    • hinge

    • head region

Light Chains

  • 2 alkali (or essential) light chains

  • 2 regulatory light chains

Heads of the Heavy Chains

  • 2 globular heads of the heavy chains
    = crossbridges between the thick and thin filaments of the sarcomere

Binding Sites

Actin Binding Site

  • site for binding actin

ATP Binding Site

  • site for binding and hydrolyzing ATP

Light Chain Complex

  • forms a complex with two light chains:

    • one regulatory

    • one alkali

Regulatory Light Chain

  • regulates the ATPase activity of myosin

Alkali Light Chain

  • stabilizes the myosin head region

Regulation of Myosin Regulatory Light Chain

  • regulated through phosphorylation

  • by:

    • Ca2+-dependent kinases

    • Ca2+-independent kinases

Calcium Switch for Skeletal Muscle Contraction

When Ca²⁺ is LOW (< 10⁻⁹ M)

  • No Ca²⁺ binds to troponin

  • Tropomyosin blocks the binding sites on actin

  • Myosin cannot interact with actin

  • Contact between binding sites is inhibited

  • Muscle is relaxed

When Ca²⁺ is HIGH (> 10⁻⁵ M)

  • Ca²⁺ binds to troponin

  • Tropomyosin moves away from the binding sites

  • Myosin can interact with actin

  • Contact between binding sites is permitted

  • Muscle is contracted

Main Idea

Ca²⁺ ions control skeletal muscle contraction through the troponin–tropomyosin complex by regulating whether myosin heads can bind to active sites on actin.

Muscle Fiber Structure

T Tubules

  • T tubules are tubular invaginations of the plasma membrane

  • Radially oriented

  • Plunge into the muscle fiber

  • Surround the myofibrils at the junctions of the A and I bands

  • Two T tubules in each sarcomere

Sarcoplasmic Reticulum (SR)

  • T tubules associate with two cisternae

  • Cisternae are specialized regions of the sarcoplasmic reticulum (SR)

  • SR serves as a storage organelle for intracellular Ca²⁺

Triad

A TRIAD consists of:

  • One transverse tubule (T tubule)

  • Two neighboring sarcoplasmic reticulum cisternae

Function

  • Important in coupling excitation to contraction in skeletal and cardiac muscle

Ca²⁺ Movement

  • Action potential travels along the cell membrane and T tubule

  • Causes Ca²⁺ release

  • Ca²⁺ translocation occurs

  • Ca²⁺ is later taken back up into the SR (Ca²⁺ reuptake).

Electrical Activity at the Neuromuscular Junction

Key Concept

Neuromuscular transmission occurs when a motor neuron action potential (AP) releases acetylcholine (ACh) at the neuromuscular junction, producing depolarization of the muscle end plate.

(A) Small Amount of Acetylcholine Released

Sequence

  1. A motor axon AP reaches the axon terminal.

  2. Small amount of ACh is released into the neuromuscular junction.

  3. A small end plate depolarization occurs.

  4. Depolarization spreads through the myoplasm by electrotonic conduction.

  5. Electrotonic conduction occurs with decrement (signal weakens with distance).

  6. Depolarization reaching the first voltage-gated Na⁺ channel is below threshold.

  7. Na⁺ channels do not open.

  8. No muscle action potential is formed.

Important Physiology Points (Exam Focus)

  • ACh causes inward membrane current.

  • End plate potential spreads electrotonically.

  • Electrotonic conduction is:

    • passive

    • decremental

  • If depolarization is below Na⁺ channel threshold:

    • no AP

    • no muscle fiber excitation

(B) Greater Frequency of Motor Axon APs

Sequence

  1. Many motor axon APs arrive at the terminal.

  2. More ACh is released.

  3. Higher ACh concentration in the neuromuscular junction.

  4. Larger end plate potential (EPP) is produced.

  5. Depolarization still spreads with decrement.

  6. Depolarization reaching first Na⁺ channels is now above threshold.

  7. Voltage-gated Na⁺ channels open.

  8. Muscle fiber generates a muscle AP.

  9. Muscle AP is:

    • self-reinforcing

    • propagated without decrement

  10. AP travels along the muscle fiber similar to conduction in unmyelinated nerve fibers.

Important Physiology Points (Exam Focus)

  • Increased AP frequency → increased ACh release.

