Muscles Flashcards
Outline the intermediate structures between a sarcomere and a muscle
Fascicle - bundle of muscle fibres
Muscle fibre
Myofibrils - filaments of actin/myosin arranged in myofibrils
Define myofibril
‣ Within a fibre many chains (filaments) of actin, myosin arranged in myofibrils surrounded by sarcoplasmic reticulum - i.e. multiple sarcomeres
How big is a myofibril
2 micrometres
What are some characteristics of a skeletal muscle cell
10-100 micrometres in diametre
100 - 300mm in length
Fusion of myoblasts pre birth creating long multinucleated cells unable to divide only expand. Nuclei peripheral
What is a sarcomere
The basic sturtcural unit within a myofibril
Why does striation exist?
Sarcomeres visible on the cells longitudinally due to their outline and structure
What is an A band
Myosin and some actin - myosin and the crossover area (zone of overlap)
What is the H band
- Myosin only
What is the length of the sarcomere defined by?
The Z line to Z line - the Z line being the anchoring site for actin
What is the Z line
anchoring site for actin
M line?
Myosin filaments joined together
I band
Actin filaments only
What is the name of the area with only actin filaments
I band
What is the name of the myosin only area
H zone
What is the name of the central band in a sarcomere with actin and myosin
Zone of overlap
Or the A band with both actin and myosin
Draw a sarcomere
What are 4 characteristic non sarcomere features to a skeletal muscle cell
Lots of mitochondria
Myoglobin
Sarcoplasmic reticulum
T tubules
What is the sarcoplasmic reticulum
‣ Network of vesicular elements running longitudinally around myofibril sequestering Ca by Ca/Mg dependent ATPase
How does the sarcoplasmic reticulum sequested Ca
‣ Network of vesicular elements running longitudinally around myofibril sequestering Ca by Ca/Mg dependent ATPase
What is a terminal cistern in the skeletal muscle cell
‣ Dilated end sacs of the sarcoplasmic reticulum called terminal cisterns butt against the T tubule from both sides.
What is the triad arrangement in skeletal muscle fibres
‣ A transverse tubule and the two terminal cisterns on either side of it form a triad.
What is a T tubule?
‣ These are thousands of tiny invaginations of sarcolemma at regular places on a myofibril (A-I junction)
Where do T tubules and sarcolemma generally overlap on the sarcomere
‣ These are thousands of tiny invaginations of sarcolemma at regular places on a myofibril (A-I junction)
Form a traid with 2 terminal cisterns and a T tubule
Sarcomere length relaxed
3 micrometres
Sarcomere contracted length
2.4 micrometres
Myosin structurally
◦ Myosin: (molecular motor)
‣ Large protein (thick filament) consisting of
* Long tail - 2 interwound alpha helices with a flexible hinge (S2)
* 2 globular heads (S1) connected to long tail via S2 segment - each head has 1x heavy chain that binds 1x G actin, and 2 short chains that bind ATP
How is the myosin head arranged
◦ Myosin: (molecular motor)
‣ Large protein (thick filament) consisting of
* Long tail - 2 interwound alpha helices with a flexible hinge (S2)
* 2 globular heads (S1) connected to long tail via S2 segment - each head has 1x heavy chain that binds 1x G actin, and 2 short chains that bind ATP
What happens at the M line between myosin
‣ 2x myosins fuse together at the M line via long tails forming the thick filament
* H zone contains no myosin heads.
What hapens at the H zone with myosin
There is no myosin in the H zone
How is myosin related to actin in the zone of overlap
What does a thin filament contain
‣ thin filaments - 2x chains of F actin (double stranded cord) formed from the polymerisation of G actin
* the positive is on the Z line - anchored to the Z disks
* potentiates the ATPase of myosin
What does the thin filament do with reference to actin
‣ thin filaments - 2x chains of F actin (double stranded cord) formed from the polymerisation of G actin
* the positive is on the Z line - anchored to the Z disks
* potentiates the ATPase of myosin
Where is the thin filament anchored
‣ thin filaments - 2x chains of F actin (double stranded cord) formed from the polymerisation of G actin
* the positive is on the Z line - anchored to the Z disks
* potentiates the ATPase of myosin
What is troponin
‣ Present with tropomyosin on thin filament at regular intervals (every 7 actin
monomers)
‣ Subunits
* Troponin C – calcium detecting/binds calcium
* Troponin T – binds tropomyosin
* Troponin I - inhibits myosin ATPase
‣ Binding to Calcium causes a confirmationl change in complex allowing actin to interact with myosin
What are the 3 subunits of troponin
‣ Present with tropomyosin on thin filament at regular intervals (every 7 actin
monomers)
‣ Subunits
* Troponin C – calcium detecting/binds calcium
* Troponin T – binds tropomyosin
* Troponin I - inhibits myosin ATPase
‣ Binding to Calcium causes a confirmationl change in complex allowing actin to interact with myosin
What is tropomyosin? where does it sit? What is its function
‣ 2x α-helical chains that lie between 2x chains of actin polymers → under the
influence of Troponin, it can acts to inhibit or permit myosin-actin interaction
What is titin
large elastic protein attacting myosin to the Z line
* Maintains the thick myosin filaments in the centre of the sarcomere (maintains the central A band) during contraction * Helps return the sarcomere to resting length, prevent overdistension
What are the two different types of skeletal muscle fibres
Extrafusal and intrafusal
What is the difference between intrafusal and extrafusal muscle fibres
Extrafusal - regular contract fibres supplied by alpha motor neurons
Intrafusal muscle fibres monitor length and lie parallel to extrafusal fibres. Innervated by gamma motor neurons
What si a extrafusal muscle fibre innervated by
alpha motor neuron
What is the intrafusal muscle fibre innervated by?
gamma motor neuron
If you were to subclassify extarfusal muscle fibres into 3 domains what would they be?
