Block 2 - Muscles Flashcards
Outline the functions of the skeletal system components.
Bone
- hard connective tissue
- support and protection of the body organs
- calcium metabolism
- red blood cell formation
- attachment for skeletal muscles.
Cartilage
- less rigid than bone
- located where mobility is required at articulations (joints)
Movement of the skeleton occurs at joints.
Skeletal muscles contract to move at bones, therefore without joints we wouldn’t be able to move.
Describe the 2 divisions of the skeletal system
1) axial skeleton = head, neck and trunk of the body
2) appendicular skeleton = limbs and girdles
Outline flat and long bones.
Flat bones
- protective
- example: the sternum
Long bones
- tubular
- provide leverage
- example: femur
Outline sesamoid and irregular bones.
Sesamoid bones
- develop in tendons
- protect tendon
- example: patella
Irregular bones
- complex shape
- protection
- example: vertebrae
Outline short bones.
Short bones
- cuboidal
- stability, support, some movement
- example: tarsals in the foot
Describe the different structural components of bones.
Periosteum and endosteum
-» fibrous connective tissue coverings of bone
Perichondrium
-» fibrous connective tissue covering articular cartilage
Cortical bone
-» rigid outer shell
Trabecular bone
-» interconnected struts, also known as trabeculae (found in the cranium)
Medullary cavity
-» hollow part of bone containing bone marrow
Describe joints.
An articulation of bones for stability and/or movement.
Classified into three types by type and manner of how the joint is united.
Outline the 3 types of joint.
1) cartilaginous joints
2) fibrous joints
3) synovial joints
Describe fibrous joints.
Bones united by fibrous tissue.
Used for stability:
- sutures in the cranium
- syndesmosis which are found between the radius and ulna and also the tibia and fibula
- gomphosis which hold teeth to the mandible
Describe cartilaginous joints.
Primary (synchondroses)
- temporary or permanent unions
- covered by hyaline cartilage
- examples
1) epiphyseal growth plate (temporary joint)
2) 1st sternocostal joint (permanent joint)
Secondary (symphyses)
- permanent unions by fibrocartilage
- example
pubic symphysis (the union of the pubic bones in the pelvis)
Describe synovial joints.
Joint capsule spans and encloses the joint.
Lined by synovial membrane and articular cartilage.
Filled with lubricating synovial fluid for mobility.
There are several different types of synovial joint.
Outline pivot and hinge joints.
Pivot joints
- rotation around an axis
- example: atlanto-axial joint (joins C1 and C2 vertebrae)
Hinge joints
- permit flexion and extension
- example: ulnohumeral (elbow joint)
Outline saddle and ball and socket joints.
Saddle joint
- permit flexion, extension, abduction and adduction
- example: carpometacarpal joint of the 1st digit (thumb joint)
Ball and socket joint
- movement in multiple axes and planes
- examples: hip joint
Outline condyloid and plane joints.
Condyloid joint
- permit flexion, extension, abduction and adduction
- example: wrist joint
Plane joint
- sliding movements
- example: joints in the foot
Describe ligaments.
Connect bone to bone.
Fibrous bands of dense regular connective tissue.
Stabilise articulating bones and reinforce joints.
In the musculoskeletal system they are classified into:
- capsular ligaments
- intracapsular ligaments
- extracapsular ligaments
Describe the functions of the muscular system.
Consists of muscles and tendons.
- movement of the body
- maintains posture
- circulates substances throughout the body
- controlled through the nervous system although some muscles (such as the cardiac muscle) can be completely autonomous
Describe the 3 types of muscle.
There are three types of muscle based on distinct characteristics.
1) smooth muscle (involuntary)
2) cardiac muscle (involuntary)
3) skeletal muscle (voluntary)
Describe skeletal muscle in detail.
Most skeletal muscles are attached directly or indirectly to bones, cartilage. ligaments or fascia, or even to a combination of structure.
Some attach to:
- organs (such as the eyeballs)
- skin (such as the facial muscles)
- mucous membranes (such as the tongue muscles)
Muscles are organs of locomotion, provide support, form and heat.
