neuromuscular physiology 2 Flashcards
One motor neuron can:
synapse onto multiple
skeletal muscle fibers,
but each muscle fiber is
only innervated by a
single motor neuron
neuromuscular junction:
= chemical synapse
- Motor neurones “synapse” onto specific regions on a skeletal muscle fibre
slide 6!!!!
motor end plate:
specialized post-synaptic region on the
muscle fiber plasma membrane associated with the pre-synaptic
nerve terminus
events with NMJ + synaptic cleft (schéma):
slide 7!!!
AcHE
After acetylcholine has bound to the receptors, AChE quickly degrades acetylcholine to stop the signal. AChE is located in the synaptic cleft and works very fast, ensuring that acetylcholine doesn’t overstimulate the postsynaptic cell.
(slide 8!!!!)
nicotinic AcH receptor:
- The nicotinic ACh receptor
(nAChR) is a ligand-gated
cation-selective channel - The nAChR has permeability to
Ca++, Na+ and K+, but the
largest flux/driving force is for
Ca++/Na+ ions, leading to a net
depolarization - Two ACh molecules bind to the
two subunits, inducing a
conformational change that
opens the channel pore - Opening of nACh receptors
produces a graded potential
called end plate potential or
EPP
(slide 9!!)
From mini-EPP, to EPP, to AP:
– The change in Vm from one vesicle’s worth of ACh is called a
miniature end plate potential (mEPP)
* An EPP is due to the release of ACh from a large number of vesicles
– Each vesicle’s worth of ACh produces an mEPP and these sum
together to create the full EPP
* An action potential is due to the opening of voltage-gated Na+ and
K+ channels as nearby membrane, away from the motor end plate,
was brought to threshold by passive spread of an EPP
(slide 10!!)
ECc def:
refers to the sequence of events that link depolarization of the muscle
fiber membrane (sarcolemma) to the contraction of actin-myosin filaments located in
the cytoplasm (sarcoplasm)
Excitation-contraction coupling:
- Action potentials
propagate - L-type voltage-gated
calcium channels (called
dihydropyridine
receptors) open along T-
tubules - This triggers opening
of another Ca++ channel
(Ryanodine Receptors)
on the sarcoplasmic
reticulum, releasing Ca++
ions to the cytosol - Calcium binds
troponins, unmasking
myosin binding site on
actin filaments - SERCA pumps Ca++
ions back into SR
(slide 11)
muscle depolarisation = Ca2+ release from SR:
slide 12!!! + 13!!!
- DHP/Ryanodine complex = link the electrical signal to the contraction process
- DHP (Dihydropyridine Receptor): This is a voltage-sensitive receptor located on the T-tubule membrane. It responds to the change in voltage caused by the depolarization.
Ryanodine Receptor (RyR): This is a calcium channel located on the membrane of the sarcoplasmic reticulum (SR), an organelle that stores calcium within muscle cells.
Coupling Between DHP and Ryanodine:
When the DHP receptor senses the depolarization (change in voltage), it undergoes a conformational (shape) change.
The DHP receptor is physically coupled to the ryanodine receptor (RyR), and this mechanical change in the DHP receptor activates the ryanodine receptor, causing it to open.
after ryanodine opening + calcium channel process (+ to remember what it’s attached to and how it works)
When the ryanodine receptor opens, calcium ions (Ca++) stored in the sarcoplasmic reticulum are released into the cytoplasm of the muscle cell.
Calcium is crucial because it binds to troponin, a regulatory protein in muscle fibers, which then triggers a series of events that allow actin and myosin filaments to interact and generate contraction.
Depolarization triggers contraction:
slide 14!!!!
hypocalcemic tetany:
slide 15!!!
T-tubule depolarization triggers Ca++
release from sarcoplasmic reticulum
(coupled by DHP and RyR)
slide 16!!!
smooth muscle contraction = (speed)
slower than skeletal
(slide 17!!!!)
smooth muscle uses:
- myosin light chain kinase (MLCK) to activate contraction
- slide 19+20
muscle electrophysiology (skeletal VS smooth VS cardiac muscle):
- Skeletal muscle:
- No intrinsic activity
- End plate potential highly reliable (‘safety factor’)
- Fast-acting due to sarcomeres T-tubule excitation and
electromechanical coupling (DHP to ryanodine) - Smooth muscle:
- Intrinsic “slow wave” potential
- Slow due to lack of T-tubules and 2nd messenger
(calmodulin) of Ca2+ to myosin light chain kinase (MLCK) - Nitric Oxide (NO) relaxes contractions (via cGMP)
- Cardiac muscle:
- Intrinsic pacemaker potential
- Intermediate speed due to Ca2+-dependent Ca2+ release by
DHP/ryanodine receptors
Muscle Energetics: ATP for muscle contraction is generated from three sources:
- creatine phosphate
- glycolysis
- oxidative phosphorylation
(slide 23)
how many twitches does sarcoplasm retain ATP for?
