NMJ / Muscle Phys Flashcards
Another name for the neuromuscular junction (NMJ)
end plate
one motor unit innervating one group of muscle fibers
motor unit
What is the neuromuscular junction?
an axon making single contact with a muscle fiber
another name for the bulge of the synaptic terminal
bouton
neurotransmitter used by the presynaptic nerve in the NMJ
acetylcholine (ACh)
Postsynaptic structure at the NMJ which is responsible for increasing surface area
postjunctional folds
Where is there a meshwork of proteins and proteoglycans in the NMJ?
synaptic cleft
Region of presynaptic membrane where synaptic vesciles fuse and relase ACh
active zones
location of a high density of AChRs in the NMJ
crest of postjunctional folds
How can the current generated by an action potential in muscle contraction be measured?
Electromyography (EMG)
ACh molecules needed to open an AChR
two
Entrance of sodium ions causing current at the postsynaptic muscle of the NMJ
End-plate current (EPC)
Change in potential in the postsynaptic muscle fiber
End-Plate Potential (EPP)
Caused by a spontaneous release of trace amounts of ACh. Changes in muscle membrane potential even when the presynaptic motor neuron is not stimulated
Miniature End Plate Potentials (MEPPs)
Defined as the difference between an actual EPP and threshold potential required to generate muscle action potential
safety factor
(True/False) There will be no action potential in the event of repetitive stimulation of the (muscle) nerve, which reduces EPPs
False.
Structure of an AChR
five subunits arranged around a central pore
Differences between adult and embryonic AChR
Adult receptors have a shorter single channel mean open time and greater single channel current
Describe the communication between motor neurons and target muscles before the formation of the NMJ
Motor neurons can release ACh before making contact; likewise the muscle membrane can respond to ACh
What happens to EPPs after a motor neuron makes contact with its muscle target?
amplitude of EPPs increases
Describe the changes in AChRs before and after muscle innervation
Before innervation, AChRs pre-aggregate at the center of the developing muscle fiber. Afterwards, they become concentrated at the region of interaction
Existing, premature receptors are clustered by the protein _____ which is released from the nerve. It binds to a receptor on the muscle which activates muscle-specific kinase (MuSK)
agrin
The activation of MuSK induces clustering of AChRs by which protein?
rapsyn
Kinase required for initiating NMJ formation and for assembling other proteins found at the junction
Muscle-specific Kinase (MuSK)
Binds to agrin and MuSK and is required for NMJ formation
low-density lipoprotein receptor-related protein 4 (LRP4)
Regulates interaction of MuSK with LRP4
agrin
muscle protein required to activate MuSK and thus aggregate AChRs
Dok-7
Changes in the receptor after muscle innervation (3)
1) receptor half-life increases
2) embyonic type receptors disappear
3) adult type receptors appear
True/False: early NMJs follow the one nerve, one muscle fiber rule
false. muscle fibers innervated by multiple motor neurons
ACh release at the NMJ is blocked by…
botulinum toxin
AChRs at the NMJ are activated by…
nicotine
AChRs at the NMJ are inhibited by… (2)
d-tubocurarine (curare) and alpha-bungarotoxin (found in snake venom)
AChE at the NMJ is inhibited by… (2)
physostigmine and neostigmine
Muscle Na+ channels are blocked by…
tetrodotoxin
These peptides produced by fish-hunting marine cone snails block neuronal Ca2+ channels, muscle Na+ channels, and AChRs
conotoxins
Most patients have antibodies against AChRs, some to MuSK. Reduced AChR levels and degeneration of post-junctional folds.
myasthenia gravis
Effects of myasthenia gravis
Both EPPs and MEPPs smaller. EPP may be so small it cannot elicit postsynaptic action potential (esp after repeated stimulation)
Treatment for myasthenia gravis (3)
1) Transmission can be partially restored by administration of AChE inhibitors
2) drugs to reduce immune response
3) removal of AChR antibodies
Clinical features of myasthenia gravis (5)
1) weakness and fatigue of voluntary muscles
2) symptoms worse or appear on exertion
3) ocular muscle weakness usually is the initial presentation
4) most cases, weakness progresses to involve other muscles
5) symptoms may fluctuate and there may be remissions
Syndrome in which you make antibodies against presynaptic voltage-gated Ca2+ channels
Lambert-Eaton Syndrome
Characteristics of Lambert-Eaton Syndrome (4)
1) reduction in neurotransmitter release (related to calcium)
2) affects primarily limb muscles
3) symptoms include skeletal muscle weakness
4) exercise improves weakness
Cause of botulism
botulinum toxin from Clostridium botulinum
Affects the autonomic nervous system as well as the NMJ. Inhibits synaptic vesicle release and NMJ symptoms include weakness and paralysis of limbs.