They have individual cylindrical cells with multiple elongated nuclei located peripherally.
- cytoplasm has alternating dark and light bands (striations) -» overlapping bands of contractile tissue (actin and myosin)
- muscle cells = muscle fibres
- tens or hundreds of muscle fibres bundles together = fascicle
Describe skeletal muscle classifications.
Pennate
Fascicles attach obliquely, can be unipennate, bipennate or multipennate.
Convergent
Arise from a broad area and converge to form a single attachment.
Circular or sphincter
Surround an opening, constrict when contracted.
Fusiform
Spindle shaped with thick round bellies and tapered ends.
Flat
Parallel fibres.
Describe tendons.
Connect muscle to bons.
Dense regular connective tissue.
Transmits mechanical forces.
Outline the 3 types of muscle contraction.
1) reflexive - automatic (such as the diaphragm)
2) tonic - muscle tone (such as the muscles used to maintain posture)
3) phasic
Outline the 2 types of phasic contractions.
1) isotonic contractions - muscle changes length, concentric = muscle shortening, eccentric = muscle lengthening.
2) isometric contractions - muscle length remains the same.
Discuss what needs to happen to initiate contraction.
If the EPP (end plate potential) exceeds the threshold for activating voltage-gated Na+ channels, an AP (action potential) is generated. Generation of an AP initiates the sequence of events leading to contraction.
There are many differences between the types of muscle however the trigger for contraction of all 3 types of muscle is the same, it requires an increase in intercellular Ca2+.
Breakdown the organisation of skeletal muscle.
Whole Skeletal muscle (an organ)
↓
A Fascicle (tens or hundreds of muscle fibres)
↓
Muscle Fibre (a single cells)
↓
Myofibril (a specialised intracellular structure)
↓
Thick and Thin Filaments (cytoskeletal elements)
↓
Myosin and Actin (protein molecules)
Define myoblasts.
Stem cells that differentiate into muscle fibres.
Describe myofibrils.
Myofibrils – specialised contractile elements that extend the entire length of the muscle fibre. Each myofibril consists of a regular arrangement of cytoskeletal elements – the thick and thin filaments.
Thick; special assemblies of the protein myosin.
Thin; made up primarily of the protein actin.
Discuss the sarcomere in the structure of a myofibril.
The smallest component of a muscle fibre that can be stimulated to contract, each relaxed sarcomere is about 2 and a half micrometers in width and consists of one whole A band between two I bands.
Discuss the A band in the structure of a myofibril.
Made up of stacked thick filaments along with portions of the thin filament that overlap on both ends of the thick filaments, the thick filament lie only within the A band and extends its entire width.
Discuss the H zone in the structure of a myofibril.
The lighter area found within the middle of the A band where the thin filaments do not reach.
Discuss the M line in the structure of a myofibril.
A system of supporting proteins hold the thick filaments together vertically within each stack, these proteins can be seen as a M line extends vertically down the middle of the A band within the centre of the H zone.
Discuss the I band in the structure of a myofibril.
Contains only thin filaments from two adjacent sarcomeres but not the entire length of these thin filaments.
Discuss the Z lines in the structure of a myofibril.
Visible in the middle of each I band is a dense vertical Z line, the area between two Z lines is a sarcomere, it is a flat cytoskeletal disc that connects the thin filaments of two adjoining sarcomeres.
Describe the arrangement in a myofibril.
During growth, a muscle increases in length by adding new sarcomeres on the ends of myofibrils not be increasing the size of each sarcomere.
Each thick filament is surrounded by six thin filaments and each thin filament is surrounded by three thick filaments.
Discuss in detail the structure of thin filaments.
Consists of three proteins:
1) actin
2) tropomyosin
3) troponin
In relaxed filaments the main structural component is a double stranded alpha helical polymer of filamentous actin (F-actin). Each F-actin molecule has a special binding site for attachment with myosin and is also associated with two regulatory actin binding proteins called tropomyosin and troponin.