  • Larger EPP increases likelihood of reaching threshold.

  • Threshold opening of Na⁺ channels is essential for muscle AP generation.

  • Muscle AP propagation is:

    • regenerative

    • non-decremental

High-Yield Final Exam Notes

Definitions

End Plate Potential (EPP)

Local depolarization at the motor end plate caused by ACh.

Electrotonic Conduction

Passive spread of depolarization with gradual decrease in amplitude.

Threshold

Minimum depolarization needed to open voltage-gated Na⁺ channels.

Depolarization of the T-Tubule Membrane Results in Ca²⁺ Release from the Sarcoplasmic Reticulum

Main Concept

Action potential (AP) propagates into the T tubules → activates voltage-gated L-type Ca²⁺ channels (DHP receptors) → activates SR Ca²⁺-release channels (RYR1) → Ca²⁺ released from sarcoplasmic reticulum (SR).

Step-by-Step Mechanism

1. AP Propagation into T Tubules

  • Muscle action potential travels along sarcolemma.

  • AP enters T tubules.

  • T-tubule membrane becomes depolarized.

2. Triad Region

TRIAD =

  • 1 transverse (T) tubule

  • 2 terminal cisternae of sarcoplasmic reticulum

3. Activation of L-Type Ca²⁺ Channels

L-type Ca²⁺ Channels

Also called:

  • DHP receptors

  • Voltage-gated L-type Ca²⁺ channels

Located in:

  • T-tubule membrane

Function:

  • Activated by depolarization.

4. Conformational Change of DHP Receptor

Depolarization causes conformational change in DHP receptor.

This:

  • allows small Ca²⁺ entry into cell

  • mechanically activates SR Ca²⁺-release channels

5. Activation of Ryanodine Receptor (RYR1)

RYR1

  • Ca²⁺-release channel in SR membrane

  • Also called ryanodine receptor

Mechanism:

  • Activated by mechanical coupling with DHP receptor

  • Not dependent on extracellular Ca²⁺ entry

6. Result

  • Large amount of Ca²⁺ released from SR into cytoplasm.

  • Increased intracellular Ca²⁺ initiates muscle contraction.

Tetrad

Definition

Four voltage-activated L-type Ca²⁺ channels grouped together near one SR Ca²⁺-release channel.

This arrangement is called:

TETRAD

High-Yield Final Exam Notes

Must Memorize

  • AP in T tubule triggers Ca²⁺ release from SR.

  • DHP receptor = L-type voltage-gated Ca²⁺ channel.

  • RYR1 = SR Ca²⁺-release channel.

  • DHP receptor and RYR1 are mechanically coupled.

  • Skeletal muscle Ca²⁺ release does NOT depend on extracellular Ca²⁺ entry.

  • TRIAD:

    • 1 T tubule

    • 2 terminal cisternae of SR

  • Four DHP receptors form a tetrad.

Drug Associations

DHP Receptor

Inhibited by:

  • Dihydropyridines

Uses:

  • Ca²⁺ channel blockers

  • Antihypertensive drugs

  • Antiarrhythmic drugs

RYR1

  • Inhibited by ryanodine

  • Activated by caffeine

Flow Chart

AP in T tubule
→ DHP receptor activation
→ conformational change
→ RYR1 activation
→ Ca²⁺ release from SR
→ increased cytosolic Ca²⁺
→ muscle contraction

EC Coupling

  • Electrical excitation increases intracellular Ca²⁺.

  • Increased intracellular Ca²⁺ triggers contraction.

