W7 - Physiology & Pathophysiology of skeletal muscle contraction Flashcards
How are skeletal muscles organised?
Skeletal muscles exist in Group of bundles (fascicle) with a sheath called epimysium. Each fascicle consist of numerous skeletal muscle cells. And each of the bundles have a perimysium (external sheath), endomysium (internal structure). Within the muscle bundles are the skeletal muscle cells - muscle fibres.
Muscle fibre originates from differentiation of a myofibroblast into a muscle fibre.
A single muscle fibre has multiple nuclei as many cells fuse together to create a long skeletal muscle cell. It has a membrane - sarcolema, lots of mitochondria, and contractile proteins are arranged in units.
One cell -> bundle of cells -> fascicles
These are connected to bones to allow locomotion.
How are skeletal muscle cells organised?
Looking at one skeletal muscle cell, the arrangement of contractile proteins within the cells.Sarcomere is the functional unit of skeletal muscle contractions.
In a transverse place, you can see that Thick filaments - Skeletal muscle myosin, is surrounnded by thinner filaments - actin. The overlap of the thin and thick filaments give the striated pattern. Area of little overlap = I band, defracts light far less than A band, where there is considerable overlap.
The sarcoplasmic reticulum is also an organelle lies closely opposed to the contractile proteins. It is an endoplasmic reticulum modified to store calcium.
What are the thin and thick filaments?
There is a thin filament made of a helix of filamentous a-actin. This actin is then structurally constrained by an interaction with a Z disk, made of a-actinin.
troponin - has a calcium binding domain.
tropomyosin
Thick filaments are mainly made of globular protein myosin.
Myosin tail
Myosin Head (ATPase) - can break down ATP to create phosphate, phosphorylated myosin - high energy state and can release phosphate.
Hinge structure = flex
Head = allows myosin protein to hydrolyse ATP and energise structural changes.
Troponin-C = Calcium binding
Troponin-T = tropomyosin binding
Actin is pulled along myosin with the rise in calcium, shortening the sarcomere length pulling the muscle together. Large complex between protein dystrophin and peptidoglycan on the cell membrane stabilises the cell membrane as this process occurs linking the actin to cell membrane. This shows other structures aid the process.
How do muscles contract?
Contraction is the
interaction of actin & myosin
-fuelled by ATP
-driven by a rise in [Ca2+]
How is the interaction between actin and myosin allowed?
->Membrane events
-> Rise in calcium
->Binding to sensor
-> Contractile Mechanism or ATP hydrolysis by myosin
->Actin – myosin interaction
->Cell shortens
ATP hydrolysis by myosin puts myosin into a structural shape that allows it to move actin, but it cannot interact with actin.
Membrane events like activation of receptors leading to opening of sodium channels and a wave of activity moving throughout cycle and through structures known as transverse tube systems (T-tubule system) leading to release of Ca+ from stores. This then binds to a calcium sensor, Troponin, allowing the interaction between actin and myosin.
How do actin and myosin move?
Binding - Myosin cross bridge binds to actin molecule.
Power stroke - Cross bridge bends, pulling thin myofilament inwards
Detachment - Cross bridge detaches at end of power stroke and returns to original conformation.
Binding - Cross bridge binds to more distal actin molecule, cycle repeats.
Normally, the actin site is blocked by tropomyosin, but is removed when binding with calcium. Upon binding to actin, you get a release of ATP and the myosin molecule kinks forward. It then detaches from actin and the shape changes again. Then reattaches and gets a power stroke. This is cyclic. Happens about 15 times a second.
What is the contractile cycle?
There is a priming of myosin molecule. This happens when ATP binds to myosin and gets hydrolysed. This is now a high energy form of myosin - ADP bound and phosphate released. The interaction then occurs and the phosphate is released. The power stroke then means myosin moves forward as ADP is released. And the actin molecule moves in the same direction as it’s pushed. This leaves myosin at a low energy configuration - structurally different state.
This then detaches from actin so that we can have another movement of the active molecule. It detaches because of ATP binding, reducing the affinity of myosin for actin and causes the myosin to detach. It can now attach to a different myosin binding site on the actin filament.
What causes the rise in calcium?
Anatomy of a skeletal muscle fibre (cell):
Sarcoplasmic reticulum lies around contractile protein.
The transverse tubule network - it in an invagination of the membrane. It folds in taking the membrane and everything on it deep into the cell ready to interact with sarcolemma organelles.
T tubules have a voltage sensitive dihydropyridine receptor closely linked to the SR. When we get a wave of depolarisation, this receptor moves away from the T-tubule release channels and we get a lot of calcium being released. The calcium then binds to troponin and the troponin pulls the tropomyosin away, allowing the actin myosin interaction.
What is the whole neuronal process to reach the contractility point?
1) Activation of motor neurones starting at axon, you get opening of voltage sodium channels and influx of sodium into the nerve, which causes charge repulsion and spreads electronically the depolarisation of the axon.
2) Axons are myelinated and this stops the dissipation of the charge spread to go much further. Nodes of Ranvier boosts that signal.