Tropomyosin are thread like molecules consisting of two identical alpha helices that coil around each other to form a ribbon that lies along the inside groove of the actin helix. In the relaxed shape the tropomyosin can physically cover the binding sites on actin molecules for attachment with the myosin cross bridges.
Troponin molecules consist of three small spherical subunits that form a hetero trimer, made up of troponin T which binds to a single molecule of tropomyosin. Troponin C binds calcium ions and troponin I which binds to actin and inhibits contraction. When troponin is not bound to calcium, this protein stabilises tropomyosin in its blocking position over the actins cross bridge binding sites.
Discuss in detail the structure of thick filaments.
Myosin molecules form the thick filaments, each myosin molecule consists of two identical golf club shaped subunits with their tails intertwined and their globular heads. Each globular head contains an actin binding site and a myosin ATPase site projecting out at one end.
A thick filaments is made up of myosin molecules lying lengthwise parallel to one another, half are orientated in one direction and half in the opposite direction. The globular heads protrude at regular intervals along the thick filaments from the cross bridges.
Thick filaments are composed of multiple mysoin-2 molecules, each myosin molecules is a double trimer composed of:
- 2 intertwined heavy chains
- 2 regulatory light chains
- 2 alkali (or essential) light chains
The two heavy chains have 3 regions; a tail, a hinge and a head region.
- the tail portions are alpha-helices that intertwine
- at the hinge region the molecule opens up to form 2 globular heads
- the head region (also known as S1 fragments) are the cross-bridges between the thick and thin filaments of the sarcomere
The heads of the heavy chains each possess a binding site for actin and a site for binding and hydrolysing ATP. The head portions of each myosin forms are complex, with two light chains, one alkali and one regulatory. It is the alkali light chain that stabilises the myosin head region, the regulatory light chain regulates the ATPase activity of myosin the activity of this chain is regulated via phosphorylation by kinases.
Describe muscle contraction.
Is a cycle in which myosin-ll heads bind to actin, these cross-bridges become distorted and finally the myosin heads detach from actin.
Energy for this cycling comes from the hydrolysis of ATP.
In all 3 muscle types, an increase in intercellular calcium triggers contraction by removing the inhibition of cross-bridge cycling.
Upon stimulation the intercellular calcium may rise from its resting level of less than 10-7 M to 10-5 M.
The subsequent decrease in intercellular calcium is the signal to cease cross-bridge cycling and relax.
Describe the role of Ca2+ in muscle contraction.
Ca2+ modulates contraction via regulatory proteins rather than interacting directly with the contractile proteins.
In the absence of Ca2+, these regulatory proteins act together to inhibit actin-myosin interactions, thus inhibiting the contractile process.
When Ca2+ bind to one or more of these proteins, a conformational change takes place in regulatory complex that releases the inhibition of the contraction.
Discuss troponin C and Ca2+ interactions in skeletal muscle.
Troponin contains troponin C that binds Ca2+. Each troponin C molecule has:
- 2 high-affinity Ca2+ binding sites that participate in binding troponin C to the thin filament. Ca2+ binding to these sites does not change during muscle contraction.
- 2 additional low-affinity Ca2+ binding sites. Binding of Ca2+ to these sites induces a conformational change in troponin complex that has 2 effects:
1) Troponin I shifts, permitting the tropomyosin molecule to move.
2) Via troponin T, tropomyosin is moved away from the myosin-binding site on actin and the actin groove.
- The myosin head is now able to interact with actin and engage in cross-bridge cycling.
Outline the steps in the cross-bridge cycle.
During the cross-bridge cycle, contractile proteins convert the energy of ATP hydrolysis into mechanical energy. The cross-bridge cycle occurs in 5 steps:
1) ATP binding
2) ATP hydrolysis
3) Cross-bridge formation
4) Release of Pi from myosin
5) ADP release
Draw a diagram of the cross-bridge cycle.
[see notes for answer]
Describe the sliding filament mechanism.
Sliding Filament Mechanism
- Cross-bridge interaction between actin and myosin brings about muscle contraction by means of the sliding filament mechanism.