Sarcoplasm retains enough ATP for ~8 twitches (myosin recycle + sarcoplasmic Ca2+ pumps)
crossbridge meaning:
Crossbridges in muscle contraction refer to the molecular connections formed between actin and myosin, the two main proteins involved in the contraction process within muscle fibers. This mechanism is central to the sliding filament theory, which explains how muscles contract on a microscopic level
single fibres tension, “all-or-none” principle:
The all–or–none principle
* As a whole, a muscle fibre is
either contracted or relaxed
* Tension of a Single Muscle
Fiber depends on:
– The number of pivoting
cross-bridges
– The fibre’s resting length
at the time of stimulation
– The frequency of
stimulation
single fibre tension, length-tension relationship:
- Number of pivoting cross-
bridges depends on:
– amount of overlap
between thick and thin
fibers - Optimum overlap
produces greatest amount
of tension:
– too much or too little
reduces efficiency - Normal resting sarcomere
length: 75% to 130% of
optimal length
skeletal muscle innervation:
- origin = spinal cord
- y’a 300 motor units
- Motor Unit: one motor
neuron and all muscle
fibers it innervates (~50
to 500 fibers) - !!The fewer the number of fibres
per neurone → the finer the
movement (more brain power)!! - tension = produced by whole skeletal muscle (slide 27)
motor units characteristics
- The smallest amount of
muscle that can be activated
voluntarily. - Gradation of force in skeletal
muscle is coordinated largely
by the nervous system - Recruitment of motor units
is the most important means
of controlling muscle tension - Since all fibers in the motor
unit contract simultaneously,
pressures for gene expression
(e.g. frequency of stimulation,
load) are identical in all fibers
of a motor unit
to increase motor units’s force:
To increase force:
1. Recruit more
M.U.s
2. Increase freq.
(force –frequency)
slow VS fast motor units (have fibres):
- Slow motor units contain slow fibers:
- Myosin with long cycle time and therefore uses ATP at a slow rate.
- Many mitochondria, so large capacity to replenish ATP.
- Economical maintenance of force during isometric contractions and efficient performance of repetitive slow isotonic contractions
- Fast motor units contain fast fibers:
- Myosin with rapid cycling rates.
- For higher power or when isometric force produced by slow motor units is insufficient.
- Type 2A fibers are fast and adapted for producing sustained power.
- Type 2X fibres are faster, but non-oxidative and fatigue rapidly.
- 2X/2D not 2B
non-oxidative fibre meaning:
A non-oxidative fibre refers to a type of muscle fiber that primarily generates energy through anaerobic pathways, meaning it does not rely on oxygen for its main energy production. Instead, these fibers produce energy quickly through processes like glycolysis, where glucose is broken down without the need for oxygen
increase VS decrease muscle use: (slide 30)
- Increase muscle use
– endurance training
– strength training
(cannot be optimally
trained for both strength
and endurance) - Decrease muscle use
– prolonged bed rest
– limb casting
– denervation
– space flight
Endurance training:
Little hypertrophy but major biochemical adaptations within muscle fibers.
Increased numbers of mitochondria; concentration and activities of oxidative
enzymes (e.g. succinate dehydrogenase, see below)
(slide 31!!)
Disuse causes autotrophy: (slide 31)
Individual fiber atrophy (loss of myofibrils) with no loss in fibers.
Effect more pronounced in Type II fibers.
“Completely reversible” (in young healthy individuals)
= prolonged bed rest
types of muscle contraction:
- Isotonic: muscle shortens and movement occurs (slide 34!!!)
- Isometric: muscle does not shorten but tension increases (slide 35!!)
Action potentials:
- Phases:
- Depolarization
- Inside plasma membrane
becomes less negative - Repolarization
- Return of resting
membrane potential - All-or-none principle
- Like camera flash system
- Propagate
- Spread from one location
to another - Frequency
- Number of action potential
produced per unit of time
(slide 36!!!)