Fast fatiguable
Slow fatigue resistance
Fast fatigue resistant
Describe the key characteritics of fast fatiguable muscle fibres and give an example of location
e.g. hand muscles
White muscle, no myoglobin
Fast myosin ATPase
Less mitochondria
Fine precise movements
Fast twitch
Short duration of action 10msec
very fatiguable
Glycolysis energy only, minimal ATP made and consumed rapidly
What is a type 1 extrafusal muscle fibre
Slow fatigue resistnt or slow oxidative fibre
What is a type 2a extarfusla muscle fibre
fast fatigue resistant fibre, fast oxidative
What is a type 2b extrafusal muscle fibre
fast fatigauble, glycolytic
Describe the key characteritcis of slow fatigue resisant fibres and where you’d find them?
Postural muscles e.g erector spinae
Red muscle - myoglobin, lots of mitochondria, slow myosin ATPase
Strong sustained contraction, slow twitch
Sustained contraction 100msec
Not very fatiguable
Aerobic metabolism - more ATP made and less consumed
What are the characteristics of fast fatigue resistant fibres
Red muscle with myoglobin
Fine precise movements
Fast twitch
10msec contraction
Aerobic metabolism with increased mitochondria
Slow mysoin ATPase and low SR calcium pumping capacity
More fatiguable than slow fatigue resistant muscles
How does the nerve supply differ between slow tonic fibres and fast twitch fibres?
◦ Uncommon - laryngeal, extra ocular muscles
◦ Multiple nerve terminals for one nerve distributed over the whole muscle –> repeated nerve stimulation required for one muscle action potential
◦ Slow tonic contraction - non fatiguable, do not produce propogated action potentials, do not respond rapidly and require repeated stimulation before responding. Innervation by multiple grape like nerve endings rather than end plates and distirbuted over whole muscle. Therefore respond to stimulation with tonic contraction rather than a twitch response.
How is a fast twitch fibre supplied anatomically by a nerve
Single nerve, single nerve terminal –> stimulation causing action potential that propogates form the end plate
How many fibre types might a alpah motor neurone supply
May supply multiple myocytes but only 1 fibre type per nerve
What is a motor unit
- Consists of a single anterior horn α-motor neuron, its axon and all the extrafusal skeletal muscle fibres it supplies
- Considered the “functional unit of contraction” → b/c it produces the smallest amount of
muscle contraction in response to stimulation of the α-motor neuron - The number of muscle fibres in a motor unit varies - muscles for fine movement have small motor units (few fibres per motor neurone)
- Unique to skeletal muscle
- Adjacent skeletal muscle cells electrically separated by connnective tissue prohibiting depolarisation travelling between adjacent cells
What happens to an alpha motor neuron as it approaches a NMJ
Loses myelin
◦ myelinated, cell body and dendrites then long axon) to motor end plate of cell - loses myelin as it approaches a muscle fibre dividing into several terminal buttons or end feet containing acetylcholine. These fit into folds of the thickened motor end plate - one fibre ends at one endplate (no convergence)
◦ single motor nerve for all muscle fibres it innervates (motor unit) which are not necessarily next to each other to ensure uniform contraction
What is the purpose of prejunctional nicotinic receptors? Are they different?
◦ Prejunctional nAChR – Cause +ve feedback on ACh release when stimulated by ACh
Prejunctional nAChR
◦ Specialised nAChR that differs structurally and functionally cf. postjunctional nAChR
What important enzyme is contained within the synaptic cleft
◦ Contains AChE which rapidly hydrolyses ACh into choline and acetate within the
‣ junctional folds
‣ extracellular material (basal lamina)
What does acetylcholine get broken down to?
acetate and choline
How many ACh receptors per endplate
‣ 15-40 million ACh receptors per endplate
What si the trigger for the release of synaptic vesicles from the motor neuron
◦ VG-Ca2+ channel – Permit Ca2+ influx in response to motor nerve AP –> causes increased IC [Ca2+] that mobilise synaptic vesicles for ACh release (via SNAP and VAMP proteins)
Draw a nicotinic receptor
What type of recepotr is a nicotinic receptor
Ligand gated ion channel
What % of nicotinic receptors at a NMJ need to be stimulated for an action potential to occur
10%
What causes upregulation of nicotinic receptor production?