- The thin filaments on each side of a sarcomere slide inward over the stationary thick filaments.
- As they slide inward, the thin filaments pull the Z lines (to which they are attached) closer together, so the sarcomere shortens.
- As all sarcomeres throughout the muscle fibre’s length shortens simultaneously, the entire fibre shortens.
Describe what happens in a myofibril during contraction.
What happens during contraction?
Due to interactions of thin and thick filaments, the filaments slide over one another. The length of the filaments (thick and thin) themselves do not shorten.
A band; determined by thick filaments therefore stays the same width.
I band; thin filaments overlap the thick filaments therefore the I band width decreases.
H zone; within the A band, thick filaments not overlapping therefore width decreases.
Z lines; distance between Z lines decrease.
Describe rigor mortis.
Rigor Mortis – “stiffness of death”
* Begins 3-4 hours after death and completes in ~12 hours.
* Following death, [Ca2+]i begins to rise.
* This calcium lets the regulatory proteins move aside, letting actin bind myosin cross-bridges that were already charged with ATP prior to death.
* Dead cells cannot produce ATP, so actin and myosin once bound cannot detach.
* During the next several days, rigor mortis gradually subsides as proteins involved start to degrade.
* It is an increase [Ca2+]i that triggers muscle contraction, the time during which [Ca2+]i remains elevated determines the duration of muscle contraction.
* The process by which excitation triggers the increase in [Ca2+]i is known as excitation-contraction (E-C) coupling.
Describe the spread of action potentials via ‘transverse tubules’.
APs spread to the interior of the muscle fibre by way of ‘transverse tubules’.
o The skeletal muscle fibre is so large that APs spreading along its surface cause almost no current flow deep within the fibre.
o Maximum muscle contraction requires the current to penetrate deeply into the fibre to the vicinity of separate myofibrils.
o This penetration is achieved by transmission of APs along transverse tubules (T tubules).
o T tubules penetrate all the way through the fibre, from one side to the other.
Draw a labelled diagram detailing Ca2+ movement in SR and T tubules.
[see notes for answer]
Describe CICR.
Local elevations in [Ca2+]i can also activate the Ca2+ release channel in skeletal muscle. This mechanism is known as Ca2+ induced Ca2+ release (CICR). CICR is not necessary for contraction in skeletal muscle, however, it does play a critical role in cardiac muscle.
1) Na-Ca and exchanger and Ca2+ pump in the plasma membrane both extrude Ca2+from the cell.
2) Ca2+ pump sequesters Ca2+ within the sarcoplasmic reticulum.
3) Ca2+ is bound in the sarcoplasmic reticulum by calreticulum and calsequestrin
Describe the mechanism of how CICR works.
1) An action potential depolarises the cell membrane.
2) Voltage-gated calcium channels open, allowing calcium ions to flow into the cell.
3) The calcium ions activate ryanodine receptors (RyRs) on the SR membrane.
4) The RyRs release more calcium ions into the cytosol.
5) The calcium ions bind to troponin C, which moves tropomyosin out of the way.
6) The thin filament can interact with the thick filament, when generates force.
Describe the excitatory pulse of Ca2+.
- Resting state [Ca2]i (= <10-7 M) is too little to elicit contraction.
- Conversely, full-excitation of the T-tubule/SR system causes the release of the Ca2+ to increase the [Ca2+]i to 2x10-4 M (500 fold increase. This is about 10x the level required toc cause maximum contraction.
- Immediately thereafter, the SERCA calcium pump depletes [Ca2+]i again.
- The total duration of this Ca2+ “pulse” in a skeletal muscle fibre is ~1/20 of a second.
- During this pulse contraction occurs.
- If the contraction is to continue for longer periods, a series of calcium pulses must be initiated by continuous series of repetitive action potentials.
Describe relaxation after muscle contraction.
- The contractile process is tuned off when Ca2+ is returned to the SR when electrical activity stops.
- The SR expresses Ca2+ - ATPase pumps, which actively transport Ca2+ from the cytosol and concentrates it in the SR.
- The thin filaments then return passively to their resting position. The muscle fibre has relaxed.
