Physiology of

M. Stefanova,MD, PhD
Lecture outlines:
Skeletal and smooth muscles

Structure
Mechanism of contraction
Control of muscle activity
Mechanics of whole muscle contraction
Classification of fiber types

Characteristics of muscles
Excitability - respond to stimuli (e.g.nervous
impulses)

Contractility - shorten in length

Elasticity - return to original shape & length
after contraction or extension
3 types of muscles:
Skeletal muscle
Cardiac muscle
Smooth muscle

Differences:
Structure
Function
Location
Activation
Contraction

Types of muscle:
Skeletal muscle:
attached to bones
striated
voluntary

Cardiac muscle:
muscle of the heart
striated
involuntary

Smooth muscle:
muscle of the viscera
unstriated
involuntary

Skeletal muscle
Functions :
Stability (Static) : Maintenance of joint position
Mobility (Dynamic) : Initiation and control of movements

Structure of skeletal muscle

The SARCOLEMMA and the TRANSVERSE TUBULES

The primary function of the sarcoplasmic reticulum is to

store calcium ions. Ca 2+ release is a key step in muscle
contraction.

Triad
I band

A band

I band

Myofibrils = contractile organelles of myofiber

Types of proteins:
Actin
Myosin
Tropomyosin
Troponin
Titin
Nebulin
- actinin

Contractile

Regulatory

Accessory, supportive

Sarcomere
the functional contractile unit of the muscle fiber.

I-band

A-band

Sarcomere = the area between 2 Z-lines

The light areas = I-BANDS ; the dark areas = A-BANDS

Light (I) bands isotropic =>contain thin filaments only (actin), I-band
bisected by Z-line.
Dark (A) bands - anisotropic, refract light => contain thick filaments (myosin)
and thin filaments.
H zone - portion of the A band that contains thick filaments only.
Z-line = adjacent sarcomeres come together, the thin myofilaments of
adjacent sarcomeres overlap slightly.

Thick myofilaments - Myosin

Myosin is a dimer - each monomer consists of one heavy chain
and two light chains.

MYOSIN HEAD
ATP- binding sites and ATPase activity
ACTIN - binding sites into which fit molecules of actin.
It is flexible.

Myosin

Myosin heads bind to actin => cross-bridges.

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Thin myofilaments - composed of 3 types of protein:

ACTIN, TROPONIN, and TROPOMYOSIN
Thin filaments are composed primarily of ACTIN a double
stranded helix;
Tropomyosin and troponin are regulatory proteins

Actin
Tropomyosin - long, thin molecules that prevent myosin heads from
binding to actin in relaxed muscle (at low Ca2+)

Troponin - a complex of 3 globular proteins :

Tn-I = binds Actin, Inhibits the actin-myosin
interaction.
Tn-T = binds Tropomyosin.
Tn-C = binds Calcium ions

Regulation of contraction by
Troponin and Tropomyosin

Titin and Nebulin -

keep actin and myosin in place as a network.

Titin: big protein; elastic properties

Nebulin: inelastic big protein

-Actinin s necessary for the attachment of actin filaments

to the Z-lines in skeletal muscle cells,

Skeletal muscle physiology

The neuromuscular junction (NMJ)
Excitation contraction coupling
The sliding filament theory
Energetics of muscle contraction
Mechanics of whole muscle contraction
Control of muscle tension
Types of muscle contractions
Types of muscle fibers

The neuromuscular junction

- the contact zone between the axon of a motor
neuron and a striated muscle fibre;
One junction per muscle fiber.
Axon terminals have vesicles containing
acetylcholine.
N type cholinergic R located on postsynaptic
membrane (motor end plate).

Nicotinic cholinergic receptor

a ligand (ACh)-gated ion channel (Na+, K+,Ca2+) =>
depolarization of the sarcolemma
Continued presence of ACh in the synapse causes
desensitization of receptors.

Action potential triggers muscle contraction

PSP called End plate potential
(EPP) in the motor end plate.

Ratio EPP : AP = 1 : 1
=> precise control of contraction

NMJ differs from the conventional synapses

1) Each AP in a motor neuron produces AP in a muscle
fiber
2) Only excitatory PSP generated.

Blockade of NMJ
A. Botulinum toxin;
B. Organophosphates (AchE inhibitors);
C. Curare.

Excitation-Contraction Coupling

Intracellular structures with special significance for contraction

T-tubules and Sarcoplasmic reticulum

2+

AP releases Ca

from SR ! initiates contraction

Excitation - Contraction coupling

A receptor protein (dihydropiridine receptor,DHP) senses the
membrane depolarization, alters its conformation, and activates the
ryanodine receptor (RyR) that releases Ca2+ from the SR.

