Dr Andrew Paterson

Production of body movements whole body movements and localized movements What are Muscles For?

Stabilizing body positions hold joints in place allowing maintenance of posture

Storing and Moving Substances within the body Cardiac muscle, smooth muscle sphincters, smooth muscle in blood vessels and gut, skeletal muscle (blood and lymph)

Thermogenesis production of heat normal operation, shivering

Contractility ability of muscle to contract forcefully

Electrical excitability can produce electrical signals which allow regulation of contraction via excitation contraction coupling Control! How does muscle

achieve this?

Extensibility can stretch without being damaged allows contraction even after stretching e.g. cardiac muscle after filling of heart, digestive tract after meal

Elasticity returns to original length after contraction or extension

Not all muscles are the same 3 types of muscle tissue in humans

Orientation of cells direction of contraction Three types of muscles have different microscopic anatomy

But similarities in contractile mechanisms

Three Types of Muscle Tissue

Skeletal muscle tissue often moves bones of skeleton. Striated. Mainly voluntary can consciously control activity via somatic nervous system. Some unconscious control e.g. control of diaphragm during breathing.

Cardiac Muscle Tissue forms myocardium of heart. Striated, involuntary control

Smooth Muscle Tissue: walls of hollow internal structures blood vessels, airways, digestive tract. Appears nonstriated/smooth. Involuntary control and sometimes autorhythmicity.

Images courtesy Wellcome Photo Library and Wellcome Images

Skeletal Muscles:
Each muscle a separate organ composed of hundreds to thousands of cells called muscle fibres (elongated shape). Muscle cell = muscle fibre.

Image courtesy Miles Kelly Art Gallery and Wellcome Images

Skeletal Muscle Fibres are Controlled by Neurons Communication via Neuromuscular Junctions

But one Neuron may Control many Muscle Fibres!

Each muscle fibre has a single neuromuscular junction

Neuromuscular Junction

Each somatic motor neuron may branch to innervate multiple muscle fibres (average 150 fibres)

As action potential in nerve all or nothing, muscle cells within a motor unit muscle contract in unison fine movements vs large scale powerful movements

Image courtesy of John Wildgoose and Wellcome Images

Some Muscle Fibre Anatomy

Muscle fibres diameter 10-100m, Length 10cm typically, up to 30cm. Why so long? Fusion of hundreds of myoblasts during development fibres multinucleate. Non-mitotic at this stage. Nuclei located below sarcolemma (plasma membrane of muscle fibre). Transverse tubules travel into muscle fibre from sarcolemma filled with interstitial fluid allows depolarisation to spread throughout fibre Sarcoplasm (interior of muscle fibre) contains lots of glycogen and myoglobin (binds oxygen molecules)

Image Courtesy Miles Kelly Art Gallery and Wellcome Images

Sarcoplasm filled with myofibrils contractile component of skeletal muscle. 2m diameter. Prominent striations.

Longitudinal section through striated muscle

Each myofibril composed of filaments. Thick filaments and thin filaments. Thin filaments (actin) 8nm in diameter, 1-2m long. Thick filaments (myosin) 16nm in diameter, 1-2m long. Involved in contractile process. Filaments do NOT run length of muscle fibres form sarcomeres striped appearance

Image courtesy of MI Walker and Wellcome Images

Three types of muscle protein:

Generate the force during contraction. Actin and myosin (motor protein). Contractile Proteins Switch contraction on and off Regulatory Proteins

Structural Proteins Hold contractile components in proper alignment. Allow elasticity and extensibility.

Contractile Mechanism
Sarcomere

Actin

Myosin

The Sarcomere:
Sarcomere runs from Z Z line
M-line = centre of myosin H zone = myosin alone

A band = myosin alone + actin and myosin overlap

I band = actin alone So what happens to each zone when muscle contracts?
M-line stationary Z-lines move together I band and H zone shorten A bands stay same i.e. more overlap of fibres but myosin length constant Note filament lengths do NOT change

Image courtesy Wikimedia Commons

Image courtesy of University of Edinburgh and Wellcome Images

How do the filaments move?

Myosin filaments possess multiple heads which are used to walk along the actin filaments

So Actin filaments and Myosin Filaments have to be arranged next to each other and they are!

Each thick filament is surrounded by thin filaments and vice versa!

A More Complicated Diagram! Most of it should make sense now!

Image courtesy Wikimedia Commons

How does actin move along myosin?

Cross bridges between filaments form then opening of ADP binding site causes a change in shape of cross bridge twisting motion - which moves actin along myosin
Known as the

Power Stroke

Contraction Cycle Sequence of Events:

ATP Hydrolysis: ATP used to re-energize (reset) myosin head Myosin head attaches to actin (Cross-bridge formation) occurs only at myosin binding sites on actin Power Stroke: ATP binding site opens, ADP released and cross-bridge rotates Thin filament slides along thick filament

Cross bridges keep rotating back and forth contracting the muscle. Each thick filament has 600 cross-bridges cycling 5 times per second smooth contraction. How does this explain rigor mortis?

Myosin detaches from Actin. Another ATP binds

But preceding mechanism would allow contraction whenever ATP available! Excitation Contraction Coupling permits regulation of contraction

Nervous Input: Striated muscle with axons and motor endplates

At rest, calcium concentration in cell cytosol is LOW 0.1mole per litre. But can release calcium from intracellular calcium stores sarcoplasmic reticulum to initiate contraction

Image courtesy of MI Walker and Wellcome Images

http://www.youtube.com/watch?v=CepeYFvqmk4

Exciting the skeletal muscle cell the neuromuscular junction:

Challenge: Using your knowledge of Synaptic Transmission, Summarise the events that lead to muscle depolarisation following excitation of the motor neuron

Activation of NMJ results in muscle action potential

Propagates along sarcolemma and into T-tubules i.e. through muscle fibres. Depolarisation causes opening of calcium release channels, calcium released into cytosol (where the contractile filaments are), so increases cytosolic calcium concentration Regulatory proteins found in association with contractile fibres (actin) troponin and tropomyosin Calcium binds to troponin changing conformation of troponin-tropmyosin complex clears myosin binding sites on actin.