botulism
How does one die from botulism?
respiratory muscle paralysis
What can botulinum toxin be used to treat (3)
1) muscle contractures and spasms
2) strabismus (cross-eyes)
3) headaches
Effects of aging on the NMJ (4)
1) becomes unstable over time
2) synaptic area decreases (AChRs fragments and number of post-synaptic folds decreases)
3) eventually lose motor nerves
4) reinnervation less likely to occur
Single cell myoblasts fuse to form a multinucleated _____
myotube
Transcription factors necessary for cells to become myogenic (4)
1) MyoD
2) myogenin
3) myf-5
4) MRF-4 (aka herculin or myf-6)
Nuclear phosphoprotein containing a bHLH (basic helix-loop-helix) region. Found as a dimer.
MyoD
Basic region of MyoD is required for binding….
DNA
HLH region of MyoD is required for what
dimerization with other proteins. (MyoD binds to DNA 10x better as a heterodimer than homodimer)
DNA binding sequence in muscle genes
E-box
Early and late roles of myogenic proteins
Early - MyoD and myf-5 determination factors
Late - myogenin and MRF4 differentiation factors
Myostatin is a member of what family of signaling protein
TGFβ family of signaling proteins
Result of myostatin mutation
increased muscle mass
How is myostatin a negative regulator of muscle growth?
It inhibits myoblast proliferation and progression of myoblasts from G1 to S
This protein binds to the E box in the myostatin promoter, activating myostatin transcription
MyoD
Recruited to supply myoblasts for repair and regeneration. Located on the surface of muscle fiber, beneath basal lamina
satellite cells
Components of myosin
1) 2 heavy chains (each has globular head and filamentous tail)
2) 2 light chains (two pairs, essential and regulatory)
3) cross bridges (composed of head region, project laterally from thick filament serving as a link between thick and thin myofilaments)
Biochemical properties of myosin, both located on the globular head (2)
1) Acts as an ATPase, which releases the chemical energy for contraction
2) binds to actin
Lies in the groove between the two strands of actin. Has a regulatory function and provides structural rigidity to actin.
tropomyosin
Subunits of troponin
Troponin T, C, and I
Function of Troponin T
Serves to bind troponin to tropomyosin
Function of Troponin C
contains two high and two low affinity sites for Ca2+
Function of Troponin I
Inhibits interaction between actin and myosin
Easy way to remember the Troponinins
T - tropomyosin
C - Calcium
I - inhibits interaction
Acts as a spring to keep myosin filaments centered in the sarcomere and maintain resting tension that allows muscle to snap back if overextended. Extends from M line to Z disc
Titin
Regulates assembly and alignment of actin filaments.
Nebulin
Name of the muscle plasma membrane
sarcolemma
The wave of depolarization from an action potential in the sarcolemma travels through what system
T-tubular system
Name of specialized voltage-gated calcium channels in T-tubules
Dihydropyridine (DHP) – long lasting Ca2+ currents
What part of the sarcoplasmic reticulum does calcium get released from during contraction?
terminal cisternae
Ca2+ channel in charge of release from sarcoplasmic reticulum during contraction
ryanodine receptor 1 (RyR1)
Channel responsible for Ca2+ reuptake into sarcoplasmic reticulum
Sarcoendoplasmic Reticulum Calcium ATPase (SERCA)
Myosin has a very high affinity for acting and will form very tight bonds in absence of ____ and ____
tropomyosin and ATP
What causes actin-myosin complexes to dissociate by binding to myosin
ATP
During contraction (Ca2+ enters sarcoplasm), tropomyosin moves and exposes active sites on ____
actin
What attaches to the actin active sites?
myosin crossbridges
Channel responsible for large resting chloride conductance of skeletal muscle. Stabilizes resting membrane potential to prevent false action potential.