- They can be upregulated (in response to SC injury, CVA, burns, prolonged immobility, MS, GBS, prolonged NMBD exposure)
Why might someone have less nicotonic receptors at the motor end plte than usual
downregulated (in response to myasthenia gravis, AChE overdose, OP poisoning)
Where do you find nicotonic receptors on muscle cells
Junctional and extra-junctional
For extrajunctional they are outside the motor end plate and present in small numbers iunless denervation event
What is required for post junctional receptor activation
◦ Simultaneous binding of the two α subunits by an ACh each causes a brief conformational change in the receptor
How is foetal nicotnonic receptor different to adult type
‣ Foetal - has a gamma instead of a E but still contains pentameric structure
* When foetal nAChR is activated it has amore prolonged opening of ion channel causing a single quanta of ACh can elicit a muscle AP, greater release of K from muscle (contributing to hyperkalaemic response to denervation).
* Usually disappears during synaptic maturation, however when denervation occurs foetal nAChR can be upregulated in extrajunctional areas of skeletal muscle membrane
What ions flow through a nicotinic post jucntional receptor? Does this differ to prejunctional
‣ Central ion channel pore (permits transmembrane flow of Na+, Ca2+, K+)
‣ different pentarmeric structure with altered binding characteristics * Functionally Na selectivity (not Ca) and preferential blockade during high freuqency stimulation of post junctional receptor
What is the end result of nicotinic receptor stimulation at the NMJ
◦ produces a localised membrane depolarisation (or endplate potential), which can summate and trigger a skeletal muscle AP (via activation of perijunctional VG Na+ channels) if VTHRESHOLD of -50 mV is reached (RMP -90mV)
What is threshold potential
-50mV
What is a minature end plate potential
- Baseline intermittent ACh vesicle fusing with presynaptic membrane causing miniature end plate potential - this may be the cause of localised nicotinic receptors
How is a Acetylcholine synthesised
What is the enzyme implicated in synthesis of acetylcholine
What does a nerve terminal vesicle contain?
◦ Each vesicles contain – ACh (ATPase actively pumps ACh into the vesicle), ATP, Ca2+, cholesterol, phospholipids, vesiculin
Where in the nerve terminal do you find vesicles pre junctionally
Dense bar
‣ nerve terminal cytoplasm and ‣ along the presynaptic membrane flanking a “Dense bar” * (Nb. 2x vesicles line up on either side of the “dense bar” to form an “Active zone” opposite to nAChR on the MEP)
What two stores are there of ACh within the nerve cell
Nerve terminal vesicles 80%
Stationary store in nerve cytoplasm 20%
Can ACh be released without a depolarisation event?
Yes
This causes minature end plate potentials
How much ACh is in one vesicle
1500
What voltage change does a minature end plate potential cause?
0.5-1mV
How does an action potential get translated to vesicle release
AP stops at last node of Ranvier with local electrical currents produced
Voltage gated calcium channels open –> Ca influx
Calcium binds to calmodulin –> calci-calmodulin complex –> activates enzymes changing structural proteins in the vesicle and membrane
How many vesicles are released with motor nerve depolarisation
50-200 –> 60-300k ACh
How much ACh is released per depolarisation
60-300k
What is the relationship between amount of ACh release and required release for motor nerve depolarisation
10x
How is the prejunctional membrane potnetial returned to baseline state?
Delayed rectifier K channels
How long does it take between depolarisation and exocytosis
<1msec
How long does a nicotonic receptor channel open for post ACh binding
1msec
RMP of motor cells
-90mV
How is acetylcholine removed from the synapse
- Diffuses away
- Acetylcholinesterase breaks down to choline and acetate with reabsorption into prejunctional membrane for reformation
How does acetylcholinesterase work
◦ ACHe is found in synaptic cleft within junctional folds and extracelular material
‣ Possesses 6 sites each with anionic and esteric components to attract and hydrolyse
Define excitation contraction coupling
Describes the electro-mechanical process implicated in skeletal muscle contraction – involves motor nerve release of ACh at the NMJ → produces a muscle AP → leads to muscle contraction
Summarise excitation contraction coupling
- AP in alpha motor neuron
- ACh release
- Depoalrising of motor end plate and spreading throughout sarcolemma through T tubules
- Depolarisation triggers L type Ca channels 00> ca influx and SR Ca release channels opened (Ryanodine receptors)
- Calcium binds to troponin C –> tropomyosin change exposing myosin binding site on actin
- Crossbridging as troponin I inhibition of myosin ATPase is removed
What is charge movement in the context of excitation contraction coupling
◦ Depolarisation triggers voltage sensitive L type Ca channels (dihydropyridine receptors)
‣ Ca influx into the cytoplasm
‣ Charge movement into the SR membrane - opens SR Ca release channels (Ryanodine receptor) –> Ca release from sarcoplasmic reticulum
* The two calcium channels (SR and cell membrane) are physically close and linked by cytoplasmic loop of membrane L type channel
How does Ca triggered Ca release occur
◦ Depolarisation triggers voltage sensitive L type Ca channels (dihydropyridine receptors)