Calcium is the "switch" that turns

muscle "on and off.

MECHANISM OF CONTRACTION
Sliding filament mechanism
Control of contraction

AP along T- tubules =>

opens Ca2+ channels in SR

The myosin heads cycle hydrolyzing ATP to form

cross bridges, sliding the thin filaments along the
thick filaments.

[Ca2+]i !

Active sites of
actin exposed

Acin binds Myosin

Myosin walks down an actin fiber towards Z-line.

Each contraction = cross-bridge cycle

Lymn-Taylor mechanism = different
biochemical steps involved in m.contraction
4 steps:
1)
Attachment of cross bridge to a thin filament
2)
Movement of cross bridge
3)
Detachment of cross bridge
4)
Energizing of the cross bridge

ATP performs 2 roles:

1) ATP hydrolysis provides energy required for muscle
contraction
2) The binding of ATP to myosin disconnects actin and
myosin.
* Another role of ATP in muscle contraction - providing energy for
the removal (active transport) of Ca2+ back into the lateral sacs
of SR thus ending contraction and initiating muscle relaxation.

Three sources of ATP production during

muscle contraction

1) creatine phosphate; 2) oxidative phosphorylation; 3) glycolysis

Mechanics of whole muscle

contraction
Single contraction = muscle twitch
Twitch - the response of a skeletal m. to a single stimulation (or
AP); lasts 7.5 - 100 ms
Components:
Latent phase - time during which impulse is travelling along
sarcolemma & down T-tubules to SR, Ca2+ is being released,
etc.; (period btwn application of the stimulus and beginning of
contraction).
Contraction phase - tension increases (cross-bridges are
cycling).
Relaxation phase - muscle relaxes (tension decreases) &
returns to its original length.

Relationship between action potential

and contractile response

Control of muscle tension

Force of contraction depends on:

1) The amount of tension developed by each fiber (muscle twitch

summation);
2) The number of fibers contracting at any time (recruitment of
motor units).

Mechanisms for grading force of contraction

A skeletal muscle has the ability to contract to varying

degrees.

The force of contraction is graded by:

Twitch summation (by frequency of APs);

Motor unit summation (recruiting >> muscle fibers).

1/ Twitch summation
Increasing frequency of stimulation increases the
strength of contraction.

Incomplete tetanus
(unfused)

Complete tetanus
(fused)

The motor unit

Dfn: A motor neuron and all of the muscle fibers
it stimulates.

The number of muscle fibers in a

motor unit varies (10 -1500 ).

When an electrical impulse travels down the axon, all muscle cells
in the motor unit contract simultaneously.

Contractile strength of a muscle is proportional to the

number of motor units recruited.

Motor unit

The size of the neuron is directly

related to the number of muscle fibers
in a motor unit.
The excitability of a neuron is Inversely
related to its size.

Factors responsible for grading of muscular activity

Motor unit summation

The degree of contraction of a SkM is influenced by the number
of MU being stimulated.
MU are recruited according to nerve and muscle characteristics
based on speed, size and fatiguability.
.

 Recruitment of MU helps provide smooth m. action

rather than jerky movements
Asynchronous recruitment of m. units prevents
fatigue; (some MU are active others are inactive).

Types of muscle contraction

Load = the force exerted on the muscle by the weight of an
object
Tension = the force exerted on an object by a contracting
muscle

Isotonic contraction: Tension remains constant as muscle

changes Length
Concentric: Muscle shortens
Eccentric: Muscle lengthens

Isometric contraction: Length remains constant (muscle

does not shorten) - changes Tension

Length- Tension relationship

- states that tension generation is a function of fiber length
(depends upon the overlap between thick and thin filaments).
Maximal tension is produced at the muscle's optimum length.

Skeletal muscles produce

maximum force when they
contract from the
resting length (maximum
overlap).
Length-tension curve

Force - Velocity relationship

The velocity of shortening decreases as the load increases.

