Block 7 - Muscle physiology

Question 1

How are muscles attached to the bone?

Answer 1

Muscles are anchored to the skelton by tendons.

Muscle cells are very large and aligned in parallel or at a slight angle to the long axis of muscle.

Question 2

Explain the structure of skeletal muscle

Answer 2

Arranged in a striated pattern, called sarcomeres

A-band that includes the M-band in the centre surrounded by myosin (thick filaments)
Actin partially between myosin layers (thin filaments)
Z lines marking the edges of the sarcomere

Question 3

What are myofilaments?

Answer 3

Protein complexes that form thick or thin filaments

Thick - formed from large numbers of myosin II molecules

Thin - formed from actin in a complex with troponin and tropomyosin

Question 4

What are the 5 steps of the cross-bridge cycle?

Answer 4

Cross-bridges between myosin and actin generate force.

1) ATP binds to myosin head
2) ATP is hydrolysed. Myosin head returns to resting position
3) Cross-bridge forms at new position on actin
4) Phosphate is released and conformational changes results in power-stroke
5) ADP is released

Question 5

How is a signal passed from a nerve to a muscle?

Answer 5

Through the NMJs (neuromusular junctions), the chemical synapses between a nerve and a skeletal muscle fibre.

Question 6

How does contraction rely on calcium?

Answer 6

Low calcium - resting state - tropomyosin covers the myosin binding sites

High calcium - myosin binding sites are exposed allowing cross-bridge cycling to occur

Question 7

How is intracellular calcium regulated in skeletal muscle?

Answer 7

Through transverse tubules (T-tubule system) on the sarcolemma and sarcoplasmic reticulum.

Ryanodine receptors on the SR are coupled to dihydropyridine receptors on T-tubules.

Works through excitation-contaction coupling.

Question 8

What do RYR (ryanodine receptors) do?

Answer 8

Release calcium from SR into the cytoplasm

Question 9

What are DHPR (dihydropyridine receptors)?

Answer 9

Voltage-gated channels that sense changes in membrane potential in the T-tubles during action potentials

Question 10

How does excitation-contraction coupling work in skeletal muscle?

Answer 10

1) End plate potentail triggers action potential (AP) in muscle fibre

2) AP propagates along sarcolemma and down transverse tubules (T-tubules)

3) Depolarisation of T-tubules is sensed by dihydropyridine receptors (DHPRs) that are mechanically coupled to ryanodine receptors (RYR) on the sarcoplasmic reticulum (SR).

Voltage dependent calcium release

4) Ca2+ is released into the cytoplasm which initates cross-bridge cycling and muscle contraction.

5) Ca2+ is pumped back into SR by sarcoplasmic and endoplasmuc reticulum calcium ATPase (SERCA) and this terminates cross-bridge cycling.

Question 11

What are two factors that determine the force of contraction?

Answer 11

1) Frequency of action potentials
2) The number and size of motor units activated

Question 12

What is a syncitium?

Question 13

What is the conduction system of the heart?

Answer 13

1) Sinoatrial node (SAN) is the primary pacemaker region

2) Action potentials spread across atria

3) Atrioventriular node (AVN) is the secondary pacemaker region. It also delays conduction to the ventricles

4) Conduction propagates slowly through the AVN and then along the ventricular conducation system consisting of Purkinje fibres

Question 14

Cardiac refractory periods - explain ARP and RPR

Answer 14

ARP (absolute refractory period) - nearly all Na+ channels are in the inactivated state

RPR (relative refractory period) - Na+ channels are recovering from inactivation, the excitability returns towards the normal as the number of channels in the inactivated state decreases

Question 15

Why are long cardiac refractory periods physiologically important?

Answer 15

1) Provides time for calcium transient and contractile force to decrease before the start of the next cardiac cycle.
- Cardiac muscle relaxation has to occur for refillingof ventricles

2) Protects the heart against arrhythmias

Question 16

Where are action potentials generated in the cardiac muscle?