Sources of Ca²⁺

  1. Extracellular space via voltage-gated Ca²⁺ channels

  2. Sarcoplasmic reticulum (SR)

Excitation–Contraction (EC) Coupling in Skeletal Muscle

Main Concept

In skeletal muscle, EC coupling can occur without extracellular Ca²⁺.

Reason:

  • Direct mechanical coupling between:

    • L-type Ca²⁺ channel (DHP receptor)

    • SR Ca²⁺-release channel (RYR1)

This mechanism is called:

Electromechanical coupling

Sequence of EC Coupling

1. Motor Neuron Stimulation

  • Acetylcholine (ACh) released from motor neuron.

  • ACh binds receptors on motor end plate.

  • End plate potential generates muscle AP.

2. AP Propagation

  • Muscle AP spreads along sarcolemma.

  • AP enters T tubules.

3. DHP Receptor Activation

  • T-tubule depolarization activates L-type Ca²⁺ channels (DHP receptors).

4. Mechanical Activation of RYR1

  • DHP receptor mechanically activates RYR1 in SR membrane.

5. Ca²⁺ Release from SR

  • Ca²⁺ rapidly released from sarcoplasmic reticulum.

  • Rapid increase in intracellular Ca²⁺ concentration ([Ca²⁺]i).

6. Troponin C Activation

  • Ca²⁺ binds troponin C.

  • Tropomyosin moves away from myosin-binding sites.

7. Cross-Bridge Formation

  • Actin and myosin form cross-bridges.

  • Cross-bridge cycle begins.

  • Muscle contraction occurs.

8. Relaxation

  • Ca²⁺ actively transported back into SR.

  • Tropomyosin again blocks myosin-binding sites.

  • Muscle relaxes.

1. Motor Nerve Stimulates Muscle

A motor neuron sends an action potential (AP) to the muscle fiber.

At the nerve ending:

  • acetylcholine (ACh) is released.

ACh binds to:

nicotinic ACh receptors

on the muscle membrane.

2. Na⁺ Enters Muscle Fiber

When nicotinic receptors open:

  • large amounts of Na⁺ enter the muscle fiber.

This causes:

depolarization

If depolarization reaches threshold:

muscle action potential forms.

3. AP Spreads Through Muscle

The muscle AP spreads:

  • across the sarcolemma

  • down the T tubules

This carries the electrical signal deep into the muscle fiber.

4. EC Coupling Begins

Depolarization in T tubules activates:

DHP receptors (L-type Ca²⁺ channels)

DHP receptors are mechanically connected to:

RYR1 Ca²⁺-release channels

in the sarcoplasmic reticulum (SR).

This mechanical coupling opens RYR1.

5. Ca²⁺ Released from SR

The SR releases large amounts of stored Ca²⁺ into the cytoplasm.

Inside SR, Ca²⁺ is stored bound to:

  • calsequestrin

  • calreticulin

Now intracellular Ca²⁺ concentration rises rapidly.

This increased Ca²⁺ is the key signal for contraction.

6. Ca²⁺ Initiates Contraction

Ca²⁺ binds:

troponin C

This moves:

tropomyosin

away from actin binding sites.

Now:

myosin heads bind actin

Cross-bridges form between:

  • actin filaments

  • myosin filaments

7. Sliding Filament Mechanism

Myosin pulls actin filaments:

sliding alongside each other

This shortens the muscle fiber:

contraction

8. ATP Is Required

ATP is needed for:

  • cross-bridge cycling

  • muscle contraction

  • Ca²⁺ pumping back into SR

Without ATP:

  • contraction cannot continue

  • relaxation cannot occur

9. Relaxation

After contraction:

SERCA pump

actively pumps Ca²⁺ back into SR.

As Ca²⁺ leaves cytoplasm:

  • troponin loses Ca²⁺

  • tropomyosin blocks binding sites again

  • cross-bridges stop

Result:

muscle relaxation

Cross-Bridge Cycle (Mechanism of Muscle Contraction)

This slide explains:

how myosin and actin interact to produce contraction.

