Muscle Physiology & Pathology

Question 1

How does the microscopic appearance of skeletal, smooth and cardiac muscle differ?

Answer 1

Skeletal and Cardiac muscle cells are striated
Skeletal - cylindrical in shape
Cardiac - branched cells with intercalated discs
Smooth - spindle shaped
Smooth muscle cells can regenerate, whereas this is limited/not present in skeletal or cardiac cells

Skeletal muscle under voluntary control
Cardiac muscle spontaneously controlled
Smooth muscle controlled by ANS/Endocrine system

Question 2

How is skeletal muscle organised?

Answer 2

Myofilaments make up Myofibrils
Many Myofibrils make up Muscle Fibre (endomysium)
Muscle fibres make up Muscle Fascicle, bound by perimysium and arranged to form skeletal muscle, bound by epimysium

Question 3

What are the 3 different types of muscle fibre?

Answer 3

Type 1 slow twitch (aerobic respiration so lots of mitochondria for slow contraction, eg long run)
Type 2a (aerobic and anaerobic respiration)
Type 2b fast twitch (anaerobic respiration for fast, powerful contraction which fatigues quickly)

Question 4

What’s a motor unit?

Answer 4

Single alpha motor neurone and the muscle fibres it innervates
(each nerve fibre is innervated by only one motor neurone; but motor neurones can innervate many muscle fibres)

Question 5

Outline what happens at the NMJ?

Answer 5

1) AP arrives in presynaptic membrane of motor neurone
2) Voltage gated Ca2+ channels open: Ca2+ moves in down its electrochemical gradient
3) Vesicles containing ACh move to membrane, fuse and release into synaptic cleft by exocytosis
4) ACh diffuses across the cleft and binds to nAChR on motor end plate
5) nAChR are ligand-gated channels: binding causes conformational change allowing Na+ to move into the motor end plate as K+ leaves, motor end plate potential reached as it depolarises
6) EPP causes adjacent membrane to depolarise to voltage gated Na+ channels open and AP propagates down muscle fibre
7) ACh binds briefly, broken down in cleft by AChE and recycled in presynaptic terminal

Question 6

How does NMJ differ from normal synapse?

Answer 6

Between presynaptic and postsynaptic neurone rather than presynaptic neurone and muscle fibre end plate

In a synapse any NT can be released, NMJ relies on ACh

Question 7

Outline Myasthenia Gravis

Answer 7

Autoantibodies against nAChR on postsynaptic membrane = skeletal muscle weakness and fatiguability
Commonly affects extraocular muscles
Treated with AChE inhibitors (Neostigmine)

Question 8

How does Botulinum Toxin result in flaccid paralysis?

Answer 8

Produced by Clostridium Botulinium

Degrades SNARE protein complex (mediates vesicle movement) so blocks ACh release from presynaptic terminals to totally block NMJ
= flaccid paralysis (of respiratory muscles)

Question 9

What are myofilaments composed of?

Answer 9

Thick Myosin and think Actin myofilaments

Question 10

Basic contractile unit of muscle fibre is a sarcomere - what are the different components?

Answer 10

I band - thin Actin filament
Z lines in the middle of each I band
Between 2 Z lines = sarcomere
A band - in the centre of the sarcomere: thick and thin filaments overlap
H zone - only thick Myosin filaments
M line - where thick filaments meet and connect with cell membrane

Question 11

What are the 3 proteins thin filaments are made up of?

Answer 11

Actin
Tropomyosin
Troponin

Question 12

What 2 binding sites do Myosin heads have and for what purpose?

Answer 12

ATPase and Actin binding sites

For cross-bridge formation to allow filaments to slide over one another to contract

Question 13

What are the Myosin head binding sites on Actin filaments covered by at rest?

Answer 13

Tropomyosin - needs to move out of the way for cross-bridge formation and contraction process

Question 14

Outline the first stages of excitation-contraction coupling until intracellular Ca2+ rises

Answer 14

Depolarisation of sarcolemma
AP propagates down T-Tubules
T-Tubule depolarisation = conformational change in Dihydropyridine receptors -> conformational change in Ryanodine receptors
RR in close contact with SR so SR Ca2+ storage released to cause a rise in intracellular Ca2+

Question 15

In excitation-contraction coupling, outline what happens once intracellular Ca2+ rises

Answer 15

Intracellular Ca2+ concentration rises as it’s released from SR storage
Ca2+ binds to Troponin C on thin filament
Conformational change causes Tropomyosin to move and expose the Myosin head binding site on Actin
Cross bridges are formed between Myosin head and Actin

Question 16

How many Ca2+ molecules can Troponin C bind? What’s the relevance of this?

Answer 16

4 Ca2+ binding sites on each Troponin C molecule
Cooperative binding = binding of one Ca2+ molecule increases the affinity of Troponin C for Ca2+ so small intracellular changes increase the likelihood of Ca2+ binding to all 4 sites and inducing the conformational change necessary for Tropomyosin to move

Question 17

What’s the sliding filament theory of muscle contraction?

Answer 17

Thick and thin myofilaments slide over one another

Question 18

Where are the thick myosin and thin actin filaments anchored within the sarcomere?

Answer 18

Myosin at the M line

Actin at the Z line

Question 19

What are the steps of cross-bridge cycling?

Answer 19

Ca2+ binding to Troponin C allows Myosin head to bind to Actin by moving Tropomyosin out of the way
Initially Myosin and Acting bound together tightly (rigor)
ATP binds to Myosin head to reduce affinity
ATP hydrolysed and energy released causes Myosin head to bend in high energy position
Myosin rebinds to Actin further along original binding site
= Myosin walks along Actin filament

Question 20

What happens to form the power stroke in cross bridge cycling?

Answer 20

ATP hydrolysed -> ADP + Pi by ATPase = myosin head bent in high energy position
Pi released and Myosin springs back to original position, pushing Actin towards the M line = thick and thin filaments slide over each other - ‘power stroke’

Question 21

What terminates contraction?

Answer 21

Fall in intracellular Ca2+
Ca2+ no longer bound to Tropomyosin so recovers Myosin binding site on Actin
Ca2+ taken back up into SR by SERCA

Question 22

Outline Duchenne Muscular Dystrophy (DMD)

Answer 22

Absence of Dystrophin to link cytoskeleton with ECM
Necrosis of muscle fibres -> replaced with adipose tissue
= pseudohypertrophy
Onset: 3-4 years old and rapid progression

Question 23

What’s Gower’s sign?

Answer 23

Push on thighs to help stand up

Question 24

What’s Becker’s Muscular Dystrophy?

Answer 24

X-linked genetic disorder
Reduced amount of Dystrophin (compared to DMD which has absence)
= symptoms present later than DMD and progression not as rapid

Question 25

What’s Polymyositis?

Answer 25

Autoimmune inflammatory disorder affecting skeletal muscle
Inflammatory cell infiltration -> muscle fibre necrosis
Treatment: steroids/immunosupressants
Proximal symmetrical muscle weakness and wasting -> dysphagia, dysphonia, resp and cardiac muscle weakness

Question 26

What’s Dermatomyositis?

Answer 26

Polymyositis + skin features: heliotrope rash and/or Gottron’s papule