Image Courtesy of Wikimedia Commons

Permits cross-bridge cycling

Excitation-Contraction Coupling!

A Better Picture of the Regulatory Proteins:

Regulation of Skeletal Muscle Contraction in summary:

Muscle relaxes when cytosolic calcium concentration low tropomyosin blocks cross-bridge sites on actin Muscle contracts when cytosolic calcium concentration high tropomyosin cleared away from cross bridge sites calcium conc increases following action potential

Calcium concentrations returned to resting level by calcium reuptake into sarcoplasmic reticulum contraction ceases

What happens when you stimulate a muscle fibre?

A Twitch!

Twitch vs Tetanus
Tetanic Contraction: Once Twitch Contraction: Brief refractory period is over, contraction of a motor unit. contractions can summate if Stimulate nerve and muscle depolarises. Calcium released inadequate time for relaxation. from stores, muscle contracts. If get partial relaxation between Delay before contraction. stimuli (stim 20-30Hz) unfused Contraction longer than muscle tetanus action potential need to clear calcium. Refractory period If no relaxation between stimuli (stim 80-100Hz) get fused cannot immediately contract tetanus individual twitches again! undetectable

So What Do These Look Like?

As Frequency of Stimulation Increases, Strength of Contraction Increases up to a Maximum Level

Types of Muscle Contraction: Isotonic and Isometric Contractions

 Isometric Muscle exerts force without changing length Pulling against immovable object Postural muscles
Isotonic (dynamic) Concentric

Muscle shortens during force production

Eccentric

Muscle produces force but length increases

Initial Length of The Muscle Fibre Affects Strength: Length Tension Relationship!
So the strength with which a muscle contracts varies with how long it is! What is the optimal length?

But Need to Control Muscles: Muscles Contain Receptors!

Muscle spindle
Detect dynamic and static

changes in muscle length Stretch reflex

Stretch on muscle causes reflex contraction

Golgi tendon organ

(GTO)

Monitor tension developed

in muscle Prevents damage during excessive force generation

Stimulation results in reflex relaxation of muscle

Cardiac Muscle (well come back to this in CV system lectures):

Similar arrangement of contractile proteins to skeletal muscle Skeletal muscles arranged into motor units, cardiac muscle acts as a single unit cells connected by gap junction to allow depolarisation spread (next slide) Cells branch spread depolarisation, consider directions in which heart has to contract! Heart has autorhythmicity constant process of contraction and relaxation. Requires LOTs of energy larger and more numerous mitochondria heart muscle is primarily aerobic
Image Courtesy Gordon Museum and Wellcome Images

Cell can communicate with each other electrically as well as chemically:

These types of synapse allow electrical signals to directly spread from one cell to another through pores known as gap junctions

A: Neuron (Transmitter) B: Neuron (Receptor) 1. Mitochondrion 2. Gap junction (made from connexins) 3. Electrical signal

Courtesy Utilizateur:Dake and Wikimedia

Smooth Muscle:
Non-striated, involuntary muscle

Cells 30-200m long, 3-8m in diameter, taper at ends

Contractile fibres travel through sarcoplasm, but not orderly like skeletal muscle so not striped
Image courtesy medical Art Service Munich and Wellcome Images

Similar physiological contraction muscle to skeletal BUT:

Contraction slower and longer

Greater contraction/extension distances

Calcium does initiate contraction, but via binding calmodulin and activating myosin light chain kinase. Phosphorylates myosin head making it active.
Responds to autonomic innervation and to local factors pH, oxygen, carbon dioxide, hormones.

The distribution of myofilaments determines the changes in cell shape associated with contraction and relaxation, and result in no stripes!

Smooth muscle function requires both mechanical linkage and cell-to-cell communication in order to achieve synchrony in activation - Gap Junctions!

Sometimes smooth muscle found orientated longitudinally and transversely Why would this be?

Image courtesy of Prof Giorgio Gabella and Wellcome Images

Skeletal Muscle, Cardiac Muscle and Smooth Muscle all contract in response to the presence of intracellular calcium ions BUT they use different mechanisms to achieve this! Smooth Muscle can also relax in response to the chemicals cAMP and cGMP (intracellular messengers) Control contraction + relaxation!

Two Main Control Mechanisms in Smooth Muscle:

Electromechanical (membrane potential change)

Pharmacomechanical (receptor binding)

Smooth Muscle Contractile Mechanism:

Calcium enters the smooth muscle cell

Calcium binds calmodulin

Activation of MLCK (myosin light chain kinase)

Phosphorylation of myosin leading to contraction If calcium drops, loose phosphorylation, muscle relaxes Cyclic nucleotides can reduce calcium levels in the cell (interplay with cell signalling pathways)

Smooth muscle can maintain force with reduced energy expenditure! Smooth muscle has the ability to maintain force development even when a high [Ca2+] and hence cross-bridge turnover is not maintained. Maintained force development, but with reduced velocity of movement, confers a clear physiological advantage to smooth muscle and is absent from striated muscle. [Ca2+] force velocity & crossbridge phosphorylation

stimulation