The cycle repeats many times during contraction.

Step 1 — ATP Binding

ATP binds to:

myosin head

Effect:

  • decreases affinity of myosin for actin

  • myosin detaches from actin

Result:

cross-bridge breaks

If all myosin heads were detached:

muscle would be relaxed

Step 2 — ATP Hydrolysis

ATP is broken down:

ATP → ADP + Pi

This occurs on:

myosin head

The energy released causes:

myosin head to cock

Meaning:

  • myosin head pivots into high-energy position

  • about 90° angle

Important:

  • ADP and Pi remain attached to myosin head.

The cocked myosin head moves:

~11 nm along actin filament

Now it is ready to bind a new actin site.

Step 3 — Cross-Bridge Formation

Cocked myosin head binds:

actin filament

This forms:

actin–myosin cross-bridge

At this stage:

  • myosin still contains ADP + Pi

Step 4 — Power Stroke

Pi is released from myosin head.

This triggers:

power stroke

During power stroke:

  • myosin head bends about 45°

  • pulls actin filament toward center

Result:

force and movement generated

This is the main force-producing step.

Step 5 — ADP Release

After power stroke:

  • ADP leaves myosin head.

Now myosin remains tightly attached to actin:

rigid state

The cycle stops here until:

another ATP binds

New ATP binding:

  • detaches myosin

  • starts another cycle

Most Important Concept

ATP has TWO major roles:

1. Detaches myosin from actin

2. Cocks/energizes myosin head

Very High-Yield Exam Point

No ATP →

myosin cannot detach from actin

Result:

rigor state (rigor mortis)

Mechanism of Calcium Removal — Muscle Relaxation

This slide explains:

how Ca²⁺ is removed from cytoplasm to stop contraction.

Remember:

  • Muscle contraction requires ↑ intracellular Ca²⁺.

  • Relaxation requires ↓ intracellular Ca²⁺.

So after contraction, Ca²⁺ must be removed from cytoplasm.

Main Mechanisms Removing Ca²⁺

There are:

1. Sarcolemma mechanisms

(remove Ca²⁺ out of the cell)

2. SR mechanisms

(move Ca²⁺ back into SR)

1. Sarcolemma Mechanisms

A. Na⁺–Ca²⁺ Exchanger (NCX)

Function:

  • removes Ca²⁺ from cell

  • exchanges intracellular Ca²⁺ for extracellular Na⁺

So:

Ca²⁺ goes out, Na⁺ comes in

B. Plasma Membrane Ca²⁺ ATPase (PMCA)

Function:

  • pumps Ca²⁺ out of cell

Important:

  • uses ATP

2. SR Mechanism — MOST IMPORTANT

SERCA Pump

Full name:

Sarcoplasmic Reticulum Ca²⁺ ATPase

Function:

  • pumps Ca²⁺ from cytoplasm back into SR

This is:

the major mechanism causing relaxation

Important:

  • ATP-dependent

  • active transport

What Happens to Ca²⁺ Inside SR?

After Ca²⁺ enters SR:
it binds storage proteins:

  • calsequestrin

  • calreticulin

Purpose:

  • store large amounts of Ca²⁺ inside SR

Phospholamban & SERCA

Phospholamban

Regulates:

SERCA activity

Important point:

phosphorylation of phospholamban enhances SERCA function

Meaning:

  • more Ca²⁺ pumped into SR

  • relaxation becomes faster

Especially important in:

slow-twitch skeletal muscle fibers

Key Physiological Idea

Contraction

↑ cytoplasmic Ca²⁺

Relaxation

↓ cytoplasmic Ca²⁺

So:

relaxation depends on Ca²⁺ removal

High-Yield Final Exam Notes

Must Memorize

  • SERCA is the most important Ca²⁺ removal mechanism.

