2017.10.03.

1

Physiology of muscle contraction

Learning objectives 21-24

Muscle tissue accounts for almost half of the human body mass.

Topics:

Skeletal muscle (ca. 400 muscles)

Structure

Muscle contraction

Excitation-contraction coupling

Energetic of muscle contraction

Mechanics of muscle contraction

Smooth muscle - compared to skeletal muscle

2017.10.03.

2

Types:Smooth muscle

Cardiac muscle

Skeletal muscle-cross-striation-nervous stimulation induces contraction-voluntary control-lack of anatomical connections of individual muscle fibres

Muscle contracts and relaxes Body moves and transports

-respiration

-heart/circulation

-gastrointestinal tract

Sarcomere (2 µm)

diameter: 10-100 µm

Z line Z line

2017.10.03.

3

L tubule

„TRIAD”

T (transversal) tubule

12

3

Sarcoplasmic reticulum

with its terminal cisterns

mitochondriaMuscle fiber

L (longitudinal) tubule

2

3

1

Thick filament: MYOSIN

Thin filament: ACTIN

TROPOMYOSIN

TROPONIN

α-Aktinin

Titin

contractile proteins

regulatory proteins

relaxed contracted

structure proteins

2017.10.03.

4

Diagram of muscle cell membrane (sarcolemma),

dystrophin, and the dystrophin-associated protein

complex. Dystrophin is located inside the cell and

binds actin at its N-terminus and the syntrophins,

sarcoglycans, and dystrobrevin at the C-terminus.

Mutations in dystrophin are responsible for Duchenne

muscular dystrophy.

G-Actin

F-Actin

Tropomyosin Troponin

Thick filament Thin filament thin filament

thick filament

Structure of the filamentsMyosin (2 heavy and 4 light chains):

Binding site for actin

Binding site for ATP (ATP-ase activity)

Flexible neck region

Actin monomers

have binding sites for:

Other actin monomers

Myosin

Tropomyosin

TroponinMyosin

2017.10.03.

5

Components of the thin filament

Troponin subunits

TnI TnC TnT

TnI: holds the tropomyosin over the active sites on actin

TnC: binds Ca2+

TnT: binds to tropomyosin

2017.10.03.

6

length of the sarcomere (µm)

length of the A-band (µm)

Sliding filament mechanism

Huxley A.F., Niedergerke R.: Structural changes in muscle during contraction. Interference microscopy of living muscle fibres. Nature, 173, 971-973. (22 May 1954)

Huxley H.E., Hanson J.:Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation. Nature, 173, 973-976. (22 May 1954)

Dying Lioness, ca. 650 B.C.

Palace of Ashurbanipal at Ninevah

Motor unit

2017.10.03.

7

Electromyography

Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal muscles when they are activated.

resting

slight

contraction

moderate

contraction

maximal

contraction

myelin sheath

axon of the motoneuron

Schwann cell

motor end-plate

junctional folds

muscle

active zone

terminal

buttons

muscle

Neuromuscular junction

2017.10.03.

8

end-plate potential

nicotinic ACh receptors

Neuromuscular blockade

Inhibition of ACh releaseBotulinum toxin

Drugs inhibiting the binding of ACh to its receptorCurare, tubocurarine (non-depolarizing)Succinylcholine (depolarizing)

Autoantibodies directed against ACh receptorsMyastenia gravis

Drugs inhibiting acetylcholinesterasereversible inhibitor: Neostigmineirreversible inhibitor: Organophosphates (insecticides), Nerve gases

Acetat

2017.10.03.

9

Excitation-contraction coupling

T-tubule

sarcoplasm

Ryanodine

Receptor

(RyR)

Dihydropiridine

Receptor (DHPR)

Depolarisation

induces opening

of Ca2+ channels

ActinMyosin

sarcolemma

action

potential

sarcoplasmic

reticulum

terminal

cistern

T-tubule terminal

cistern

sarcoplasm

action

potential

Ca2+<10-7 MCa2+≈10-3 M

Calsequestrin: 44-67 kDa protein

1 molecule binds 40-45 Ca2+

actinmyosin

troponintropomyosin

2017.10.03.

10

Molecular basis of contraction

Formation of cross-bridges

Z-line

ATP is hydrolyzedlow-affinity binding

high-affinity bindingpower strokepower stroke

dissociation

Ca2+

Mg2+-dependent ATPase

Excitation-contraction coupling

T-tubule

sarcoplasm

Ryanodine

Receptor

(RyR)

Dihydropiridine

Receptor (DHPR)

Depolarisation

induces opening

of Ca2+ channels

ActinMyosin

sarcolemma

action

potential

sarcoplasmic

reticulum

terminal

cistern

T-tubule terminal

cistern

sarcoplasm

action

potential

Ca2+<10-7 MCa2+≈10-3 M

SERCA: Sarcoplasma-endoplasma reticulum ATP-ase

2017.10.03.

11

Molecular basis of contraction

Formation of cross-bridges

Z-line

ATP is hydrolyzedlow-affinity binding

high-affinity bindingpower strokepower stroke

dissociation

Ca2+

Mg2+-dependent ATPase

2017.10.03.

12

ATP

Ca2+

Mg2+

5 cycles /sec

Source of energy for skeletal muscle contraction

ATP

Creatine phosphateCreatine phosphate + ADP ↔ Creatine + ATP

Carbohydrate and Lipid breakdownFree fatty acids, Glucose, Glycogen

- anaerobic (production of lactic acid) - aerobic (myoglobin)

Myoglobin is a monomeric heme protein found in muscle tissue where it serves as an intracellular storage site for oxygen. During periods of oxygen deprivation oxymyoglobin releases its bound oxygen which is then used for metabolic purposes.

2017.10.03.