Describe the detailed steps of muscle contraction and then relaxation.
1) An action potential arriving at a terminal button of the neuromuscular junction stimulates release of acetylcholine, which diffuses across the cleft and triggers and action potential in the muscle fibre.
2) The action potential moves across the surface membrane and into the muscle fibre’s interior through the T tubules. An action potential in the T tubule triggers release of Ca2+ from the sarcoplasmic reticulum into the cytosol.
3) Ca2+ binding to troponin on thin filaments.
4) Ca2+ binding to troponin causes tropomyosin to change shape, physically moving it away from its blocking; this uncovers the binding sites on actin for the myosin cross bridges.
5) Myosin cross bridges attach to actin at the exposed binding sites.
6) The binding triggers the cross bridge to bend, pulling the thin filaments over the thick filament toward the centre of the sarcomere. This power stroke is powered by energy provided by ATP.
7) After the power stroke, the cross bridge detaches from actin. If Ca2+ is still present, the cycle returns to step 5.
8) When action potentials stop, Ca2+ is taken up by the sarcoplasmic reticulum. With no Ca2+ on troponin, tropomyosin moves back to its original position, blocking myosin cross bridge binding sites on actin. Contraction stops and the thin filaments passively slide back to their original relaxed positions.
Define the term excitation-contraction coupling.
The term excitation–contraction coupling (ECC) describes the rapid communication between electrical events occurring in the plasma membrane of skeletal muscle fibres and Ca2+ release from the SR, which leads to contraction.
Describe the somatic nervous system.
A branch of the peripheral nervous system which consists of the skeletal muscle and their neural control elements.
Describe biceps brachii and brachialis.
Biceps brachii and brachialis work together as a synergist.
Biceps brachii and brachialis (as flexors) oppose triceps brachii and ancones (as extensors), these groups are antagonists to each other.
Axial muscles control movements of the trunk, proximal muscles are found in shoulder, elbow, pelvis and knee (mediating locomotion) and distal muscles move hands, feet and digits.
Describe motor neurons of the somatic nervous system.
Upper motor neurons mediate lower motor neurons, they arise in cerebral cortex and use glutamate as a neurotransmitter.
Lower motor neurons generate force, they arise in the spinal cord and use acetylcholine as neurotransmitter.
Describe lower motor neurons.
Lower motor neurons exit the spinal cord in spinal nerves. This provides both motor and sensory supply to skeletal muscle (a sensory input from skin, visceral receptors too). 30 spinal nerves which innervate muscles roughly at the spinal segment.
The efferent/motor nerve leaves the spinal cord via the anterior root.
The afferent/sensory nerve eaves the spinal cord via the posterior root.
Describe motor units and motor pools.
Motor unit = [alpha] motor neurons and all of the skeletal muscle it innervates.
Motor pool = single muscle innervated by a group of [alpha] motor neurons.
Force of contraction from [alpha] motor neuron is influenced by:
- Motor unit recruitment
- Frequency of action potentials generated
Describe the various sizes of motor units.
Motor units vary in size.
Smaller motor units control finer movements (like the extraocular muscles of the eye), they are innervated by smaller [alpha] motor neurons. Larger motor units control postural muscles (such as the pectoralis and erector spinae), they are innervated by larger [alpha] motor neurons.
Outline features of slow muscle fibres.
Synonyms: red muscle fibre.
Myosin ATPase activity: slow.
Fatigue resistance: high.
Oxidative capacity: high.
Myoglobin: high.
Glycolytic capacity: low.
Outline features of fast muscle fibres.
Synonyms: white muscle fibre.
Myosin ATPase activity: fast.
Fatigue resistance: low.
Oxidative capacity: low.
Myoglobin: low.
Glycolytic capacity: high.
Describe the different types of motor units.
o Fast fatiguing
- Very high tension
- Fast fatiguing
- Large [alpha] motor neurons
- High threshold
- Type llx fibres
- ‘burst’ power
o Fatigue resistant
- High tension
- Slow fatiguing
- Intermediate [alpha] motor neurons
- Intermediate threshold
- Type lla fibres
- Sustained locomotion
o Slow
- Low tension
- Fatigue resistant
- Small [alpha] motor neurons
- Low threshold
- Type 1 fibres
- Antigravity, sustained movement
Describe factors which influence force of contraction.