Characteristics of skeletal muscle fibres

Red (I)

Red (IIA)

White (IIB)

Slow oxidative
Slow-twitch red

Fast oxidative glycolytic

Fast-twitch red

Fast glycolytic
Fast-twitch white

Myoglobin
Oxidative enzymes
Mitochondria
Mitochondrial ATPase

High Red
High
High
Intermediate

High
Intermediate
High
High

Low White
Low
Low
Low

Glycolytic activity

Low

Low

High

Glycogen

Low

High

High

Fibre diameter

Small

Intermediate

Large

Contractions

Postural

Endurance

Powerful

Tension produced

Small

Intermediate

Large

Recruitment

First

Second

Last

Classification

Size recruitment principle:

- Small slow MU active during low force contraction = smooth control
- Large fast MU active during high force contractions = poor control

1. The slow motor units (MU) contain red fibres. Light work: small, excitable motor
neurons activate fibres suited for prolonged (or endurance) activities.
2. Fast-twitch, fatigue-resistant MU => IIA fibres (oxidative&glycolytic metabolism).
=> contractions of intermediate force & duration.
3. Fast-twitch fatiguable MU produce fast contractions. Large white fibres are
adapted to activities requiring large forces.

Oxidative

Muscle fiber
classification

Oxidative or
glycolytic

Muscle tone (resting muscle tonus)

=> Muscles are always at least partially contracted. Even
seemingly relaxed muscles possess a small degree of tension
(muscle tone).
Resistance of a muscle to stretch is called TONE.
Stretch reflexes maintain muscle tone
Muscle spindles detect slight changes in muscle tone and send
signals to the spinal cord to allow tone to be maintained.

muscle tone hypertonia

(UMN lesion)
muscle tone - hypotonia
(LMN lesion)

Muscle Fatigue
- a decline in muscle tension
Mechanism - poorly understood; multiple factors
ATP insufficiency => ATP production fails to keep pace with ATP
utilization; ATP depletion very rare: usually seen with maximum
efforts (cramps).
Fatigue from high-intensity, short duration exercise occurs
primarily because of a failure of the muscle AP to be conducted
along the T tubules => a failure to release Ca2+ from SR.
With low-intensity, long-duration exercise one of the major
factors for fatigue is the build up of lactic acid (low pH).

Smooth muscle
in the walls of hollow organs & tubes e.g. gut, blood
vessels, bladder, uterus, bronchi, etc.;
No cross-striations (smooth);
Sheets of spindle-shaped cells, connected by gap
junctions (electrical coupling);
Contain actin, myosin and intermediate filaments.
Involuntary muscle; innervated by the Autonomic NS;
Contraction is slow, fibers capable of sustaining partial
contraction indefinitely (= tonus).

 Smooth muscle cells - small, spindle shaped, mononucleate

5-10 m wide; 50-200 m long
Great variety of orientation of the fibers.

Characteristics of smooth muscle: Structure

No T system. Membrane invaginations (caveolae).

Poorly developed SR => dependent on extracellular Ca2+ as a
source for contraction;
Ratio of thick/thin filaments 1:15 (smooth m);1: 2 (skeletal m)
No Z lines, no sarcomeres, no striations;
Dense bodies;
No troponin. Regulatory proteins: caldesmon & calmodulin.
Calcium ions bind to calmodulin. Ca2+-calmodulin complex
activates myosin light chain kinase
Innervation: Autonomic nervous system
No NMJ; release of mediator into space around muscle cells.

Characteristics of smooth muscle

* Three types of filaments
* Dense bodies (equivalent to
Z-lines)
* Gap junctions - electrical
communications between
adjacent cells.

Innervation of
smooth muscles

Neurotransmitter released from varicosities (swellings) along the length of axons

Stimuli influencing
smooth muscle contractile activity
1. Spontaneous electrical activity in the sarcolemma;
2. Neurotransmitters released by autonomic nerves;
3. Hormones;
4. Locally induced changes in the chemical composition
(paracrine agents, acidity, oxygen, osmolarity, ion
concentrations) of the extracellular fluid surrounding
the fiber;
5. Stretch.

2 types of smooth muscle

Single unit (visceral) & Multi unit subtypes

1// Unitary (single unit, visceral) smooth M

(visceral organs: intestinal tract, uterus, bladder, small-diameter
blood vessels).
Gap junctions => a functional unit.
Spontaneous activity (pacemaker cells).Slow wave potentials spontaneous, rhythmical, graded oscillation in MP.
Activity can be altered by nerves, hormones, local factors,
stretch.
Sparse innervation; nerves modulate the rate and strength of
contraction.

Single unit smooth muscles

Single unit smooth muscle has rhythmic pacemaker cells

Single unit smooth muscles

Slow wave potentials spontaneous, rhythmical

oscillations in MP.
- The graded depolarization
sometimes causes AP
= > associated contraction.

Mechanical properties of unitary smooth muscle

1/ Spontaneous contraction.
2/ Plasticity = also called stress relaxation.
3/ Stretch induced contraction.
4/ Tone - constant and stable low level of contraction.

may be modified by nerves; hormones, drugs.