  • SERCA pumps Ca²⁺ back into SR.

  • SERCA requires ATP.

  • NCX and PMCA remove Ca²⁺ across sarcolemma.

  • Ca²⁺ stored in SR by calsequestrin and calreticulin.

  • Phosphorylation of phospholamban enhances SERCA activity.

Specialized Energy Stores in Muscle Cell

1. Phosphocreatine System

  • Immediate ATP reserve in muscle.

  • Creatine kinase transfers phosphate from phosphocreatine to ADP → ATP.

  • Very rapid ATP regeneration.

  • Effective for <10 seconds of intense activity.

2. Glycogen / Anaerobic Glycolysis

  • Glycogen = major stored energy source in skeletal muscle.

  • Glycogen → pyruvate → ATP.

  • Occurs by anaerobic metabolism (without O₂).

  • Can sustain muscle activity for ~1 minute without oxygen.

3. Oxidative Metabolism

  • Pyruvate further metabolized by oxidative metabolism.

  • Main long-term ATP source.

  • Requires oxygen.

  • ATP production depends on oxygen delivery to muscle.

High-Yield Points

  • Creatine kinase regenerates ATP rapidly.

  • Phosphocreatine supports short bursts of activity.

  • Glycogen supports anaerobic ATP production.

  • Oxidative metabolism is the major long-term ATP source.

  • Oxygen availability limits oxidative ATP generation.

Muscle Fatigue

Definition

Muscle fatigue =

  • inability to maintain desired power output during contraction.

Results in:

  • ↓ force production

  • ↓ velocity of shortening

Why Fatigue Occurs

Main causes:

  • ↓ number of active cross-bridges

  • ↓ force produced per cross-bridge

Important Features of Fatigued Muscle

  • Force declines earlier and more than shortening velocity.

  • Slower contraction and relaxation.

  • Fast movements become difficult.

Reason:

impaired Ca²⁺ release and reuptake from SR

Protective Role

Fatigue may protect muscle by:

  • reducing contraction rate and force

  • preventing cellular damage

Important Point

Muscle fatigue:

reversible with rest

Unlike muscle damage/weakness:

  • force generation remains impaired even after rest.

Types of Fatigue

1. Central Fatigue

Occurs in:

CNS

Causes:

  • altered sensory input

  • reduced excitatory input from brain/spinal cord

  • altered motor neuron excitability

2. Peripheral Fatigue

Occurs in:

muscle itself

Causes:

  • impaired muscle excitability

  • impaired Ca²⁺ release

Metabolic Causes of Fatigue

  • ATP depletion

  • lactic acid accumulation

  • glycogen depletion.

Muscle Fiber Types

Slow Fibers (Type I, Red Muscle)

Characteristics

  • Small muscle fibers

  • Innervated by small nerve fibers

  • Rich blood supply and many capillaries

  • Many mitochondria

  • High myoglobin content

Metabolism

  • Mainly:

    oxidative metabolism

  • Slow but efficient ATP production

Functional Features

  • Fatigue resistant

  • Good for prolonged activity/endurance

Why Called “Red Muscle”?

  • High myoglobin content gives red color.

  • Myoglobin stores and transports oxygen to mitochondria.

Fast Fibers (Type II, White Muscle)

Characteristics

  • Large muscle fibers

  • Strong contractions

  • Extensive SR for rapid Ca²⁺ release

  • High glycolytic enzyme content

  • Fewer mitochondria

  • Less blood supply

  • Low myoglobin content

Metabolism

  • Mainly:

    glycolytic / anaerobic metabolism

  • Rapid ATP production

Functional Features

  • Powerful rapid contractions

  • Fatigue easily

Why Called “White Muscle”?

  • Low myoglobin content gives pale/white appearance.