Motor unit recruitment
Greater number of motor units which can be recruited increases the force of contraction that a muscle can produce.
There is a fixed order of recruitment in response to increasing activity of the lower motor neurons stimulating the muscle (the muscle pool).
* Starts with slow motor units
* Then fast fatigue-resistant units
* Finally fast fatigable units
This is known as the size principle.
Frequency of action potential generated.
Frequency (temporal) summation of muscle fibre contraction.
Twitch muscle contraction – the muscle contracts with a force of 5 hz but quickly comes back down to normal.
Wave summation – the muscle contracts and as the wave is beginning to come back down it contacts again, this repeats the force generated is 10 hz.
Unfused tetanus – the muscle contracts repeatedly in rapid succession generating a force of 20 hz.
Fused tetanus – the muscle contracts producing a very large and steep wave generating a force of 40 hz.
Describe the 2 types of muscle spindle.
Two types of muscle fibres:
- Extracellular
Bulk of skeletal muscle fibres -> force generation.
Innervated by an [alpha] motoneuron.
- Intracellular
Remaining specialised fibres -> muscle spindles.
Innervated by [gamma] motoneuron and sensory afferents.
Describe sensory innervation in muscle fibres.
Sensory innervation
Provided by either the group 1a or group 2 afferents.
Motor innervation
Provided by [gamma] motoneuron.
Describe how muscle spindles sense and respond to changes in muscle length.
Muscle spindles sense changes and respond to changes in muscle length to return skeletal muscles to resting state after they have been used. In action:
* Abdominus rectus is contracted to stand or sit.
* Extrafusal (and intrafusal) fibres shorten.
* Sensory afferents (group 1a and 2 fibres) in the intrafusal relay information to the [alpha] motoneuron in the spinal cord.
* Activation of the [alpha] motoneuron stimulates abdominus rectus to relax.
* At the same time the [alpha] motoneuron is stimulated, the [gamma] motoneuron is activated.
Describe reflex arcs.
Reflex arcs consist of:
Sensory receptors.
Sensory afferents (group 1a and 2)
Interneurons in the spinal cord
Motor efferents ([alpha] motoneuron)
All part of the stretch reflex.
Describe the myotatic reflex.
Stretch (myotatic) reflex – example: knee jerk
Muscle is stretched and group 1a afferent fibres in the muscle spindle start firing.
These group 1a afferent fibres synapse on [alpha] motoneurons in the spinal cord. -> the [alpha] motoneurons innervate the same muscle from which the group 1a afferent relayed the sensory information.
[alpha] motoneurons induce contraction of skeletal muscle.
Muscle returns to resting length and firing frequency of group 1a decreases.
Describe inverse myotatic reflex.
Golgi tendon (inverse myotatic) reflex – example: claps knife
Muscle contracts and the extrafusal fibres shorten and this stimulates the golgi tendon organ.
Group 1b afferents start firing and send sensory information to the inhibiting interneurons they synapse on in the spinal cord.
Inhibiting interneurons synapse on the [alpha] motoneurons.
Muscle returns to resting length and firing frequency of group 1b decreases -> synergistic muscles also relax and antagonist muscles contract.
Describe flexion-withdrawal reflex.
Flexion – withdrawal reflex. Example: touching something hot or stubbing your toe.
- When you detect something painful/noxious, there are multiple afferents fibres activated which then synapse on multiple interneurons in the spinal cord.
- On the same side as the painful/noxious stimuli flexors are contracted and extensors are relaxed.
- On the opposite side as the painful/noxious stimuli flexors are relaxed and extensors are contracted.
Describe the different muscle types in regards to striation, control and innervation.
Skeletal muscle is striated, voluntary and somatic innervation ([alpha]- and [gamma]- motor neurons).