5/ Marked shortening during contraction (up to 2/3 its

stretched length (for skeletal:1/3) allows sm.m to perform

functions in hollow viscera (lumen dm changes from large to 0).

2// Multi unit smooth muscles

Each cell acts relatively independently of other cells in the organ.
In this sense multi unit smooth muscle is like skeletal muscle.
Ex: ciliary m, iris m, bronchial and tracheal m, vas deferens,
GI sphincters, large blood vessels.
1) No // fewer gap junctions
2) Richly innervated by autonomic nerves.
3) Hormones can affect contractile activity
4) Stable MP => no spontaneous depolarization.
Note: No strict division of the two types of smooth muscles =>
many smooth muscles having characteristics that overlap the two
groups.

Compare the two types of smooth muscle

The electrical properties of smooth muscle -

Membrane potential (mV)

much less uniform than those of striated muscle

Action potential

Ca2+ influx
K+ efflux

-45
Threshold of VOCs

-60

20 msec

MP low (- 50 to - 60 mV)
AP => Na+ / Ca2+ influx
AP 10- 50 ms long (vs 2-5 ms in skeletal m) => can produce Ca2+ plateau.

NB! Ca2+ triggers contraction

Excitation - Contraction coupling

(mechanisms linking the stimulation to contractile activity)

A. Electro - mechanical coupling - change in the MP

(depolarization) causes contraction.

B. Pharmaco - mechanical coupling - contraction

produced with no changes in MP.
* Both mechanisms play a role in contraction.

A. Electro- mechanical coupling

AP =>L type Ca2+ channels (DHPRs) open=>mediate Ca2+entry
=> Ca2+ release:
Stretch:

Calcium-activated
potassium channel (KCa)

Ca2+

Depolarization
Voltage-operated
calcium channel
(L-type)

1-2 mM Ca2+

EXTRACELLULAR

100 nM Ca2+

INTRACELLULAR
K+ Repolarization prevents
overstimulation

Increased Ca2+

SR
Activates enzymes

E-C coupling
Electro - mechanical

Ca
IP3R

In skeletal M, Ca2+ release from SR is activated in the absence of

Ca2+ influx, by a physical interaction of the two Ca2+ channels.
In smooth M L-type Ca2+ channels (DHPRs) mediate Ca2+entry,
=> Ca2+ release via ryanodine receptors (RyRs = Ca2+channels)

Control of smooth muscle contraction

Calcium binds calmodulin (regulatory protein)
=> Ca2+/CaM activates MLCK =>
Phosphorylation of myosin
light chains by Myosin Light
Chain Kinase (MLCK)
activates myosin, causing
it to bind to actin.

The Latch state

- allows SmM to maintain tone with minimal expenditure of ATP =>
Shortening is not occurring; economy is high.
If MLC are dephosphorylated myosin ATPase activity is low => it is more difficult to
release myosin heads from actin which requires ATP hydrolysis.

Pathways leading from increased cytosolic Ca2+ to cross-bridge

cycling in smooth - and skeletal muscle fibers.

B. Pharmaco - mechanical coupling

Activation of receptor by neurotransmitters, hormones,
drugs can lead to contraction or relaxation.
The receptors can directly affect the contractile
machinery through G-proteins and 2nd messengers
without a change in membrane potential.
Phospholipase C (PLC) dependent contraction
cAMP - dependent relaxation (-adrenergic agonists)
cGMP - dependent relaxation (NO, ANP)

Pharmaco-mechanical coupling
Agonists: AT II, 1-adrenergic agonists, endothelins
=> Phospholipase C dependent contraction

Ca2+

Ligand

PLC
G-protein
releases
intracellular
Ca++ stores.

IP3

PIP2
Ca2+

SR

1)

Pharmaco - mechanical
coupling

Electro-mechanical
coupling

2)

Principal mechanisms determining myoplasmic [Ca2+] in smooth muscle..

Special features of SM contraction

Smooth muscle tone

Slow, prolonged contractile activity
Low energy requirements
Response to stretch:
stress relaxation => muscle responds to stretch only
briefly, and then adapts to its new length
Stimulus can be excitatory or inhibitory

Length-tension relationship for smooth muscle

Sm. M. respond to stretch with tension then slow
relaxation to the initial tension value => stress relaxation.
=> Response unique to smooth muscle: controls level of tone,
adjusting volume of organ to the volume it contains.
smooth m shortens more than skeletal
or cardiac muscle.
change in length > 2/3rd of initial length
=> crucial for function
Length-tension relationship of
smooth m. can vary.