Muscle Structure & Pathologies

Question 1

What are the microscopic features of skeletal muscle?

Answer 1

Cylindrical cells
Striated
Multinucleate
CM in length
Limited regeneration (satellite cells)
Voluntary control

Question 2

What are the microscopic features of cardiac muscle?

Answer 2

Branched cells w/ intercalated discs
Striated
Mono/binucleate
Length = 100μm
No regeneration
Spontaneous contraction

Question 3

What are the microscopic features of smooth muscle?

Answer 3

Spindle shaped-cells with a central nucleus
Length = 20-200μm
Regenerate
Present in vessels, hollow organs and glands
Regulated by ANS and endocrine system

Question 4

What is the organisation of skeletal muscle?

Answer 4

1. Skeletal muscle all surrounded by dense collagenous EPIMYSIUM
2. Group of muscle fascicles form the muscle and these are covered in PERIMYSIUM (contain vessels, nerves and lymphatics)
3. Muscle fascicles contain groups of muscle fibres which are surrounded by ENDOMYSIUM which is thin, loose connective tissue containing capillaries and nerves that supply them
4. The cell membrane of a muscle fibre is the SARCOLEMMA
5. Muscle fibres are made up of regular arrangement of MYOFIBRILS formed from arrangement of myofilaments (actin + myosin) which are the contractile element

Question 5

What are muscle fibres?

Answer 5

Individual muscle cells which have fused their membranes together to create 1 multinucleated cell

Question 6

What are the features of type 1 (slow twitch) muscle fibres?

Answer 6

Respiration: slow oxidative and aerobic

Mitochondria: lots

Contraction: slow but fatigue resistant

Question 7

What are the features of type 2A muscle fibres?

Answer 7

Respiration: aerobic (fast oxidative) + anaerobic that is

Mitochondria: lots

Contraction: intermediate speed and moderate fatigue resistance

Question 8

What are the features of type 2B (fast twitch) muscle fibres?

Answer 8

Respiration: anaerobic

Mitochondria: few

Contraction: fast + powerful but rapidly fatigable

Question 9

What is a motor unit?

Answer 9

The motor neurone and muscle fibres it innervates (connected via NMJ) - each nerve fibre of a muscle is innervated by only one motor neurone, but one motor neurone may innervate multiple muscle fibres

Question 10

What are the stages of transmission at the neuromuscular junction (NMJ)?

Answer 10

1. AP arrives + depolarizes pre-SM of motor neurone
2. Voltage-gated Ca+ channels open so Ca2+ moves into pre-SM terminal down its electrochemical gradient
3. ACh containing vesicles move to pre-SM, fuse with it and release ACh into synaptic cleft by exocytosis
4. ACh diffuses across to bind to nicotinic ACh receptors (ligand-gated ion channels) on the post-SC (motor end plate)
5. Conformational change induced opening the channel allowing Na+ to enter + K+ to leave motor end plate depolarising it to reach end-plate potential
6. Opening of voltage-gated Na+ channels in adjacent membrane initiating AP which propagates down muscle fibre
7. ACh only binds briefly to receptor, dissociates + broken down by AChE into acetate + choline which is taken up into pre-SM + recycled

Question 11

What is myasthenia gravis (MG)?

Answer 11

An autoimmune disease where autoAbs against nicotinic ACh receptor on post-SM causes generalized muscle weakness commonly of the extraocular muscles, facial muscles and bulbar muscles and fatigability where contractions cannot be sustained (upwards gaze test)

Question 12

What is the treatment for myasthenia gravis (MG)?

Answer 12

AChE inhibitors e.g. Neostigmine

Question 13

What is botulinum toxin A?

Answer 13

Potent neurotoxin produced by Clostridium Botulinum which degrades the SNARE protein complex so that ACh cannot be released from pre-SM causing a total blockade at the NMJ resulting in flaccid paralysis and paralysis of respiratory muscles (used specifically in face muscles to prevent wrinkles i.e. Botox)

Question 14

What are the subcellular components of muscle fibres?

Answer 14

1. T-tubules: invaginations of sarcolemma (cell membrane of muscle fibres)
2. SR: tubular network storing Ca2+

Question 15

What is a sarcomere?

Answer 15

The basic functional contractile unit made up of the overlap between thick (myosin) and thin (actin) myofilaments - between 2 Z discs/lines

Question 16

What are the different components of the sarcomere?

Answer 16

1. A band: in centre, mainly thick filaments with some overlapping thin filaments (dark)
2. I bands (x2): either side of A, only thin filaments (light)
3. Z discs/lines: run down middle of I bands + thin fibres from adjacent sarcomere joins here (dark)
4. H zone: area in centre of A band with only thick filaments
5. M line: where thick filaments are anchored + connect with cell membrane

Question 17

What are thick filaments?

Answer 17

Myosin molecules that a tail (heavy chain) with 2 globular heads (light chains)that contain an actin (thin filaments) binding site necessary for cross-bridge formation between actin and myosin as well as an ATPase site - many myosin molecules in A band with heads at different points allow multiple cross-bridges to be formed at same time and different places

Question 18

Where are thin filaments?`

Answer 18

Composed of 3 proteins:

1. Actin: α-helical structure w/ myosin (thick filament) binding sites covered by tropomyosin
2. Tropomyosin: filamentous protein running along groove of each twisted actin filament
3. Troponin: protein complex of troponin I, C + T that connects to tropomyosin where I inhibits and C binds Ca2+

Question 19

What are the steps of excitation-contraction coupling?