Cardiac muscle is striated, involuntary and autonomic innervated (sympathetic and parasympathetic postganglionic fibres).
Smooth muscle is unstriated, involuntary and autonomic innervated (sympathetic and parasympathetic postganglionic fibres).
Describe muscle fibres in each muscle type.
In skeletal muscle, individual muscle fibres are large, elongated, cylindrical and possess multiple nuclei.
In cardiac muscle, individual muscle fibres are large, cylindrical and possess multiple nuclei.
In smooth muscle, individual muscle fibres are relatively small, spindle shaped and possess one nucleus.
Describe the function of smooth muscle in various areas of the body.
Smooth muscle is the most diverse muscle type in function.
Vasculature – controls diameter, regulates flow and pressure.
Airways – controls diameter, regulates flow and resistance.
Urinary system – propulsion of urine into ureters, bladder tone, tone of internal sphincter of bladder.
Gastrointestinal tract – controls tone, motility, opening/closing of sphincters.
Male reproductive system – secretion, propulsion of semen.
Female reproductive tract – propulsion (fallopian tubes), parturition (uterus).
Skin – pili erection.
Describe types of smooth muscle.
Multiunit
- Electrical isolation of cells allows finer motor control.
- Tonic, function individually, such as iris and vas deferens.
Unitary
- Gap junctions permit coordinated contraction.
- Phasic, function as a syncytium, such as stomach, urinary bladder and bronchioles.
Describe the contractile machinery in smooth muscle.
Like in skeletal muscle, smooth muscle relies on sliding filament mechanism of generated during actin-myosin cross-bridge formation to facilitate contraction.
Describe the steps of cross-bridge formation and sliding filament mechanism in smooth muscle.
1) Driven by a rise in [Ca2+]i which binds calmodulin.
2) Ca2+ - calmodulin complex activates myosin light chain kinase (MLCK).
3) Myosin light chain (MLC) is phosphorylated on the myosin head.
4) Phosphorylation of myosin head ‘cocks’ it and increases its ATPase activity reading it to interact with actin to form a cross-bridge.
- Basal [Ca2+]i is about 100 nm.
- Increase in [Ca2+]i is about 1 micrometre and evokes maximal contraction.
- Elevated [Ca2+]i results from:
* Ca2+ release from the SR
* Ca2+ influx across the plasma membrane
Outline the factors affecting striated muscle cross-bridge formation.
Increased intracellular Ca2+.
Stretch (Frank-Starling relationship).
Describe the factors affecting smooth muscle cross-bridge formation.
Increased intracellular Ca2+.
Phosphorylation of myosin light chain kinase (MLCK).
Inhibition of myosin light chain phosphatase.
Describe calmodulin and provide a supporting diagram.
Calmodulin is a multifunctional Ca2+ binding protein present in the cytoplasm of all eukaryotic cells.
[see notes for supporting diagram]
Describe relaxation of smooth muscle.
Relaxation involves a drop in intracellular Ca2+ and dephosphorylation.
- Returning [Ca2+]i to pre-excitation concentrations.
Membrane bound Ca2+ ATPases and Na+-Ca2+ exchangers expel calcium from the cell and calcium is sequestered into stores by sarco-(endo)plasmic reticulum calcium ATPase (SERCA).
- Dephosphorylation
Myosin light chain phosphatase (MLCP).
Describe innervation of smooth muscle.
Innervated by autonomic nervous system.
Arterial smooth muscle – sympathetic innervation with noradrenaline.
Other smooth muscle – sympathetic and parasympathetic innervation with noradrenaline and acetylcholine, respectively.
Describe the excitation-contraction coupling in smooth muscle.
By convention of contraction of smooth muscle can be described as:
Pharmacochemical coupling
Refers the processes by which an agent causes a change in smooth muscle tone without a change in membrane potential.
Involves the production of intracellular second messengers that either contract or relax the muscle. Inositol triphosphate (IP3) causes contraction. Cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) both cause relaxation.
Electrochemical coupling
Refers primarily to the opening of plasma membrane voltage-activated L-type Ca2+ channels to depolarisation with, or without, action potential generation.