‣ Ca influx into the cytoplasm
‣ Charge movement into the SR membrane - opens SR Ca release channels (Ryanodine receptor) –> Ca release from sarcoplasmic reticulum
* The two calcium channels (SR and cell membrane) are physically close and linked by cytoplasmic loop of membrane L type channel
What does intracellular Ca change in concentration amount to
◦ Total Ca intracellualr change from 0.1microM at rest to 10microM
What state is a myosin head in when relaxed
Bound to ADP and phosphate with heads facing the Z line (away from M line) in cocked position
Describe the sliding filament theory
- Resting state - Bound to ADP and phosphate with heads facing the Z line (away from M line) in cocked position; myosin ATPase inhibited in resting state, cannot bind to actin
- Actin site uncovered - myosin ATPase no longer inhibited. Attaches to actin, cross birdge attachment (high energy conformation)
- Power/working stroke - myosin head pivots and bends pulling actin filment TOWARDS M line, ADP and inorganic phosphate are released. Z lines move together, smaller I band, same A band
- Myosin head now in lower energy configuration, ATP attaches and cross bridge detaches
With contraction what happens to the A band
Remains the same
With contraction what happens to the I band
Shrinks
What happens to the Z line in contraction
Moves closer together
How much movement is acheived with 1 myosin contraction
10nm
1% shortening of muscle
What degree of rotation does a myosin head achieve
90 degrees
What 2 factors are required for ongoing contracction
Sufficient calcium
Sufficient ATP
How often can a myosin head contraction
5x a second
Why does a muscle contraction end
- Reduction in action potential stimulation - ACh breakdown, reduced Ca channel opening
- Calcium removed by sarcoplasmic reticulum (ATP required) which occurs constantly but with reduction in AP becomes dominant process
- Ca concentration dropping causes dissociatoin from troponin
What is calsequestrin
◦ Calsequestrin binds calcium in the sarcoplasmic reticulum enhancing storage (10, 000 :1 baseline concentration difference when relaxaed)
What is the pattern of Ca reuptake into the sarcoplasmic reticulum
- Calcium is removed and taken up by sarcoplasmic reticulum (ATP required - active transport) from the cytosol
◦ This is occuring constantly
How is ATP created in muscle cells (3)
reatinine phosphate store - with intense excercise it is rapidly generated from creatinine phosphate
‣ ADP + creatinine phosphate –> ATP + creatinine
* Via creatine phosphokinase
* The reverse reaction can be performed in times of rest
◦ Aerobic generation from glucose/glycogen through glycolysis (substrate phosphorylation) and oxidative phosphorylation; and from fat via beta oxidation
◦ Anaeorbic generation - anaerobic glycolyiss
What are the two main factors regulating skeletal msucle contraction
Muscle spindles/intrafusal muscle fibres
Golgi tendon organs
What is a muscle spindle
Spindle has 10 intrafusal fibres in parallel which are either nuclear bag fibres or nuclear chain fibres and provide reflexiv control of muscle length, and dynamic control of muscle length change
What are the two types of intrafusal muscle fibres
Nuclear bag fibres or nuclear chain fibres
What is a nuclear bag fibre? What innervates it? What is its definining characteristic
Type of intrafusal muscle fibre
Many nuclei in a centre zone
Innervation
- Afferent - 1a primary afferents
- Efferent - gamma motor neuron
Provides information on length AND rate of change
What is a nuclear chain fibre? What innervates it? Function?
Thinner, shorter and more cylindrical with spread out nuclei compared to a nucelar bag fibre
Innervates by both 1a and 2 sensory afferents
- 1a static and dynamic feedback
- 2 static stretch only
Gamma motoro neuron efferent
Gamma motor neurons innervate what
intrafusal muscle fibres
Why do intrafusal muscle fibres need efferent supply
To keep them the same tone as extrafusal muscle fibres to detect changes that are not related to internal motor unit impulses
What is a golgi tendon organ?
Monitor tension (rate and force of contraction) in tendons
WHat is a golgi tendon organ supplied with afferent nerve supply
1b sensory afferent
What is the relationship between golgi tendon organs and extrafusal muscle fibres
In series
Intrafusal muscle fibres are in parallel
What is the purpose of a golgi tendon organ
◦ Less sensitive than muscle spindles
◦ Protect against excessive tension in muscle with a inhibitory spinal reflex loop when extrafusal fibres contract too strongly —> 1b afferent to interneuron with inhibitor action on the alpha motor neurone of the muscle weakening contraction removing stimulation from Golgi apparatus
Relate timing of muscle action potential to muscle tension
◦ Singel motor nerve AP stimulus produces a brief muscle AP lasting 1-3 msec
◦ This muscle AP produces a slower and longer mechanical response in muscle lasting 7.5-100msec (muscle action potential and its refractory period is MUCH shorter than the actual contraction and relaxation)
What is muscle tension dependent on 3
- Action potential frequency - more frequent causes force summation
- Resting length
- Recruitment of multiple motor units
Describe the passive and active tnesion relationship fo muscle length
What is velocity of contraction related to
Inversely with load
What is tetanus?
