5. Physiology of muscle contraction Flashcards
How does troponin unmask the myosin binding site on actin?
4 Ca2+ bind to troponin C (C = calcium binding),
In heart TnC only binds to 3 Ca2+ ions
TnC changes conformation
conformational change in TnC “shuts off” TnI
tropomyosin-troponin leaves F-actin groove
unmasks the myosin binding site on actin
What happens after actin’s myosin binding site is exposed?
next myosin heads make cross bridges (cycling) to actin
Myosin breaks down ATP
Myosin pulls thin filaments
What is TnI a marker for?
Total TnI = marker for total muscle breakdown
Cardiac TnI = marker for myocardial infarct
What is cross bridge cycling?
Molecular cycle of actin-myosin interaction
Mechanism of Contraction at Molecular level
What does contraction depend on?
contraction depends on binding of myosin heads to thin filaments (actin) at specific binding sites
What stops contraction when the sarcomere is at rest?
in resting state of sarcomere, myosin heads are blocked from binding to actin by tropomyosin, which occupies the specific binding sites (in F-actin double helical groove)
Force generation vs sarcomere length
Increasing overlap thin and thick filaments -> increased force UP TO the optimal length
Greatest force generation occurs when sarcomere is at optimal length
When sarcomere is really small, everything overlaps so get no force at all
BUT if stretch sarcomere really far, then myosin heads don’t overlap with any actin so can’t generate any force
Cross bridge cycle reactions
- Myosin releases actin
- Myosin head cleaves ATP
- Myosin binds actin
- Power stroke
Creatine
creatine found in muscle fibres
phosphorylated to creatine phosphate
Stored in muscle as creatine phosphate
What role does creatine have in cross bridge cycling?
keeps ATP levels stable (buffering and regenerating it)
when ATP is hydrolysed to ADP and Pi, creatine phosphate donates a high energy phosphate to ADP, restoring it to ATP
What enzymes catalyse ATP to ADP + Pi with creatine phosphate?
the reaction is catalysed in both directions by the enzyme creatine phosphokinase (a/k/a CK, CPK)
Is creatinine and creatine the same?
No!
Creatine is a small molecule that can accept high energy phosphate bonds from ATP
Creatine-phosphate is the above molecule after phosphate has been added to it
Creatine-phosphokinase (CPK) is the enzyme the adds phosphate to creatine
This is a plasma marker of muscle destruction
It is a large molecule detected by antibodies
Creatine-kinase (CK) is just another name for creatine phosphokinase (above). They are the same thing.
Creatinine is a diagnostic marker of kidney function. It is a breakdown product of creatine.
What triggers contraction?
Calcium triggers contraction
Calcium gradients in contraction
There are two Ca2+ gradients
Extracellular vs. cytosolic free Ca2+
SR vs. cytosolic free Ca2+
efflux of Ca2+ from sarcoplasmic reticulum to cytoplasm provides most of calcium
Calcium entering cell from outside provides only small fraction of calcium needed for contraction
What does depolarisation lead to?
Increase in Ca2+
Depolarisation
ACh -> Depolarisation
Active Nicotinic AChR -> net inward current
depolarisation spreads via T-Tubules
Local action potentials trigger Ca2+ efflux from terminal cisternae
->
Across membrane of sarcoplasmic reticulum
->
into the fibre cytoplasm
Excitation contraction (EC) coupling
the molecular mechanism for how the depolarisation of the plasma membrane leads to the release of Ca2+ into the cytoplasm followed by contraction.
Ryanodine receptor (RyR) aka Ca2+ release channel
In SR membrane
Releases Ca2+
From SR
Triggered by voltage sensor on Ca2+ channel
SERCA
In SR membrane
Pumps Ca2+ Back into SR
Needs ATP
What is the molecular basis of tetany?
A single AP -> Ca2+ release from SR -> twitch
Ca2+ ions are rapidly pumped back into SR -> end of twitch
Frequent APs -> insufficient Ca2+ resequestration -> summation of contraction
What are muscle fibres divided into?
Slow twitch (type I, red)
Fast twitch (type II, white)
Slow twitch fibres
oxidative, small diameter
high myoglobin, many mitochondria
Fast twitch fibres
nonoxidative, wide diameter
lower myoglobin, more energy from glycolysis
How do fibre types differ?
aerobic (slow) vs anaerobic
faster calcium re-uptake (fast)
maximum tension produced (fast)
fatigue resistance (slow)
Distribution of fibre types
muscles contain mixtures of fibre types
composition depends on muscle action:
soleus = 80% type I (slow), 20% type IIA
vastus lateralis = mixture of type I, IIA, IIX
Proportions of fibre types depend on what?
proportions depend on physical fitness: inactive moderately active endurance athlete anaerobic athlete
Types of coordination of muscle contraction
3 types of co-ordination
Motor Units
Recruitment & size principle
Tetany
Fusion of myocytes into long myofibres
Motor units
Definition:
A single alpha motor neuron and all muscle fibres it innervates.