13

Source of energy

ATP

Creatine phosphate

Anaerobic glycolysis

Aerobic glycolysis

Time (s)

Creatine phosphate

Slow-oxidative Fast-oxidative Fast-glycolytic

mitochondria many many few

capillaries many many few

myoglobin content high high low

myosin ATPase activity

low high high

contraction velocity slow fast fast

rate of fatigue slow intermediate fast

muscle fiber diameter small intermediate large

innervating neuron size

small intermediate large

motor unit size small intermediate large

short distancerunner

marathonrunner

Types of muscle fibres

Type I. Type II.

II.a II.b

Slow-oxidative Fast-oxidative/glycolitic

Fast-glycolitic

2017.10.03.

14

Michael Phelps - the most decorated olympian ever

Genetic variants associated with over 200 genes are documented to effect athletic performance. They affect a variety of functions including blood flow to muscles, muscle structure, oxygen transport, lactate turnover, and energy production.

Types of muscle fibres

Muscle fatigue

Depletion of ATP

Acidic pH in the muscle (lactic acid)

Depletion of ACh

+ psychological fatigue

Heat production in muscle: efficacy of the muscle contraction is max. 40-50%

Thermogenesis: shivering

voluntary contraction

2017.10.03.

15

Rigor mortis

Contracture – contraction without AP

Muscle soreness

Lack of ATP!

Androgen hormones, growth hormone – anabolic effect (doping)

Muscle fiber action potential

Muscle fiber shortening

Latent period Time (ms)

(mV)

Electrical and mechanical responses of skeletal muscle

2017.10.03.

16

before stimulus

sarcomere

5 ms after stimulus 20 ms after stimulus

Action potential

Contraction

Temporal relationships between AP, Ca2+ signal and muscle contraction

Twitch

Unfused (incomplete) tetanus

Fused (complete) tetanus

Time (ms)

Summation of contractions

2017.10.03.

17

Factors increasing the force of muscle contraction:

1) Motor unit: frequency of AP

2) Recruitment of motor units

The size principle: when a muscle contracts against a load, the

smallest motor units (which have only a few muscle fibres in them)

are recruited first. If the force generated is insufficient, then the

larger motor units are recruited.

Distance

shortened

Muscle

tension

Muscle

TimeTime

Muscle

Force sensor

Types of muscle contraction

ISOTONIC CONTRACTION

(„same tension”)

ISOMETRIC CONTRACTION

(„same length”)

AUXOTONIC CONTRACTION

(both length and tension change)

Preload Afterload

2017.10.03.

18

Length – tension relationship

ten

sio

n

passive

tension

Isotonic

maxima

Isometric

maxima

ten

sio

n

Length

Isotonic contraction Isometric contraction

Passive tension: produced by titin

Active tension: force generated by the deformation of myosin heads

Length

Sarcomere (µm)

% o

f m

ax. fo

rce

Length – active tension relationship in skeletal muscle fibres

Sarcomere (µm)

2017.10.03.

19

Relationship between force (load) and shortening velocity

Isotonic contraction

ve

loc

ity

elo

ng

ati

on

sh

ort

en

ing

force/load

Isometric contraction

relaxed

contracted

Actinfilament

Myosinfilament

Minisarcomere

Smooth muscle

α-aktinin

2017.10.03.

20

Contracts to 30% of its initial length

(skeletal muscle contracts to 60% of its initial length)

Actin

+ Tropomiozin, Caldesmon, Calponin

NO Troponin

Calmodulin is a Ca2+-bindig

cytoplasmic protein

(one light chain has

regulatory function)

Mechanism of smooth muscle contraction

MLCK: Myosin light chain kinase

Cross-bridge

formation

Cross-bridge formation

is inhibited

MLCP: Myosin light chain phosphatase

low-affinity binding

high-affinity binding

It does not contain troponin!

2017.10.03.

21

Action potential

Voltage-gated Ca2+-channel

Ligand-gated

Ca2+-channel

catecholamines

α1-receptor

Activation Relaxation

Electromechanical

coupling

Pharmacomechanical

coupling

smooth

muscle

antiport

catecholamines

β2-receptor

sarcoplasmic

reticulum

„Ca2+ signal”

Ca2+-induced Ca2+ release

+ Mechanomechanical coupling

stretch-sensitive Ca2+ channels on the

sarcolemma RyR: Ryanodine Receptor

Regulation of „Ca2+-sensitivity”

Ca2+-desensitization

Phosphorylation of Myosin light chain

tension

Ca2+-sensitization

Phosphorylation of Myosin light chain

tension

Myosin light chain kinase

Myosin light chain phosphatase

Ca2+-desensitization

Ca2+-

sensitization

Force o

f con

tra

cti

on

(%

)

Ca2+-concentration (mol/l)

Nitric oxideNO

MLCK

MLCP

2017.10.03.

22

MULTI-UNIT

SMOOTH MUSCLE

ciliary muscle

piloerector muscle

SINGLE-UNIT

(VISCERAL)

SMOOTH MUSCLE

blood vessels, airways, gut, uterus

Types of smooth muscles

gap junctions – functional syntitium

Smooth muscle has low energy-requirement for contraction.

Latch mechanism

Sustained contraction with little energy expenditure!

2017.10.03.

23

gap junctions – functional syntitium„pacemaker cells”

Myogenic tone- stretch may increase the activity- transmitters of the autonomic nervous system modulate the activity

SINGLE-UNIT (VISCERAL) SMOOTH MUSCLE

membrane potential

contraction

MULTI-UNIT SMOOTH MUSCLE

Spontaneously not active smooth muscle.

Autonomic nervous system innervates the muscle (BOTH stimulatory and inhibitory transmitters).

Mechanical stretch induces muscle relaxation (storage in the urinary bladder, gallbladder).

"stress relaxation"