Excitiation-contraction coupling:
- Increasing levels of calcium ion (Ca2+) will start muscle contraction.
Decreases will stop it. - Muscles at rest contain about 0.1 micromole per liter of calcium ion.
- Much greater concentrations of Ca2+ are stored in the SR.
Concentrations may be 10,000x that of cytosol in relaxed muscle
fiber. - As muscle action potentials propagate along the T tubules, calcium
ion release channels in the SR are caused to open. - When these channels are open, calcium ion flows into the cytosol of
the muscle fiber. - As a result of this, calcium ion concentrations rise 10x or greater.
- Calcium ions bond with troponin and cause it to change shape.
The troponin-tropomyosin complex moves a way from myosin-
bonding sites on actin. - This allows the myosin heads to bond with the actin, thus the
contraction cycle begins
when action potential causes
muscle fibre contraction, it involves:
- Sarcolemma
- Transverse or T tubules
- Terminal cisternae
- Sarcoplasmic reticulum
- Ca2+
- Troponin
(slide 38!!) + 39 !!!
Muscle twitch:
- Muscle contraction in
response to a
stimulus that causes
action potential in
one or more muscle
fibers - Phases
- Lag or latent
- Contraction
- Relaxation
(slide 40!!!!)
muscle length and tension:
- le + petit et le + grand = shortest tension (presque 5)
- le moyen = longest (presque 20)
(slide 41!!!)
Stimulus strength and muscle contraction:
- All-or-none law for muscle
fibers
- All-or-none law for muscle
- Contraction of equal force in
response to each action
potential - Sub-threshold stimulus
- Threshold stimulus
- Stronger than threshold
- Motor units
- Single motor neuron and all
muscle fibers innervated - Graded for whole muscles
- Strength of contractions range
from weak to strong depending
on stimulus strength
!!! * A whole muscle contracts with a small or large force depending on number of motor units stimulated to
contract !!! (slide 43!!!)
Multiple wave Summation: (how it works)
- As frequency of action
potentials increase, frequency of contraction increases - Action potentials come
close enough together so
that the muscle does not
have time to completely
relax between contractions
(slide 44!!)
Incomplete tetanus:
Muscle fibers partially relax between contraction
* There is time for Ca
2+ to be recycled through the SR
between action potentials
(slide 45!!)
Treppe:
(also known as the staircase effect, is a phenomenon in muscle contraction where a muscle, when stimulated repeatedly with the same strength and frequency, exhibits progressively stronger contractions over time, even though the stimuli are of equal intensity
- Graded response
* Occurs in muscle
rested for prolonged
period
* Each subsequent
contraction is stronger
than previous until all
equal after few stimuli
(slide 46!!)
muscle fatigue:
- Fatigue is inability to maintain desired power output.
- Occurs when rate of ATP utilization > rate of ATP synthesis. Drop in
sarcoplasmic pH due to lactate production contributes to fatigue (inhibits metabolic enzymes that produce ATP). Low glycogen levels also lead to fatigue
Endurance athletes “hit a wall” when muscle glycogen stores are depleted.
Why? + f endurance exercise utilizes blood-borne fatty acids (and some blood-borne glucose) how can depletion of muscle glycogen stores lead to fatigue?
(Muscle glycogen is critical for maintaining energy production, especially during prolonged, high-intensity exercise.
When glycogen is depleted, fatty acids become the main fuel, but they cannot supply energy fast enough to sustain the same level of performance.)
en plus glycogen = substrate in krebs cycle (aerobic metabolism), y a plus
muscle fatigue (how u need glycogen and pyruvate + process + cycle):
- Need for basal level of muscle
glycogen metabolism even when
blood glucose is available and fatty
acids are being oxidized. - Glucose metabolism provides
pyruvate. - Pyruvate→ OAA (pyruvate
carboxylase). Replenishes OAA to
maintain activity of TCA Cycle to
oxidize AcCoA from fatty acids.
Fats burn in the flame
of carbohydrates - Carbohydrate loading before
endurance exercise increases
muscle glycogen stores and
increases stamina.
(slide 48!!!)
Results of muscle fatigue:
- Depletion of metabolic reserves
- Damage to sarcolemma and sarcoplasmic reticulum
- Low pH (lactic acid)
- Muscle exhaustion and pain
Types of fatigue:
- Psychological
- Depends on emotional state of individual
- Muscular
- Results from ATP depletion
- Synaptic
- Occurs in neuromuscular junction due to lack of acetylcholine
(slide 52!!!!) (peripheral VS central fatigue + mechanisms proposed)
fatigue VS rigor mortis:
- Peripheral fatigue:
- When only ~30% of cellular ATP is depleted!