- High frequency motor nerve stimuli cause summation of individual muscle twitches into a continuous contraction constantly maintaing a high level of muscle tension –> tension is 3-4x that of a single twitch
What is force summation? What level fo change can occur
- High frequency motor nerve stimuli cause summation of individual muscle twitches into a continuous contraction constantly maintaing a high level of muscle tension –> tension is 3-4x that of a single twitch
What is incomplete tetany
Incomplete relaxation between summated stimuli
What is tetany in comparison to incompelte tetany
Complete absence of relaxation between impulses
What is the critical frequency of tetany dependent on
‣ Critical frequency depends on muscle fibres single twitch duration as twitch summation only occurs if the proceeding motor nerve a muscle AP occur prior to the end of the muscle fibres contraction/relaxation cycle e.g. twitch duration 10msec the critical frequency 100x per second for summation
Why is tetany so energy consuming
- This process is higher energy requirement as both contraction/relaxation processes occuring
What is isotonic contraction
Same tension created, moves a load
Concentric - muscle shortens as constant tension
Eccentric - musle lengthens despite constant tension
What is isometric contraction
Force without moving a load, now ork is done
Explain the pthway of a reflex arc
- Receptor – A stimulus generates a “Receptor potential” whose magnitude is proportional to the stimulus strength
- Afferent neuron – It enters into the central integrating station (Ie. via the dorsal roots, cranial nerves or autonomic nerves to cell bodies in the DRG, CN ganglia, or ANS ganglia, respectively) → “receptor potential” generates an AP in the afferent nerve, with the frequency of AP being proportional to the size of the “receptor potential”
- Central integrating station – Found in the CNS (brain or spinal cord) or in the ANS ganglia → responses are graded by EPSPs and IPSPs at synaptic junctions connecting the afferent neuron with an interneurons or motor neuron
- Efferent neuron – Often a motor neuron to the effector organ that leaves the central integrating station (Ie. via ventral roots, motor CN or autonomic nerves)
- Effector – Efferent nerve AP produces a graded response in the effector
How is a muscle stretch reflex communicated to the affected msucle
◦ Afferent nerves synapse onto alpha motor neurons in anterior horn of SC suplying the same muscle group the spindle lies in
◦ Alpha motor neuron stimulated via excitatory neurotransmission
◦ Alpha motor neuron conducts nerve impulse to NMJ
◦ Extrafusal muscle fibre stimulated to contract to maintain muscle length in the stretched muscle
What is reciprocal innervation
◦ Afferent nerves synapse with inhibitor spinal internurons –> stimulated via excitaotry NT
◦ Interneurons inhibit alpha motor neurons supplying antagonist muscles via inhibitory neurontransmitters (glycine) inhibiting contraction
What effect does a spinal cord injury have on reflex arcs
- Spinal cord disease abolishes the reflexes at the level of the lesion and exaggerates them below the level of the lesion◦ Descending control of reflex activity is generally inhibitory
◦ CNS disease or spinal cord damage above the level of the lower motor neuron cell bodies therefore exaggerate the reflex (“upper motor neuron lesion”)
How is the nerve supply to SM cells different than skeletal muscle cells
◦ Post ganglionic neurones branch extensively over the surface of smooth muscle fibres and there are NO end plates - some endings contain Na and some ACh. One neurone innervates many effector cells
Free nerve endings with pinocytosis leads to slower response systems
Self sustained contractions or contraction in response to stretch unique
How is the smooth muscle response to stimuli different than skeletal
Self contained response to stretch
What 3 characteristics of contraction broadly are different between smooth and skeletal muscle
- Speed and efficiency of excitation contraction coupling - no motor end plate, free nerve endings, multiple muscles innvervated by the one nerve with SM
- SM autocnotraction
- SM self contained contraction in repsonse to stretch
How does muscle fibre length differ between smooth muscle and skeletal
shorter in Smooth muscle - 30-200micrm long as opposed to skeletal muscle which is 50-300mm long (factor of 1000)
How does the internal contents of a smooth muscle cell differ to skeletal muscle
Single nucleus
No T tubules (there are caveolae)
No troponin (tropomyosin does exist()
Fewer mitochondria
Calmodulin more widely distributed
Sarcoplasmic rticulum smaller
Sarcomere structure diagnoal instead of linear
Is troponin in smooth muscle
no
What is calmodulin? What role does it have in smooth muscle?
‣ Intracellular Ca binding protein widely distributed
‣ 4 Ca binding domains
‣ When Ca bound to calmodulin it can activate 5 different kinases
* Ca-calmodulin kinase 1-3
* Myosin light chain kinase
* Phosphylase kinase
How does actin/myosin structure occur in smooth muscle
How does the sarcoplasmic reticulum differ between smooth muscle and skeletal muscle
‣ Much smaller sarcoplasmic reticulum
‣ calcium release can occur from
* increasing calcium in the cell (VG channels)
* more importantly it comes from inositol triphosphate which comes from the muscarinic receptors
Why is there a lack of striations in smooth muscle?
actin/myosin extend diagonally (lack striated appearance), fewer myosin fuilaments but they are longer with more heads.
