Excitation Contraction Coupling

Question 1

Steps of excitation-contraction coupling

Answer 1

1-motor action potential travels along a motoneuron to the motor endplate at the neuromuscular junction
2- the nerve endings secrete Ach which acts on local sarcolemma to open Ach gated channels
3-opening of these channels permit Na ions to flow into the muscle, depolarizing the muscle membrane potential, and initiating an AP which propagates along the muscle fiber membrane in the same way that AP propagates along the nerve axons
4- Muscle AP down the T-tubule membranes into the interior of the muscle fiber to the triad junction where it causes release of Ca that have been sequestered in the longitudinal sarcoplasmic reticulum
5-the increased concentration of calcium ions in the sarcoplasm causes the actin and myosin filaments to interact with each other, resulting in sliding motion that shortens the length of the sarcomere
6- the calcium ions are then pumped back into the sarcoplasmic reticulum by the Ca-ATPase ion pump located in the sarcoplasmic reticulum membrane-reducing the concentration of calcium in the sarcoplasm and allowing the muscle fiber to relax
7-lengthening of the muscle is achieved by contraction of an antagonist muscle

Question 2

Events at neuromuscular junction

Answer 2

1- neuronal AP travels down the motor nueron axon in saltatory fashion between nodes of Ranvier in myelin sheath to the terminal button (or bouton) also called the presynaptic terminal
2- neuronal AP depolarizes the terminal bouton which causes the voltage-gated calcium channels in the plasma membrane to open
3-elevated calcium within the terminal bouton causes the vesicles of ACh to fuse the membrane and dump their contents into the synaptic cleft
4-ACh binds ACh receptors embedded in the muscle plasma membrane
5- the ACh receptors then open allowing Na+ to rush into the muscle cell and depolarize the motor endplate this produces a change in the endplate potential. Some K can come out of the cells through the open ACh receptor
6- the depolarized endplate potential causes nearby voltage-gated Na channels in the muscle plasma membrane to open leading to the initiation of a muscle AP that propagates down the length of the muscle fiber
7-acetylcholinesterase quickly inactivates the released ACh

Question 3

Myasthenia gravis

Answer 3

• is a disorder of EC coupling caused by an autoimmune response to ACh receptor
• antibodies block or reduce the number of nicotinic acetylcholine receptors at the neuromuscular junction, resulting in muscle fatigability
• can do edrophonium test
• edrophonium chloride is a cholinesterase inhibitor and thus increases acetylcholine at the neuromuscular junction
• administered IV, it will temporarily relieve symptoms of muscle weakness, including diplopia (double vision), in myasthenia gravis

Question 4

ALS

Answer 4

• amyotrophic lateral schlerosis
• proximate- motor neuron death in spinal cord
• EC problem-loss of neuronal AP, reduced excitation
• Symptoms- weakness, spasticity, muscle atrophy

Question 5

Injury

Answer 5

• proximate- axonal damage
• EC problem- blocked neuronal action potential propagation, reduced excitation
• Symptoms- variable: paralysis, weakness, often some recovery

Question 6

Demyelination Guillan-Barre

Answer 6

• proximate- autoimmune response against myelin
• EC problem- impaired neuronal action potential propagation, reduced excitation
• Symptoms- ascending paralysis, weakness

Question 7

Muscular Dystrophy

Answer 7

• proximate- reduced attachment of muscle to ensheathing membrane
• EC problem- muscle weakness and atrophy

Question 8

Malignant Hyperthermia

Answer 8

• proximate- mutation in Ryr1 causing excessive calcium release in muscle, triggered by inhaled anesthetics
• EC-excessive and prolonged myofiber contraction (rigidity), excessive contraction
• symptoms- blood CO2 buildup, hyperthermia, circulatory collapse