Cardiac Myocyte Structure

General Features

Cardiac myocytes are:

  • shorter than skeletal muscle fibers

  • branched

  • interconnected end-to-end

Intercalated Disks

Cardiac cells connected by:

intercalated disks

Contain:

  • desmosomes

  • gap junctions

Functions of Intercalated Disks

Desmosomes

  • mechanical attachment between cells

  • prevent separation during contraction

Gap Junctions

  • allow electrical current to pass between cells

  • enable rapid spread of action potentials

Functional Syncytium

Cardiac muscle acts as:

mechanical and electrical syncytium

Meaning:

  • cells contract together as one unit

  • electrical activity spreads rapidly through heart

Important Timing

  • AP from SA node spreads through heart in:

    ~0.22 sec

  • Cardiac muscle contraction lasts:

    ~0.3 sec

Sarcolemma Structures

Includes:

  • T tubules

  • terminal cisternae

  • sarcoplasmic reticulum (SR)

These structures participate in:

excitation–contraction coupling

High-Yield Points

  • Cardiac myocytes are branched and interconnected.

  • Intercalated disks contain desmosomes and gap junctions.

  • Desmosomes = mechanical coupling.

  • Gap junctions = electrical coupling.

  • Cardiac muscle functions as a syncytium.

  • AP spreads through heart rapidly from SA node.

Phospholamban Effect on Heart Activity

Phospholamban

  • Regulatory protein in SR membrane.

  • Regulates:

    SERCA pump

Normal Function

Phospholamban normally:

inhibits SERCA

So:

  • less Ca²⁺ pumped back into SR

  • slower relaxation

Phosphorylation of Phospholamban

Stimulated by:

β₁-adrenergic stimulation

Mechanism:
β₁ stimulation
→ PKA activation
→ phospholamban phosphorylation

Effect of Phosphorylation

Phosphorylation removes phospholamban inhibition on SERCA.

Result:

SERCA activity increases

So:

  • Ca²⁺ reuptake into SR becomes faster

  • more Ca²⁺ stored in SR

Physiological Effects

1. Faster Relaxation

Because cytoplasmic Ca²⁺ decreases faster.

This is:

positive lusitropic effect

2. Stronger Next Contraction

Because more Ca²⁺ stored in SR for next beat.

This is:

positive inotropic effect

High-Yield Points

  • Phospholamban inhibits SERCA.

  • Phosphorylation disinhibits SERCA.

  • β₁ stimulation → PKA → phospholamban phosphorylation.

  • Increased SERCA activity → faster relaxation.

  • More SR Ca²⁺ storage → stronger contraction.

Action Potential Generation in Smooth Muscle

General Principle

Stimuli produce:

graded changes in membrane potential (Vm)

These changes may be:

  • depolarization

  • hyperpolarization

Summation

Graded potentials can summate:

  • temporally

  • spatially

If depolarization reaches threshold:

action potential occurs

Types of Stimuli

1. Chemical Stimuli

  • circulating hormones

  • local humoral factors

2. Mechanical Stimuli

  • stretching of smooth muscle cell

Spontaneous Electrical Activity

Some smooth muscle cells generate spontaneous activity.

Two important mechanisms:

1. Pacemaker Cells

Interstitial cells of Cajal

Function:

  • initiate rhythmic contractions

  • especially in GI tract

2. Slow Waves

Slow waves =

spontaneous oscillations in membrane potential

Important:

  • do not always produce APs

  • if threshold reached → spike potentials/APs occur

Mechanism of Slow Waves

  • Voltage-gated Ca²⁺ channels active at resting Vm
    → gradual depolarization and Ca²⁺ influx

Then:

  • Ca²⁺-dependent K⁺ channels open
    → hyperpolarization

This cycle repeats rhythmically.

Effects of Autonomic Input

Depolarization / Excitation

Caused by:

  • stretch

  • acetylcholine

  • parasympathetic stimulation

→ increases AP firing and contraction

Hyperpolarization / Inhibition

Caused by:

  • norepinephrine

  • sympathetic stimulation

→ decreases excitability and contraction.