What are thin filaments anchored to in smooth muscle cells
Dense bodies similar to Z discs which attach to cell membrane
How is action potential propogated in smooth muscle
Depolarisation of membrane, no T tubules to rapidly conduct impulses. Slower propogation but also lasts longer
Depolarisation can be self initiated or intiated by stretch
Action potential can be propogated between cells by interconnected gap junctions
2 types of smooth muscle
Visceral smooth muscle 0 single unit smoooth muscle
Multiunit smooth muscle of the iris, large blood vessels and small airways which are not linked together, and ANS modulated neuronal generation of AP
Sources of activation of smooth muscle
ANS
Hormonal
Gap junction
Stretch
Autopacemaker
How is excitation contraction coupling mediated
Excitation can occur by a number of mechanisms (ANS, hormonal, gap junctions, stretch or autopacemakers)
Generally GPCR mediated –>Phospholipase C –> IP3 –> phospholipase G and SR Ca channel activation
Additionally Ca channels activated by secondary messengers and voltage change –> voltage gated ones in calveoli –> increased IC Ca
How does stored Ca differ between skeletal and smooth muscle
Increased stored in skeletal muscle
Increased Ca translates to contraction how in smooth muscle cells?
Calmodulin binds Ca in cytosol and activates myosin light chain kinase which uses ATP to phosphorylate myosin which can then bind to actin and contraciton occurs –> this is slow
How does relaxation occur in smooth muscle?
slow movement of Ca out of the muscle cell delaying relaxation (provides higher baseline tone)
‣ Ca ATPase and Ca/Na antiporter
‣ Myosin light chain phosphatase prevents myosin ATPase activation by dephosphorylating the myosin light chain
What are 2 unique features of contraction you find in smooth muscle
Sustained low energy contraction called latch bridging
Plasticity
What is the sustained low energy contraction of smooth muscle called
Latch bridging - despite decreased Ca, and depohosphorylation of myosin light chain the myosin head continues to remain attached to actin
What does latch bridging in smooth muscle allow
espite decreased Ca, and depohosphorylation of myosin light chain the myosin head continues to remain attached to actin
What is plasticitiy in smooth muscle cells
variable tension for a given length, and tension changes with time despite constant length
How does a neural synapse work in cardiac muscle
‣ In the ventricle, the contacts between the noradrenergic fibers and the muscle are synapses en passant or synapses in passing where neurotransmitters are released along the whole axon as the nerves pass next to the muscle cell
Features of a cardiac muscle cell that are unique
Single nucleus (like smooth)
Semi striated
Shorter and wider cells than skeletal
Mitrochondria rich ++ (30% by weight)
Intercalated discs
T tubules over Z line instead of I-A; form diad
What is the function of intercalated discs in cardiac muscle cells
‣ Specialised junctions between cardiac cells permit all cardiac muscles to contract together in a coordinated manner
‣ Contain desmosomes (mechanical stability), gap junctions (low resistance direct iono movement)
What is the difference in tension at abseline between a cardiac and skeletal muscle cell
Skeletal has none
Cardiac has passive tension at baseline length
How does action potential get translated to muscle contraction in cardiac muscle
- AP arrives at muscle cell and spreads into interior via T tubules
◦ VG L type Ca channels open as part of plateau phase —> influx of extracellular Ca
◦ Ca triggered Ca release from sarcoplasmic reticulum
◦ Ca binds to troponin —> degree of Ca is related to degree of contraction (graded contraction)
◦ Contraction occurs
What mediates relaxation in cardiac muscle
◦ Ca ATPase into the SR - 1 ATP for 2x Ca
‣ Usually inhibited by phospholamban but when phosphorulated has less injibition
‣ Calsequestrin in cytosol of cardiac muscle cells serves as a sink for calcium
◦ Na/Ca exchange (requires Na/K exchange)
‣ 3Na enter for every 1 Ca exiting
Function of phospholamban
Inhibits Ca ATPase in SR which regulates reabsorption
Structure of a myocardial gap junction
◦ the gap junction contains a functional unit known as a connexon with 6 subunits which form a channel through the cell membrane - connects with adjacent cell connexin to connect cytoplasm - diametre 2mm
How is nitric oxide produced in the body
trigger its production from L - arginine (via nitric oxide synthase)
What does nitric oxide do
◦ Increase activity of guanylyl cyclase
◦ Guanylyl cyclase catalyses the dephosphorylation of GTP—> cGMP
◦ CGMP induces smooth muscle relaxation
‣ Increased intracellular cGMP inhibits Ca entry into cells
‣ Activates K+ channels hyperpolarising membrane
‣ Stimulating cGMP dependent protein kinase activating myosin light chain phsophatase
◦ Activity is calcium and calmodulin dependent
cardiac muscle
- Mcaroscopic structure
- Microscopic cellular elemetns
- RMP
- Metabolism
- Trigger for depolarisation
- Speed of depolarisation
- Calcium entry mechanism
- Ca binds to
- Ca binding function
- Duration of muscle depolarisation
- Duration of muscle contraction
- Force of contraction dependent on
- Tetanise
- termination of contraction
- Coordination of action
Skeletal muscle
- Mcaroscopic structure
- Microscopic cellular elemetns
- RMP
- Metabolism
- Trigger for depolarisation
- Speed of depolarisation
- Calcium entry mechanism
- Ca binds to
- Ca binding function
- Duration of muscle depolarisation
- Duration of muscle contraction
- Force of contraction dependent on
- Tetanise
- termination of contraction
- Coordination of action
Smooth muscle
Compare smooth and cardiac muscle
Compare smooth and skeeltal muscle
Compare skeletal and cardiac muscle
Explain the sarcomere length to tension hypothesis
Sliding filament theory
◦ As the change in overlap between actin and myosin filaments determines the number of actin-myosin head cross bridges that can be used to develop tension ◦ Maximal active tension occurs at muscles resting length providing optimal degree of cross bridging ‣ At these moderate resting lengths there is a plateau of tension created ◦ With excessive shortening from resting length - excess actin - myosin cross bridging and reduce distance the thin filament can move ◦ With excessive stretching minimal cross bridging reducing the distance the thin filament can move
What is passive length tension relationship in muscle determined by?