Question 9

Na+ dependent AP triggers Ca2+ release from the sarcoplasmic reticulum

Answer 9

• the muscle action potential
• depolarizes the sarcolemma (the muscle fibers plasma membrane), including the transverse t-tubules. The skeletal muscle AP is sodium dependent and brief (~2 msec)
• depolarization of the T tubules opens calcium cahnnels (ryanodine receptors) in the sarcoplasmic reticulum releasing Ca2+ into the sarcoplasm and rasing the sarcoplasmic calcium from 10^-7 to 10^-5M
• some calcium is bound to calsequestrin in the SR

Question 10

Triad

Answer 10

• consists of transverse T-tubule adjacent to the terminal cisternae
• the T-tubule is an invagination of the muscle cells plasma membrane (sarcolemma) and therefore Na+ dependent action potentials traveling on the surface of the muscle also travel down into the T-tubule
• the terminal cisternae are physically attached to the T-tubule through the direct coupling of L-type calcium channels embedded in the T-tubule membrane to the Ryanodine receptors embedded in the membrane of the sarcoplasmic reticulum

Question 11

Ca2+ release at triad involves physical coupling of L type calcium channels in the T tubule with ryanodine receptors in the SR

Answer 11

• negative charges represent the voltage sensor of the DHP receptor (L type calcium channel) in the T-tubule membrane
• depolarization of t-tubule membrane induces a change in the structure of DHP receptor (L type) which in turns opens a calcium channel gate in the ryanodine receptor in the sarcoplasmic reticulum membrane causing calcium release into the sarcoplasm and triggering sarcomere contraction
• the ryanodine receptor is also stimulated to open by the presence of cytoplasmic calcium
• this means that the small amount of calcium released into the cytoplasm by ryanodine receptors at the traid, triggers adjacent ryanodine receptors away from the riad to open and release calcium which in turn triggers the opening of additional ryanodine receptors

Question 12

Skeletal muscle relaxation occurs when calcium is removed from the sarcoplasm by calcium exchanger and calcium pumps

Answer 12

• skeletal muscle contraction is terminated by the removal of calcium from the sarcoplasm
• the major way this is down is via SERCA- sarcoplasmic reticulum calcium ATPase: uses the energy of ATP hydrolysis to pump calcium back into the sarcoplasmic reticulum
• two other mechanisms of calcium removal from the sarcoplasm that extrude calcium into the extracellular fluid
• plasma membrane calcium ATPase or PMCA- uses energy of ATP hydrolysis to remove calcium from the sarcoplasm, pumps out 1 Ca per 1 ATP
• second mechanism is Sodium Calcium Exchanger (NCX)- lets 3 sodium into the cell to remove 1 calcium

Question 13

Temporal relation between skeletal AP, calcium and tension during a twitch

Answer 13

• relationship between the AP, calcium transient and tension development in a generic fast twitch fiber
• AP- lasts about 10 secs
• Calcium increases after AP is done, and ends about 90 secs later
• Tension starts increasing and goes to 140 seconds

Question 14

Twitch duration for fast and slow twitch

Answer 14

• twitch tension and calcium transients of three fiber types from toadfish
• the twitch and calcium transient become briefer, going from the slow twitch red fiber to the fast twitch white fiber to the superfast twitch fiber

Question 15

Tetanus and Summation

Answer 15

• increase in muscle tension from successive APs is summation
• a maintained contraction in response to repetitive stimulation is tetanus
• if a tetanus oscillates, it is called unfused tetanus while a tetanus without oscillations is called fused tetanus
• single AP produces a twitch where tension rises and returns to baseline
• the functional refractory period of the AP is much short than the contraction time- high freq AP cause contractions that can summate
• the strength of contraction of skeletal muscle is grades by rate coding or frequency of stimulation and by recruitment of additional motor units

Question 16

Treppe

Answer 16

• repeated stimulation of the muscle at low frequency
• this is not summation because each twitch relaxes to zero tension before the next twitch initiates
• treppe successive twitches show greater peak tension
• occurs in a step wise fashion
• may occur because Ca++ released from previous twitches exceeds Ca++ reuptake and this results in an increase in Ca++ concentration
• this in turn increases the number of crossbridges that form in the following contractions
• another possibility is that frequent stimulation warms up the muscle and thereby increases the enzymatic rate

