Muscle structure and pathology Flashcards
Describe what skeletal muscle is at a cellular level and what it is used for.
Made up of cylindrical multi-nucleated cells
Striated
CM’s in length
Limited regeneration
Involved in voluntary control
Describe what cardiac muscle is at a cellular level and what it is used for.
Made up of branched cells with intercallated disks
Cells can be mono/binucleated
Striated muscle
Length = 100um
No regeneration
Involved in spontaneous contraction
Describe what smooth muscle is at a cellular level and what it is used for.
Spindle shaped cells with a central nucleus
Length = 20-200um
Cells can regenerate
Found in vessels, hollow organs and glands
Regulated by the ANS and endocrine system
What is the layer covering skeletal muscle called?
Epimysium
Dense collagenous layer
How is skeletal muscle organised?
Epimysium covers muscle (tough dense connective sheath)
Groups of muscle fascicles form a muscle
Fascicles are bound in collagenous perimysium
Muscle fibres are bundled together to form muscle fascicles
The cell membrane of a muscle fibre is called the sarcolemma
Individual muscle fibres are bound in endomysium (this is where capillaries and nerve fibres are found)
Myofibrils are bound together to form these individual muscle fibres
Myofibrils are formed from arrangements of myofilaments (actin and myosin)
Myofilaments are the contractive element of muscle
What does type 1 muscle fibre do?
How is it adapted for this function?
(Slow twitch)
Long distance running
Slow contraction
Fatigue resistant
Lots of mitochondria
Aerobic, slow oxidative respiration
What does type 2a muscle fibre do?
How is it adapted for this function?
Intermediate contraction, neither slow or fast
Normal rate of fatigue
Lots of mitochondria
Aerobic and anaerobic respiration
Fast oxidative respiration
What does type 2b muscle fibre do?
How is it adapted for this function?
(Fast twitch)
Sprinting
Fast poweful contraction
Rapidly fatigued
Few mitochondria
Anaeobic respiration
What is a motor unit?
The motor neurone and muscle it innervates
Each nerve is innervated by only one motor neuron, but one motor neuron may innervate multiple muscle fibres
Muscles used for fine motor movement will have 1 motor unit, eg. facial expression whereas large powerful muscles eg. quads will have a large number of motor units
What is the site of the motor neuron synapse with the muscle fibre?
Neuromuscular Junction
What are the stages of transmission at the Neuromuscular junction?
- Action potential arrives and depolarises the pre-synatptic memebrane of the motor neurone
- This triggers opening of voltage-gaited calcium channels
- Calcium moves into the pre-synaptic terminal down its electrochemical gradient
- Vesicles containing Ach move to the presynaptic membrane and fuse with the membrane
- Ach is released into the synaptic cleft by exocytosis and diffuses across the synaptic cleft
- Ach binds to nicotinic Ach recceptors (ligand gaited ion channels) on the post synaptic membrane
- This induces conformational change in Ach receptors allowing Na+ in and K+ out of the post-synaptic membrane
- The post-synaptic membrane depolarises to reach the ‘end plate potential’ causing opening of voltage gaited Na channels
- This causes propagation of a action potential in the muscle
- Ach dissociates from the nicotinic receptors and is broken down by acetylcholinesterase in the synaptic cleft and its products are recycled
What is Myasthenia Gravis?
Occurs when a person has autoantibodies against nicotinic Ach receptors on the post-synaptic membrane
Meaning Ach can’t bind and cause a conformational change in the ligand-gaited ion channels –> no sodium entry –> no membrane depolarisation –> no muscle action potential
Results in fatiguability of muscles
Commonly affects extraocular muscles, facial muscles and bulbar muscles
How would you treat Myasthenia Gravis?
Acetycholinesterase inhibitors
Neostigmine
What effects does the botulinum toxin have?
Degrades the SNARE protien
Blocks acetylcholine release from pre-synaptic terminals
Results in a total blockage at the neuromuscular junction
Presents as flaccid paralysis and paralysis of respiratory muscles
Botox/neuropathic pain/excessive sweating
What are myofilaments?
Myofilaments are protiens arranged in a highly organised way to enable contraction
Consists of thick myosin and thin actin
Myofilaments are arranged to form myofibrils which in turn for muscle fibres
The basic contratcile unit of a myofilament is called a sarcomere (from Z disk to Z disk)
What are the different components of the sarcomere?
A band
In centre of the sarcomere.