◦ Tension generated with muscle fibre elongation due to intrinsic elastic properties of the supporting sarcomere tissues. Only contributes after maximal active tension relationship exceeded
How is length tension affected in cardiac muscle
◦ Cardiac sarcomeres increased tension sharply from rest - due to increased calcium sensitivity of troponin C
‣ At maximal total tension in cardiac sarcomeres passive tension contributes significantly whereas in skeletal muscle barely at all
- maximal length tension relatinship at resting length 2.2 microm
- increasing cardiac myocyte length from 75% to 90% of the optimal length increases the active tension from 0 to 70% of the maximum
How is length tension affected in skeletal muscle
◦ Gradual build up in skeletal sarcomeres - optiomallength in sketeal msucle 2.7mm
‣ Steeper (increasing cardiac myocyte length from 75% to 90% of the optimal length increases the active tension from 0 to 70% of the maximum)
‣ Optimal length is more narrow (for cardiac muscle the active tension is zero at at about 75% of the optimal length, where skeletal muscle tension would be close to maximum already)
How is length tension related in smooth msucle
It isnt
What is the significance of length tension relationships in muscle
Significance of this relationship in cardiac muscle
* The physiological significance is the Frank Starling mechanism
◦ The ventricle increases stroke volume and ejection fraction in response to increased preload/venous return
◦ This is an intrinsic property of the heart allowing it to adapt to changes in venous return
◦ Increased preload –> increased sarcomere length –> greater tension –> greater velocity of contraciton
‣ Both force and rate of active tension development increase
* The optimal overlap of actin/myosin occurs at 2.2mm sarcomere length - under usual conditions this plateau extends as cardiac muscle stiffness prevents sarcomeres stretching beyond this
* This process also ensures right and left ventricular outputs remain exactly erqual
Onset of neuromuscular blockade vs receptor occupancy in non depolarising vs depoleraising
- Speed of sonetdepends on speed of 20% receptor occupancy (depolarising) or 75% receptor occupancy (non depolarising agents)
What is ED95
- Dose administered depends on the drug’s ED95 (2-3 x ED95 require to supress twitch height by 95%)
What choice of agent factors (3) play into speed of onset of neuromuscular blockade
- Non depolarising agents slower as greater receptor occupancy required
◦ Suxamethonium 30-60 seconds, ROc 60 seconds - High dose = concentration gradient and faster onset
◦ e.g. Rocuronium 1.2mg/kg 60 seconds, and 0.6mg/kg 120msec - Potency
◦ Lower potency means higher dose needed to achieve effect = high concentration gradient and faster effect
◦ High potency the opposite
What Drugs factors beyond dose, agent choice factors into speed of onset of neuromuscular blockade
Method of delivery
Drug interactions
What drug interactions matter in speed of onset of neuromuscular blockade
Priming - low dose (10%) prior
Drug increasing potency - LA, volatiles, aminoglycosides, furosemide
Drugs improving effect site delivery (inotropy)
ACh interaction (steriods increase synth)
Low protein binding increases drug availability
What patient factors influence speed of onset of neuromuscular blockade
Pathology
Age
Muscle mass
Electrolytes
Blood flow
How does blood flow impact neuromuscular blockade
◦ Reduced cardiac output slower, high cardiac output faster onset
◦ Different muscles have different blood flow and therefore onset times
‣ Greater blood flow to centrally located muscles –> faster onset
How does age impact neuromuscular blockade
◦ Infants/neonates - higher cardiac output and muscle blood flow, faster onset
◦ Onset also faster in elderly - reduced muscle mass
How does pathology influence neuromuscular blockade
◦ Burns - resistant to blockade
◦ Myasthenia gravis - faster onset, slower with suxamethonium
How do electrolytes impact neuromuscular blockade
Low K
High Mg
Low Ca
Speeds onset of action
How does smoking impact neuromuscular blockade
Slows
Is neuromuscular blockade faster in men or women
Men
How doe general anaesthetics influence neuromusculr blockade
increase skeletal blood flow, reduced tone of skeletal muscle - prolong blockade
How does regional local anaesthesia affect neuromuscular blockade
sodium channel blockade stabilising post junctional membrane or decrease prejunctional ACh release; direct muscle depression, ester LA compete for plasma cholinesterase with mivacurium
How does furosemide affect neuromuscular blockade
◦ Furosemide - hypokalaemia, inhibits protein kinases at low doses potentiating blockade
‣ In high doses inhibites phosphodiesterase increasing ACh release
How does CaB prolong blockade in NMB
◦ CaB - prolong blockade by inhibiting Ca dependent ACH release
How do aminoglycosides impact neuromuscular blockade
◦ Aminoglycosides - decreased ACh release prejunctional, competition with Ca
How does myasthenia impact neuromuscular bloackde
- Numerically fewer recpetors - myasthenia as antibodies already blocking receptors - increased potency of NDMA and reduced potency of depolarising agents
◦ Lambert Eaton increases sensitivity/increased potency, autoimmune destruction of voltage gated Ca channels preventing ACh vesicle exocytosisn
Why might someone have more nicotonic receptors
◦ Critical illness polyneuromyopathy
◦ Burns - receptor upregulation leading to resistance to NDMR; also reduced plasma cholinesterase reducing metabolism of mivacurium
◦ tetanus
◦ Spinal injury
◦ Stroke
◦ Anti-epileptic
Subclassifying reasons for neuromuscular blockade potency increasing form a pharmacodynamic POV
- Decreased ACh at basleine
- Drug interactions - aminoglycosides, furosemide, LA, volatiles - Reduced receptors
- Priming
- Pathology increasing or decreasing recepotrs - Altered post synaptic performance by electrolytes
What electrolyte pathologies increase potency of NMB?
