3. SKELETAL MUSCLE CONTRACTION & DISORDERS

Question 1

*What are the properties of skeletal muscle?

Answer 1

• Skeletal muscle is made up long, multi nucleated cells up to 30cm long
• They are fused from many myoblasts fusing together

Question 2

Why does skeletal muscle have a striated pattern?

Answer 2

• Skeletal muscle has a distinct striated pattern due to the arrangement of contractile filaments
• I BAND = ACTIN
• A BAND = Actin AND Myosin
• H ZONE = MYOSIN (within A band)
• Z line = length of sarcomere, anchor for the actin

Question 3

*Describe the structure of skeletal muscle?

Answer 3

• One muscle cell -> bundle of muscle cell -> group of muscle bundles (fascicle) -> group of fascicle
• Each muscle cell is covered in a layer of SARCOLEMMA
• Each muscle bundle is covered in a sheet of PERIMYSIUM
• Each group of muscle bundles is covered in a sheet of EPIMYSIUM

Question 4

Describe the properties of actin

Answer 4

• Actin consists of troponin & tropomyosin.
• Troponin C - binds to Ca2+, Troponin T - binds to Tropomyosin
• Tropomyosin blocks the active binding site on actin
• An increase in intracellular Ca2+ binds to Troponin C, causing Troponin T to bind to tropomyosin. This causes tropomyosin to move, exposing the binding site

Question 5

What causes contraction in skeletal muscle?

Answer 5

• Contraction occurs as a result of the interaction of the contractile filaments actin & myosin, fueled by ATP
• A rise in Ca2+ allows it to bind to Troponin C, triggering Troponin T to bind to tropomyosin allowing interaction

Question 6

What is the T-tubule system?

Answer 6

• The T-TUBULE SYSTEM is invaginations of the sarcolemma from the exterior to the interior. The t-tubule system is closely associated with the sarcoplasmic reticulum

Question 7

**Describe the process by which there’s a rise in intracellular Ca2+ (including DHPs)

Answer 7

1. Skeletal muscle is stimulated by Ach binding to a nicotinic AchR. The binding causes sufficient sodium channels to open causing depolarisation
2. The wave of depolarisation passes down the T-tubule system.
3. There DHPs (dihydropyridine proteins) which are voltage sensitive within the T-tubule.
4. The DHPs interact with RyR (ryamidine receptors) which are Ca2+ release channels in the sarcoplasmic reticulum. Leads to an intracellular rise in Ca2+

Question 8

**What are the steps of the contractile cycle?

Answer 8

1. POWER STROKE
2. BINDING
3. DETACHMENT
4. An ATP molecule binds to myosin
5. Myosin binds to actin forming a cross bridge, releasing phosphate
6. The binding of myosin to actin causes ATP hydrolysis releasing ADP.
7. Release of ADP causes a change in conformation state to a low energy, pulling the actin inwards
8. An ATP molecule binds to the myosin, to allow detachment of the myosin head & the cross-bridge dissociates
9. ATP hydrolysis occurs priming the head for interaction with actin, change in conformation to high energy

Question 9

What is the myelin sheath & how does it differ in the CNS & PNS?

Answer 9

• The myelin sheath insulates the axon, to reduce charge dissipation & speed up electrical transmission
• In between the myelin sheath, there are nodes of Ranvier where the sodium channels are located
• In the CNS - myelin sheath is made up of SCHWANN CELLS
• In the PNS - myelin sheath is made of OLIGODENDROCYTES

Question 10

Give 4 examples of disorders of skeletal muscle contraction?

Answer 10

1. Multiple sclerosis
2. Myasthenia gravis
3. Non-dystrophic myotonia
4. Dystrophic myopathy/ Muscular dystrophy

Question 11

What is multiple sclerosis?

Answer 11

• Multiple sclerosis is a skeletal disorder caused by the immune attack of the myelin sheath, causing damage
• The cause of multiple sclerosis is unknown, but it’s thought to be associated with a leaky blood brain barrier, where the infiltration of immune cells attack the myelin sheath
• Characterised by sclerotic lesions due to myelin sheath degradation. Can affect the propagation of impulses & slows down nervous activity

Question 12

What are some symptoms of of multiples sclerosis?