Question 17

Motor unit

Answer 17

• a somatic motor neuron and all the muscle fibers it innervates
• a single neuron will innervate multiple muscle fibers but a single skeletal muscle fiber is innervated by only one neuron
• large motor units comprise a single neuron and 2000 or more muscle fibers
• small- 1 neuron, 3 muscle fibers
• Large motor units= fast twitch (Type II), small motor units= slow twitch (Type I)
• when a motor unit is activated all of the innervated muscle fibers are simultaneously stimulated to contract with all or none twitches
• rate coding and summation can then occur if the motor neuron fires APs repetitively

Question 18

Recruitment order

Answer 18

• motor units are recruited according to size principles
• smaller motor units (few muscle fibers) are recruited first
• as more force is required, large motor units are recruited
• when requirements for force are low, but control demands are high (writing, surgery) the ability to recruit only a few muscle fibers gives the possibility of fine control
• small- slow
• large- fast

Question 19

Summary of mechanisms that allow force variation in skeletal muscle

Answer 19

• voluntary control of skeletal muscle force generation
• the force generated when skeletal muscle is stimulated is related to the size of the motor units stimulated, the number of motor units activated and the frequency of stimulation of the muscle fibers

Question 20

Muscle fiber types

Answer 20

• Slow Twitch- Type I, fatigue resistant, red (myoglobin), oxidative, high mitochondria, low glycogen
• Fast Twitch- Type IIb, fatigue resistant, red (myoglobin), oxidative, higher mitochondria, abundant glycogen
• Fast Twitch- Type IIa, fatigable, white (low myoglobin), glycolytic, fewer mitochondria, high glycogen

Question 21

Summary of energy source available to skeletal muscle

Answer 21

• ATP- 1-2 seconds
• Phosphocreatine- rapidly transfer a high energy phosphate to ADP regenerating ATP; lasts 5-8
• anaerobic metabolism of glucose- produces ATP rapidly but is inefficent and produces lactic acid- 60 seconds
• Oxidative metabolism of glucose(glycogen)- 2-4 hours
• Oxidative metabolism of fats, carbs, and proteins- many hours

Question 22

Muscle pain

Answer 22

• produced by lactic acid build up when heavy muscle activity and low oxygen lead cause the muscle to rely on anaerobic glycolysis to produce ATP
• anaerobic glycolysis produces 2 lactic acid molecules from 1 glucose
• lactic acid then accumulate in muscle fiber and produce burning sensation
• in heart muscle this is angina
• lactic acid not always bad- may have role in regulating muscle excitability during extreme exertion

Question 23

Delayed Onset Muscle Soreness (DOMS)

Answer 23

• is not correlated with lactic acid levels in muscle

- occurs days after use and is thought to be due to muscle damage and possibly an inflammatory response

Question 24

Muscle Fatigue

Answer 24

• defined as a decline in muscle tension as a result of previous contractile activity
• a fatigue muscle also has decreased shortening velocity and slower rate of relaxation
• it is caused by the buildup of lactic acid and of inorganic phosphates (from phosphocreatine breakdown)
• fatigue is not due to low ATP since a fatigued muscle still has quite high concentration of ATP
• fatigue may infarct be an adaptation to prevent rigor that will result from very low ATP level
• note: low ATP favors stable actin myosin complexes, high calcium levels in the sarcoplasm and therefore rigor

Question 25

High frequency fatigue

Answer 25

• accompanying high intensity, short duration exercise is due to failure in the conduction of AP in the T-tubule
• recovery from such fatigue is rapid
• low frequency fatigue seen with low intensity, long duration exercise is due to the build up of lactic acid and phosphates which may change the conformation of muscle proteins- this recovery is slow