Describe regulation f smooth muscle tone.
l-type Ca2+ channels are opened by numerous depolarising mechanisms such as G-protein coupled receptors coupled to Gq/11. This increased intracellular calcium joins with calmodulin which activates myosin light chain kinase (MLCK). This active MLCK phosphorylates myosin light chain thus causing contraction.
Cyclic guanosine monophosphate activates myosin light chain phosphatase. This MLCP dephosphorylates myosin light chain thus causing relaxation.
Describe endothelium-dependent vasodilation.
Vasodilation substances enter the cell via g-protein coupled receptors which leads to an increase in intracellular calcium. This then joins onto calmodulin which activates endothelial nitric oxide. eNOS turns L-arginine and oxygen into nitric oxide and citrulline. The nitric oxide enters adjacent smooth muscle cells and activates guanylate cyclase which converts GTP to cGMP. This cGMP activates protein kinase G which causes relaxation.
Organic nitrates (such as GTN) can enter the smooth muscle cell directly and be turned into nitric oxide which then goes through the same events to cause relaxation.
Outline the functions of protein kinase G (PKG and relaxation).
- Stimulates MLCP
- Stimulates PMCA
- Stimulates SERCA
- Activates K+ channels that cause hyperpolarization and inactivate Ca2+ channels
Describe angina.
Inadequate myocardial oxygen supply.
Fixed vessel narrowing.
Endothelial dysfunction.
Stable angina -> episodic, brought on by exertion, relieved by rest.
Unstable angina -> symptomatic even at rest, ECG is similar to that of a heart attack.
Describe the pharmacological management of angina.
Organic nitrates act directly on smooth muscle cell to increase nitric oxide (NO) production.
Same signalling cascade as endogenous NO release leads to smooth muscle relaxation and therefore vasodilation.
Acts primarily on veins to reduce preload and oxygen demand in the myocardium.
Secondary action on the coronary collaterals to improve oxygen delivery to the ischaemic myocardium.
Describe the effects of organic nitrates on venodilation.
The primary action of organic nitrates is to cause venodilation.
Venodilation reduces venous pressure and the venous return to the heart.
This reduces cardiac output (by Starling’s law.)
Reduced cardiac output leads to lower arterial pressure therefore lowering the total peripheral resistance and reducing oxygen demand.
Outline glyceryl trinitrate (GTN).
- Do not release NO
- GTN-NO2-NO-Guanylate cyclase
- Biologically inactive
- Low bioavailability if given orally
Describe isosorbide dinitrate (or isosorbide mononitrate).
- Do not directly release NO
- Isosorbide dinitrate/mononitrate-NO2-NO-Guanylate cyclase
- Biologically inactive
- Hald life of 2-4 hours
- Bioavailability varies
Describe hypertension.
Diastolic blood pressure = 90 mmHg
Systolic blood pressure = 140 mmHg
Some modifiable and non-modifiable causes.
Consequences include:
* Left ventricular hypertrophy
* Renal failure
* Stroke
Hypertension can be managed by calcium channel blockers that act on L-type calcium channels on vascular smooth muscle but also at L-type calcium channels in cardiac myocytes.
Describe calcium channel blockers (CCB).
Normally orally administered, bioavailability 10-30%, half-life of 2-4 hours.
Three main classes of CCB:
- Dihydropyridines -> nifedipine and amlodipine
- Benzothiazepines -> diltiazem
- Phenylalkylamines -> verapamil
Describe K(ATP) channel openers.
Are used in cases of severe hypertension, can be used with beta blockers and diuretics.
Open K(ATP) channels in smooth muscle cell membrane and hyperpolarise the smooth muscle cell.
Examples include minoxidil (not prescribed to women) and nicorandil.
Describe alpha blockers.
Example: prazosin.
[alpha]1 adrenoreceptors are the first part of the signalling cascade that ultimately leads to smooth muscle contraction following activation of the sympathetic nervous system.
[alpha]1 antagonists prevent this signalling cascade and therefore lead to vasodilation.