Answer 12

• Numbness, tingling, debilitating muscle weakness due to progressive degradation of myelin sheath, speech & visual problems

Question 13

What is myasthenia gravis?

Answer 13

• Myasthenia gravis is an autoimmune skeletal muscle disease that involves progressive loss of nicotinic acetylcholine receptor function & activity due to degradation of the alpha 1 sub-unit

Question 14

What causes myasthenia gravis?

Answer 14

• The nicotinic acetylcholine receptor is a LIGR (ligand gated ion channel that allows the influx of sodium ions), it is made up of 5 subunits, one of which is alpha 1
• Myasthenia gravis leads to the degradation of the alpha 1 receptor, so there’s reduced acetylcholine binding
• In the early stages of the disease, it can be treated with cholinesterase inhibitors which prevent the breakdown of Ach so that there’s more circulating Ach. More Ach can improve the loss of binding
• However, as the disease progresses, an increase in Ach will have no effect as the receptor will be too degraded

Question 15

What are some symptoms of myasthenia gravis?

Answer 15

• Drooping of eyelids, difficulty speaking, double vision, slurred speech, muscle fatigue

Question 16

What are the 4 ways in which the receptor can be inactivated/degraded in myasthenia gravis?

Answer 16

1. DESTRUCTION of the morphology of the membrane leading to receptor degradation
2. ANTIBODY BINDING
3. ANTIBODY CROSS-LINKING
4. COMPLEMENT BINDING

Question 17

What are non-dystrophic myotonias & the cause?

Answer 17

• Non-dystrophic myotonias are skeletal disorders where there’s impaired relaxation after voluntary contraction or mechanical stimulation
• It can be caused by mutations in the SNA4 gene coding for voltage gated sodium channels in skeletal muscle
• It’s characterised by highly repetitive electrical activity of the muscle fibre

Question 18

What are the 5 types of non-dystrophic myotonias?

Answer 18

1. • Potassium aggravated myotonia
2. Paramyotonia congenita
3. Hyperkalemic periodic paralysis
4. Hypokalemic periodic paralysis
5. Congenital myasthenic syndrome

Question 19

What do mutations of SNA4 lead to in non-dystrophic myotonia?

Answer 19

• A mutation of the SNA4 gene can lead to a delayed or decreased rate of inactivation of the voltage gated sodium channels. Once, depolarisation has occurred, the sodium channels will be inactivated but issues with this can lead to:
  1. More Na+ channel activity —> more persistent & longer contractions
  2. Or loss of Cl- channel activity —> prolonged contractions (can be due to mutation in CLC1 gene)

Question 20

What are the properties of the dystrophin gene

Answer 20

• The dystrophin gene is the largest gene in humans, it contains 79 genes & spans 2,200Kb
• Dystrophin is involved in stabilising the cell membrane, as the contractile filaments shorten. Dystrophin is anchored to the Z line of the sarcomere

Question 21

What is muscular dystrophy or dystrophic myopathy?

Answer 21

• Muscular dystrophy refers to a group of skeletal disorders which cause progressive muscle weakness & loss of muscle mass due to mutations which cause changes in muscle fibre

Question 22

What are two types of dystrophic myopathy?

Answer 22

1. DUCHENNE - TOTAL/COMPLETE loss of dystrophin due to exons being skipped or removed
2. BECKER - REDUCED or DYSFUNCTIONAL/MALFUNCTIONAL dystrophin

Question 23

**What are the consequences of muscular dystrophy?

Answer 23

• Loss of dystrophin leads to damage of muscles, muscle fibre necrosis, fibrosis
• The fibrosis and necrosis leads to increased permeability, so there can be infiltrations of macromolecules such as fat which is made worse with stress

Question 24

What’s the effect of Botox & ingestion of pufferfish on skeletal muscle contraction?

Answer 24

• Botox (Botulinum toxin) prevents the release of Ach from the nerve terminal so that there’s no interaction with AchR leading to muscle paralysis
• Pufferfish contains Tetrodotoxin which blocks Na+ channels, losing excitation down T-tubules = reduced contraction