CIC-1 (chloride channel)
Single action potential causes release of enough Ca2+ to fully initiate a contraction but Ca2+ ions are removed from sarcoplasm quick enough that no time to develop force
twitch contraction
The absolute refractor period of motor nerves much shorter than a twitch contraction. Second stimulus can be applied before relaxation.
summation contraction
When rate of stimulation of motor nerve increases to point where little or no relaxation is evident, maximum plateau of tension
tetanus contraction
Glycoprotein that binds Ca2+ ions and which acts to reduce sarcoplasmic reticulum of free Ca2+
calsequestrin
Enzyme catalyzing: ADP + creatine phosphate -> ATP + creatine
creatine phosphokinase
First source used to generate ATP in muscle
creatine phosphate
Muscle changes length, keeping a constant tension
isotonic contraction
muscle decreases in length against opposing load, such as lifting weight up
concentric contraction (isotonic subtype)
muscle increases in length as it resists load, such as pushing something down
eccentric contraction (isotonic subtype)
muscle does not shortern and tension builds up
isometric contraction
Length of muscle where maximum force generated
optimal length (L0)
Caused by resistance of muscle’s elasticity to stretch, not caused by actin-myosin crossbridges. Generated by stretching the muscle to different lengths. Also called preload
passive tension
Generated when muscle is stimulated to contract at different preloads. Sum of tension generated by crossbrdige formation and passive tension.
total tension
Generated by contractile process. Calculated by subtracting passive tension from total tension
active tension
Slow myosin ATPase and loaded with mitochondria. Depend on cellular respiration for ATP production. Rich in myoglobin and resistance to fatigue.
Type 1 Fibers (“slow-twitch)
Muscle fibers activated by small, thus slow-conducting, motor neurons. Used for activities involving repeated low-level contraction
Type 1 Fibers (“slow-twitch)
Muscle fibers with fast myosin ATPase
Type II Fibers (“fast twitch”) (divided into two)
Loaded with mitochondria and depend on cellular respiration for ATP production but also use glycolysis. Rich in myoglobin, moderately fatigue-resistant, and activated by large motor neurons. Used for activities involving speed, strength, and power.
Type IIa Fibers
Few mitochondria, rich in glycogen, and depend on glycolysis for ATP production. Low in myoglobin and fatigue easily. Activated by large motor neurons and used for activities requiring short, fast bursts of power.
Type IIb Fibers
Type of muscle fibers primarily lost during aging
Type II fibers
Decrease in muscle mass and strength associated with aging
sarcopenia
Progressive skeletal muscle weakness, defects in muscle proteins, and death of muscle cells and tissue.
muscular dystrophy
Duchenne and Becker’s Muscular Dystrophy involve mutations in what gene/rptein
dystrophin. Defect leads to instability of the sarcolemma and thus damage during contraction
Muscle weakness but also muscle cramps, stiffness, and spasms.
Myopathies
Causes of myopathies (3)
1) congenital
2) genetic abnormalities in mitochondria
3) mutations in genes controlling enzymes that metabolize glycogen and glucose
Loss of weight, muscle atrophy, fatigue, weakness and loss of appetite. Can be seen in patients with chronic diseases such as cancer, AIDS, diabetes, multiple sclerosis, and congestive heart failure.
Cachexia
Inflammation of the muscles, resulting in muscle weakness and pain, particularly in those muscles closest to trunk. Caused by injury, infection, or autoimmune disease.
myositis
Breakdown of muscle fibers resulting in the release of muscle fiber contents, particularly myoglobin, into circulation. Some toxic to kidney and frequently result in kidney damage.
Rhabdomyolysis
Common causes of rhabdomyolysis (5)
1) crush injury
2) overexertion
3) alcohol abuse
4) certain drugs (statins)
5) toxic substances
Defect in the RYR1 channel causes it to open more easily and close more slowly. Activated by certain anesthetics and muscle relaxers given during surgery. Leads to uncontrolled release of Ca2+ and muscles contract abnormally, leading to rigidity and heat production
malignant hyperthermia