◦ Acidosis
◦ Hypokalaemia - hyperpolarisation prolonged effect of NDMR, reduced effect of Sch; whereas hyperkalaemia partially depolarises and shortens action
◦ Hypocalcaemia - reduces ACh release, prolonged blockade. Reverse
◦ Hypermagnesaemia - prolonged blockade by competition with Ca required for ACh release reducing ACh release presynaptically
What factors to do with neuromuscular blockade distribution may affect duration f action of NMB?
- lipid soluble drugs such as vecuronium may accumulate in lipid rich tissue (esp infusion)
* Patients with decreased lipid content may lead to increased effect site conc for lipophilic (vecuronium)
* Extremely low protein increases ptoency of highly protein bound (Pancuronium only)
* Reduced extracellular fluid volume icnreases potency by reducing Vd - women; men have shorter duration of action due to larger ECG volume
◦ However hypovolaemia may slow rate of onset if reduced cardiac output and prolong duration
* Acidic pH increases solubility of rocuonrium/vecuronium (weak bases increase potency
How does metabolism affect neuromuscular blockade
- hepatic failure may lead to decreased metabolism of a drug
◦ pancuronium –> increases duration of action
* deranged pH and temperature changes the metabolism of the isoquinolones which use Hoffmann elim increasing potency and duration of action
* IOmmatureenzymes in neonates
What is an example of a minimally metabolised NMB
Rocuronium, vecuronium
What effect does K have on depolaring muscle relaxants
‣ Hypokalaemia reduces depolarising blockade; hyperkalaemia potentiates depolarising blockade
Why is the laryngeal adductors affected by neuromiuscular blockade differently to adductor pollicus
◦ Greater blood flow –> increased delivery of NDMR and faster noset (25%) but also faster recovery (33-50%)
‣ Fastest recovery diaphragm –> laryngeal adductors –> adductor pollicus
◦ Less intense action due to resistance to NDMR
‣ Faster fibres
‣ Higher density ACh receptors, increased ACh release presynaptically, and increase acetylcholinesterase activity
* Therefore more receptors need to be occupied to block a faster muscle
* Reduced peak effect
What is the differential in speed of onset and offsete with laryngeal adductors vs adductor pollicus
◦ Greater blood flow –> increased delivery of NDMR and faster noset (25%) but also faster recovery (33-50%)
‣ Fastest recovery diaphragm –> laryngeal adductors –> adductor pollicus
◦ Less intense action due to resistance to NDMR
‣ Faster fibres
‣ Higher density ACh receptors, increased ACh release presynaptically, and increase acetylcholinesterase activity
* Therefore more receptors need to be occupied to block a faster muscle
* Reduced peak effect
What is the mechanism of increased speed of onset and offset in laryngeal adductors vs adductor pollicus
◦ Greater blood flow –> increased delivery of NDMR and faster noset (25%) but also faster recovery (33-50%)
‣ Fastest recovery diaphragm –> laryngeal adductors –> adductor pollicus
◦ Less intense action due to resistance to NDMR
‣ Faster fibres
‣ Higher density ACh receptors, increased ACh release presynaptically, and increase acetylcholinesterase activity
* Therefore more receptors need to be occupied to block a faster muscle
* Reduced peak effect
Describe how adductor pollicus compares to other sites in its reaction to neuromuscular blockade
◦ Slower onset of action, greater block, slower offset
◦ Reduced blood flow, reduced ACHR receptor density and reduced acetylcholinesterase activity
◦ Relatively sensitive to NDMR
‣ Blocked more than respiratory muscles in recovery phase
What are the implications for monitoring of different muscle groups being affected ifferently?
- Intubation
◦ With depolarising muscle relaxants orbicularis oculi flickering closely aligns with laryngeal adductor/diaphragm onset of NMJ blockade
◦ With non-depolarising agents - TOF count will lag behind in adductor pollicus - Extubation
◦ Recovery at diaphragm and largyngeal adductors occurs before adductor pollicus
◦ Extubate at TOF count ratio >0.8 peripherally, and TOF count 4 via accelarometry.
◦ If medial eyebrow was used then recovery will be found before peripheral recovery and risk of residual neuromuscular blockade