Answer 19

1. Depolarisation of sarcolemma
2. AP propagated down T-tubules to muscle fibre interior
3. Conformational change in voltage-gated dihydropyridine receptors on T-tubules causes conformational change in ryanodine receptors on SR
4. Ca2+ released from SR increasing IC [Ca2+]
5. Ca2+ binds troponin C inducing a conformational change which moves tropomyosin out of the way exposing the myosin binding sites on actin
6. Cross-bridge cycling of actin molecule and myosin heads causes contraction

Question 20

How does troponin C bind calcium (Ca2+)?

Answer 20

Each troponin C can bind 4 Ca2+ molecules in a co-operative way so the binding of 1 Ca2+ molecule increases the affinity of troponin C for the next Ca2+ molecule meaning even a small increase in [Ca2+] in IC space increases likelihood that all binding sites will become occupied and that troponin C undergoes conformational change to move tropomyosin, exposing myosin binding site on actin, cross-bridge cycling will occur and subsequent contraction/tension o f muscle

Question 21

What is the sliding filament theory?

Answer 21

Thick and thin filament slide over eachother meaning that the Z lines (where thin filament are anchored) at outer edge of sarcomere will move in towards the centred M line (where thick filaments are anchored) - this is the mechanism of muscle contraction

Question 22

What are the steps of cross-bridge cycling?

Answer 22

1. Binding of Ca2+ to troponin C displaces tropomyosin allowing myosin heads to bind actin forming cross-bridges
2. Rigor: initially myosin head bound tightly to actin + ATP is required to reduced myosin affinity for actin to allow movement (if absent, binding is permanent causing rigor mortis i.e. death)
3. ATP binds to myosin head inducing conformational change reducing its affinity for actin so it releases actin
4. ATP hydrolysed to ADP + Pi by ATPase which changes conformation of myosin head to a bent position (high energy) which binds actin at a point further along from original binding site
5. Power stroke: Pi released so myosin head springs back to original position pushing actin towards M-line so thick + thin filament slide over each-other shortening sarcomeres
6. Muscle contraction occurs when this happens in lots of sarcomeres next to eachother
7. ADP released + myosin head binds tightly to actin again (rigor position)
8. If ATP is available + Ca2+ remains bound to troponin C, cycling will continue so myosin heads walk along actin filaments making sarcomere shorter + shorter

Question 23

How is muscle contraction terminated?

Answer 23

1. [IC Ca2+] falls to level insufficient for it to bind to troponin C
2. Troponin C releases Ca2+
3. Tropomyosin covers myosin head binding site
4. Ca2+ taken up into SR by sarcoendoplasmic reticulum Ca2+ ATPase (SERCA)
5. Muscle relaxes

Question 24

What does the protein dystrophin do?

Answer 24

Links cytoskeleton with ECM and holds membrane with myofibrils allowing cell membrane to move with muscle

Question 25

What is Duchenne Muscular Dystrophy (DMD)?

Answer 25

Inherited X-linked genetic early onset (3-4yrs) disorder where there is absence of dystrophin protein so that there is necrosis and destruction of muscle fibres as cell membranes are ripped apart and they are then subsequently replaced with connective tissue causing pseudohypertrophy (grow in size but reduce in strength) presenting with proximal muscle weakness (Gower's sign) and rapidly progresses

Question 26

What is Gower's sign?

Answer 26

When patients need to push hands into thighs to help them stand up due to proximal muscle weakness

Question 27

How do you treat Duchenne Muscular Dystrophy (DMD)?

Answer 27

No cure but symptom and QoL improvement by: - Steroids - Physiotherapy - MDT involvement

Question 28

What is Becker's muscular dystrophy?

Answer 28

X-linked genetic disorder where there is reduction in the amount of dystrophin but presents later in childhood or adolescence than DMD with milder symptoms and slower progression

Question 29

What is polymyositis?

Answer 29

Autoimmune inflammatory disorder affecting skeletal muscle where there is inflammatory cell infiltration and muscle fibre necrosis causing: - Proximal symmetrical muscle weakness + wasting (no pain/tenderness usually) so patients may complain of issues getting out of chair or walking up stairs - Dysphagia, dysphonia, resp. muscle weakness + cardiac involvement - General malaise, weight loss + fever in acute phase

Question 30

What is the treatment for polymyositis?

Answer 30

Steroids e.g. Prednisolone | +/- immunosuppressants

Question 31

What is dermatomyositis?

Answer 31

The version of polymyositis that also presents with skin changes so it affects muscle and skin typically but also joints, oesophagus, lungs and heart - may be part of other autoimmune conditions or a paraneoplastic syndrome(underlying malignancy)

Question 32

What are some characteristic physical signs of dermatomyositis?

Answer 32

Heliotrope rash: purple discolouration and periorbital swelling around eye Gottrons papules: scaly erythematous rash typically on hands