3) In the nerve terminal, there is a lot of acetylcholine stored in synaptic vesicles.
4) The depolarisation due to Na+ opening causes calcium channels to open and you get an influx of calcium. This causes the fusion of synaptic vesicles with the membrane. This is because of the interaction of two SNARE proteins in the vesicle and either Syntaxin 1 or SNAP 25 in the cell terminal. It comes together to drag the vesicle to the membrane fusion of the two vesicle membranes and the cell membrane causes the contents to be deposited.
This acetylcholine diffuse a very short distance because we have a lot of nicotinic acetylecholine receptors closely opposed to the nerve (ligand-gated ion channel receptors). This causes a small influx of Na+ and Ca+ that produces an excitatory junction potential - sufficient to take membrane potential to a threshold where sodium channels are open. This depolarisation zooms down the T-tubule section and the dihydropyridine gets pulled away allowing the sarcoplasmic reticulum to release lots of calcium. This goes onto the chain reaction of binding to troponin, which releases tropomyosin to enable interaction between high energy myosin and actin filaments.
What happens if something goes wrong?
Multiple sclerosis
Myaesthesia gravis
Non-dystrophic myotonias
Muscular dystrophy
What is multiple sclerosis?
CNS = oligodendrocytes wrap round axon
Immune attack of myelin
Leaky blood brain barrier
Sclerotic lesions
-Numbness
-Tingling
-Speech problems
-Visual problems - blurred or double vision
-Debilitating muscle weakness
The peripheral nervous system is created by a Schwann cell wrapping around, the axon. It insulates the axon and allows the neuronal signals to be fast. Myelin is white - that’s why there’s white matter in the brain.
The sheath stops dissipation, so the depolarisation excitation can spread further and the voltage gated Na+ channels boost the signal accumulating at the Nodes of Ranvier. This enables very fast reactions.
In multiple sclerosis, the myelin gets damaged. It is seen as an immune attack of the myelin. This is associated with the blood brain barrier becoming weak enabling the infiltration of WBCs into the brain. Cause is debatable. The symptoms can be persistent or it can be cycles of having it or not.
What is Myaesthesia Gravis?
Progressive loss of nicotinic acetylcholine receptor
Auto-immune
Targeting the a-1 subunit, which gets degraded.
-> Nicotinic acetylecholine receptors are made up of 5 proteins that makes up an ion channel. This open when two molecules of acetylcholine binds. Made up of two alpha-1, beta-1 and one gamma, delta and depending on if it’s an adult or embryonic smooth muscle, epsilon. Other nicotinic acetylcholine receptors found predominantly in the autonomic ganglia, mostly made up of combinations of alpha2 and beta2, so no alpha-1 to target.
Here the transmission deficit is at the neuromuscular junction where there is a progressive loss of nicotinic acetylecholine receptors that responds to the acetylcholine released from motor nerves.
Causes are unknown.
In early stages, the loss of the nicotinic acetylcholine receptors can be overcome to an extent by boosting the level of acetylcholine through inhibition of the choline esterases that break it down. But once there is degredation of the receptor, you lose a lot of transmission.
What are the different forms of Myasthesia Gravis?
- Distruption of the morphology of the muscle membrane, so the receptors are less concentrated.
- Antibody binding getting complement activation causing destruction of the morphology of the membrane.
- Modulation of the receptors leading to internalisation.
- Antibodies can block the acetylcholine from interaction to the binding site.
This disease mimics botulism, which binds to cholinergic neurones, but stops the fusion of acetylcholine vesicles with the membrane. In botox, there is less acetylcholine being released, but the receptors are ok, in the disease, there is less receptors to interact with.
At early stages, some symptoms can be overcome with choline esterase inhibitors by boosting the level of acetylcholine.
What is non-dystrophic myotonias?
Features:
Delayed relaxation of the muscle after voluntary
contraction or mechanical stimulation.
Electrophysiologically characterized by highly
organized repetitive electrical activity of the
muscle fibres
Five different skeletal muscle disorders are caused by mutations to
the SCN4A gene: - these genes encode for a voltage gated sodium channel
Potassium-aggravated myotonia (PAM), - like you get from increased exercise because of a lot of potassium leaking out from the skeletal muscle aggrevating the underlying disorder.
Paramyotonia congenita (PMC)
Hyperkalemic periodic paralysis (HyperPP),
Hypokalemic periodic paralysis (HypoPP),
A form of congenital myasthenic syndrome (CMS)
These are all linked to the sodium channel being affected in some way.
What are the mechanisms behind non-dystropic myotonias?
In most cases, mutations cause:
decreased rate of channel inactivation
increased rate of recovery from inactivation
OR
slower channel deactivation
More Na channel activity -> Prolonged contraction
They open and very quickly inactivity. This means they don’t pass sodium very quickly. It shows there is a lot more sodium influx, leading to prolonged contraction.
Some examples are due to loss of Cl channel (CLC-1)
Less Cl channel activity
-> Prolonged contraction