- Sufficient ATP to drive Ca++ transport
- However, [ADP]/[ATP] too high to drive cross-bridge
movement - Rigor mortis:
- Complete depletion of ATP (no metabolism!)
- No ATP also means no Ca2+ transport
- Cross-bridges cannot dissociate
- Occurs ~3 hours postmortem
- Persists up to 72 hours
slow and fast fibres:
- Slow-twitch or high-oxidative
- Contract more slowly, smaller in diameter, better blood
supply, more mitochondria, more fatigue-resistant than
fast-twitch - Fast-twitch or low-oxidative
- Respond rapidly to nervous stimulation, contain myosin
to break down ATP more rapidly, less blood supply,
fewer and smaller mitochondria than slow-twitch - Distribution of fast-twitch and slow twitch
- Most muscles have both but varies for each muscle
- Effects of exercise
- Hypertrophies: Increases in muscle size
- Atrophies: Decreases in muscle size
(!!Whole skeletal muscles are typically a mix of fast (oxidative and glycolytic) and slow (oxidative) fibres!!)
muscle fibre types compared:
56 !!!!! + 57!!!!!
Motor neurone activity determines muscle fibre type:
slide 60 !!!!
Muscle hypertrophy:
Muscle growth from heavy training
* Increases diameter of
muscle fibers
* Increases number of
myofibrils
* Increases mitochondria,
glycogen reserves
Effect of Exercise on Skeletal Muscle:
slide 62 !!!!
Glycogen Storage Diseases: Myopathies:
slide 63!!!! + 66!!!
* Inherited deficiencies in enzymes
involved in glycogen metabolism.
* Inherited as AR traits.
Mc Ardle:
= deficiency of muscle glycogen phosphorylase
- * Symptoms: muscle cramping, fatigue, myalgia and myoglobinuria with strenuous exercise. Patients experience severe muscle cramping several minutes after the onset of exercise due to inability to access glycogen stores. No increase
in lactate with exercise (reduced rate of
glycolysis)
- After a brief period of recovery, patients experience “second wind” phenomenon (improved exercise tolerance)→ due to the usage of alternate substrates (blood-
borne glucose and fatty acids) and
oxidative metabolism
- Second wind is characteristic of Mc
Ardle
(slide 65)
lack of muscle activity:
- Reduces muscle size, tone, and
power
Myasthenic diseases:
Myasthenia Gravis: autoimmune
suppression of post-synaptic
nicotinic ACh receptors (ionophores)
Classic treatment is
pharmacological inhibition of ACh
esterase
Lambert-Eaton Syndrome:
Autoimmune attack on presynaptic
V-gated channels for Ca++ (blocks
vesicle (ACh) exocytosis)
Other: Many other diseases
involving ion channels and
receptors localized to NM junction
slide 68
Neuromuscular diseases: Amyotrophic Lateral Sclerosis
- Degenerative motorneuron diseases with
associate effects on muscle atrophy. Various
forms - ~10% of cases from genetic origin, rest
unknown possibly environmental - Frequency ~5/105
(slide 69!!!)
muscular dystrophy?
A group of genetic diseases that cause progressive
weakness and degeneration of skeletal muscles.
These disorders (of which there are more than 30) vary in
age of onset, severity, and the pattern of the affected
muscles.
All forms of MD grow worse over time as muscles
progressively degenerate and weaken. Many people with
MD eventually lose the ability to walk.
Some types of MD also affect the heart, lungs,
gastrointestinal system, endocrine glands, spine, eyes,
brain, or other organs. Some people with MD may develop a
swallowing disorder. MD is not contagious and cannot be
caused by injury or activity
(slide 73)
continuation of dystrophies:
Progressive myopathy: elements
of cytoskeletal and/or extracellular
matrix degeneration => muscle
weakness
Genetic disease (>30 variants); X-
linked recessive e.g., Duchene’s
MD caused by unexpressed gene
for dystrophin protein; Beckers
Dystrophy less severe (Dystrophin
partially functional)
Associated with reduced local vasodilation reflex. Enzyme for
NO generation (nNOS) dislodges from dystrophin-less
sarcoglycan scaffolding. Lack of NO to relax vasoconstriction
=> ischemia and further muscle degeneration
(slide 74!!)
Glycogen storage diseases:
slide 75!!!!