Functions as a single contractile unit of skeletal muscle
all muscle fibres in a single motor unit are of the same type
(e.g. slow oxidative, fast oxidative, fast glycolytic).
Motor units: variety
in large muscles responsible for powerful gross contractions, a single motor neuron may synapse on 1000 fibres
in small muscles mediating precision movement a single motor neuron may synapse with as few as 2 – 3 muscle fibres
type and function of the lower motor neuron determines the muscle fibre,
There are different sorts of motor units in a single muscle
What determines type of muscle fibre?
type and function of the lower motor neuron determines the muscle fibre
Contraction: force generation
isometric – generates a variable force while length of muscle remains unchanged.
“Iso” = same, “metric” = length
isotonic – generates a constant force while the length of the muscle changes
“tonic” = tone = tension/force
What types of force generation are used when picking up a drinking glass?
stage 1: isometric – force increases, joint does not move
Muscle Force < force of gravity –> force increases
biceps and brachioradialis generate force by isometric contraction as muscles have not yet shortened
stage 2: isotonic – force remains the same, arm moves
Glass moves upward in response to force
an isotonic contraction starts as the force generated by the muscles overcomes gravitational and inertial forces keeping glass on the table
glass starts to rise as the muscles shorten and the elbow bends and force generated by the muscle is constant as the glass is moving
Types of muscular force generation
Muscle contraction ≠ (necessarily) muscle shortening
Concentric – force during contraction – tossing a ball into air
Eccentric (negatives) – force during muscle elongation
e.g. when “braking” or when the weight of the object is overwhelming – catching a ball
both types of force generation can occur in one behaviour
Proprioception controls force gen. based on length and stretch
Size principle
as the initial isometric contraction occurs:
more and more motor units are recruited starting with smaller ones and progressively adding larger ones
Allows fine gradation of force for small movements
In drinking glass example:
more and bigger motor units recruited until the glass starts moving and the contraction becomes isotonic
Upper vs lower motor neuron disease
Lower motor neuron disease
Weakness
Muscle atrophy
Upper motor neurone disease
Spasticity, hypertonia
Stretch reflex
Controls Muscle Length
Increases Muscle Force
Lack of patellar reflex = Westphal’s sign
What are intrafusal and extrafusal fibres?
Can shorten muscle when it is too long for current neural drive
Sensory = Intrafusal fibres (inside sheath)
Contraction: extrafusal fibres
An example of stretch reflex?
Patellar reflex
function: posture and balance
Stretch reflex: patellar
Sensory = Muscle Spindle Fibre
Detects Stretch
i.e. Length (NOT FORCE)
Proprioception
Spindle is Parallel to other muscle fibres
Ipsilateral Spinal reflex
Monosynaptic
Muscle spindle
A spindle consists of 3-12 intrafusal fibres
Gamma motor neurons increase sensitivity
Drive contraction of edge of intrafusal fibres
Sensors from muscle spindle are:
Called Type 1a and Type 2
Wrap around the intrafusal fibres
Detect stretch (ie length) of central non-contracting region using stretch receptors
Spindle is like a thermostat that regulates the relationship between muscle length and muscle contractility
ie the relationship between neural drive and force generation
Absence of muscle spindle reflex
Absence of this reflex = Westphal’s Sign Receptor damage Femoral nerve damage Peripheral nerve disease e.g. Peripheral Neuropathy
What can happen in upper motor neurone disease?
In upper motor neuron disease
Can lead to hypertonia and spasticity
UMN inhibits normal descending inhibitory input to spinal interneurons
The spindle reflex becomes over-sensitive
Can attempt to contract muscle all the time
Tendon reflex
Protects from overloading
Decreases Muscle Force -> dropping the load
Sensor firing -> decreased contraction
Tendon reflex pathway
Sensor to Spinal Cord
Interneuron to motor neuron
Motor neuron inhibited
Motor neuron to muscle
Tendon reflex organ
Sensor = Golgi Tendon Organ Detects Tension In series with muscle In tendon Near border with muscle
What type of reflex is the tendon reflex?
Disynaptic
Ipsilateral Spinal reflex