Mainly thick myosin filament (some overlapping thin)
Appears dark under a light microscope
I bands (x2)
Located either side of the A band
Thin actin filaments only
Appears light under a light microscope
Z disks (x2)
Boundries of the sarcomere
Run down the middle of each I band
This is the point where thin actin fibres form adjacent sarcomeres join
H zone
Area in the centre of the A band where there are only thick myosin filaments (no overlapping)
M line
In the middle of the H zone
Point where the thick myosin filaments meet and connect with teh cell membrane
Describe the structure of thick myosin filaments at a celluar level
Consists of heads and a tail
Heads contrain light chains and heavy chains
Tail is made of heavy chains
Heads of myosin molecule contains an actin binding site. This allows formation of cross bridges between actin and myosin and an ATPase site
Describe the structure of thin filaments at a cellular level
Composed of 3 protiens:
Actin, tropomyosin, troponin
Actin
Alpha helical structure
Myosin binding sites which are covered at rest by tropomyosin
Tropomyosin
Filamentous protien that runs along teh groove of each twisted actin filament
(Wraps itself around the actin chain)
What is excitation-contraction coupling?
Name given to the mechanism that translates a muscle action potential into muscle contratcion
Outline the steps in excitation-contraction coupling
- Depolarisation of the muscle fibre membrane
- Action potential is propagated to the T-tubules –> carrying a wave of depolarisation to the interior of the muscle fibre
- Depolarisation of T tubules causes a conformational change in their voltage-gated dihydropyridine receptors
- These receptors are in mechanical contact with ryanodine receptors of the sarcoplasmic reticulum.
- Conformational change in the dihydropyridine receptors causes a conformational change in the ryanodine receptors which open to release calcium from storage in the sarcoplasmic reticulum into the intracellular fluid of the muscle fibre, increasing the intracellular calcium concentration
- Calcium binds to troponin C on thin filaments, inducing a conformational change in the troponin complex which moves the tropomyosin molecule, exposing the myosin-binding site of the actin molecule
- Cross-bridges are formed between the actin molecule and myosin heads
What is the sliding filament theory?
Is the mechanism of contraction of muscle
Caused by thick and thin filaments sliding over each other.
Thick myosin filaments are anchored at the M line in the centre of the sarcomere and the thin filaments (actin, tropomyosin and troponin) are anchored at the Z line at the outer ridge of the sarcomeres
Outline the steps in cross bridge cycling
- Binding of calcium to troponin C displaces tropomyosin and allows myosin heads to bind to actin forming cross-bridges.
- Initially the myosin head is bound tightly to actin in the rigor position. ATP is required to reduce the affinity of myosin for actin and allow to move
- If ATP is absent then this binding is permanent resulting in rigor mortis.
- ATP binds to the myosin head and induces a conformational change, reducing the affinity of the myosin head for actin.
- The myosin head releases actin.
- ATP is hydrolysed to ADP and inorganic Phosphate (Pi) by ATPase which initially both remain bound to the myosin head.
- The release of energy from the hydrolysis of ATP changes the conformational state of the myosin head further. The myosin head is cocked/bent into a high energy position. It is like a spring which has been loaded.
- The myosin head binds to actin at a point further along from its original binding site.
- Phosphate is released from the myosin head and the myosin head springs back into it’s original position and pushes the actin molecule towards the M-line.
- The thick and thin filaments slide over each other, shortening the sarcomere. This is called the power stroke.
- ADP is released and the myosin head binds tightly to the actin again (rigor position). As long as ATP is available and calcium remains bound to troponin C, the cross-bridge cycling will continue and the myosin will walk along the actin filament.
- Remember that there are multiple myosin heads bound to an actin filament during this cycle.
What happens in order to terminate cross bridge cycling?
Fall in intracellular calcium concentration to a level where it is insufficent for it to bind to troponin C
Calcium is released from troponin C and tropomyosin returns to its resting position, blocking the myosin head binding site
Calcium is taken up into the sarcoplasmic reticulum by sarcoendoplasmic reticulum calcium ATPase (SERCA)
What is Duchenne Muscular Dystrophy?
DMD is caused by an absence of dystrophin, a protein that helps keepmuscle cells intact.
Dystrophin links the cytoskeleton with the ECM
This results in necrosis and destruction of muscle fibres which are then replaced with adipose and connective tissue
Progressive muscle degeneration and waisting results in Gowers sign
Inherited X linked genetic disorder - early onset (3-4yo) and rapid progression
What is Beckers Muscular Dystrophy?
Similar to DMD, but with millder symptoms and slower progression
X linked geneticd disorder
Causes a reduction in the amount of dystrophin
Presents later in childhood or adolescence
What is polymyositis?
Autoimmune inflamatory disorder that affects skeleteal muscle
Causes inflamatory cell infiltration and muscle firbre necrosis
Treatment = steroids +/- immunosuppressants
Characteristic features:
Proximal sysmetrical muscle weakness and waisting
Dysphagia, dysphonia, respiritory muscle weakness and cardiac involvemnt
General malaise, weight loss and fever in the acute phase
How does Polymyositis differ from Dermatomyositis?
Dermatomyositis had al teh features os polymyositis plus skin chnages
Typically affects muscle and skin, but can also affect joints, oesophagus, lungs and heart
Can be part of paraneoplastic syndrome