Answer 16

Generated sponataneously in pacemaker cells in the SAN and spread across the heart because cells are electrially coupled by gap-junctions

Question 17

Why is the cardiac msucle a syncitium?

Answer 17

Because all cells are electrically coupled to one another via gap junctions

Question 18

How does calcium release work in cardiac muscle?

Answer 18

Ca2+ release from the SR occurs by calcium induced calcium release.

1) Action potential is conducted down T-tubules

2) Depolarisation opens voltage gates Ca2+ channels (similar to SK DHPRs) - causing calcium influx

3) RYRs open because of the rise in Ca2+ concentration (RYRs functioning as ligand-gated Ca2+ channels)

4) Ca2+ from SR enters cytoplasm thorugh RYRs (= Ca2+ induced Ca2+ release) which leads to contraction

5) Ca2+ rise is transient as Ca2+ is pumped back into SR by SERCA or removed by a Na+/Ca2+ exchanger

Question 19

What is Frank-Starling’s law of the heart?

Answer 19

“the mechanical energy set free in the passage from the resting to the active state is a function of the length of the fibre”

ie. the amount of stretch of the cardiac muscle determines the amount of force generated during contraction.

The amount of blood returning to the heart determines how much the cardiac muscle is stretched and thus how much force is generated (intrinsic mechanism for regulating contractile force).

Question 20

Why can cardiac muscle not overextend like skeletal muscle can?

Answer 20

Because there is a strong passive component of tension.

Important as otherwise the stretching of the cardiac muscle with high venous returns would lead to decreases in force and failure of cardiac output.

Question 21

Explain how inotropy in the heart works

Answer 21

Both blood-bourne adrenaline and sympathetically released noradrenaline can interact with beta1-adrenoceptors to increase the force of contraction (+ve inotropy).

Cause an increase in calcium and contractility.

Question 22

List two positive inotropic drugs and their uses

Answer 22

1) Beta-adrenoceptor agonists - adrenaline, noradrenaline, dobutamine
- Raise cAMP and activate protein kinase A
- Increase calcium currents and calcium release from SR
- Adrenaline is used to treat shock and cardiac arrest
- Dobutamine is sometimes used for acute heart failure

2) Cardiac glycosides - digoxin and ouabain
- Inhibit Na/K ATPase leading to elevated intracellular Na and intracellular calcium
- Digoxin is used to treat heart failure

Question 23

List two negative inotropic agents and their uses

Answer 23

1) Calcium channel blockers - verapamil, diltiazem and nifedipine.
- Used to treat cardiac arrhythmias and angina

2) beta-adrenoceptor antagonists - propanolol, bisoprolol, metoprolol.
- Used clinically for treating angina, hypertension and cardiac arrhythmias

Question 24

Where is smooth muscle found?

Answer 24

In the walls of blood vessels and many ‘hollow’ or tubular organs such as the stomach and intestines

Question 25

What are 4 examples of physiological functions of smooth muscle?

Answer 25

• Regulating blood pressure
• Peristalsis in the digestive system
• Ciliary and iris muscles in the eye
• Hair standing on end - piloerection

Question 26

Explain the contractile apparatus of smooth muscle

Answer 26

Thick and thin filaments
Intermediate filaments
Dense bodies
Mechanical junctions - coupling cells
Gap junctions for electrial and chemical communication

Question 27

List 3 ways the contraction of smooth muscle is regulated:

Answer 27

1) Synaptic inputs from autonomic nervous system
2) Circulating hormones, local hormones and metabolites
3) The intrinsic activity of pacemaker cells - gap junctions spread depolaristation to neighbouring cells

Question 28

How do extracellular sources of calcium regulate smooth muscle contraction?

Answer 28

Sarcolemma pathways for calcium influx:

1) Voltage-gated calcium channels (DHPR/ L-type)
2) Ligand gated channels (e.g. P2X receptors activated by ATP and ADP
3) Store operated Ca2+ channels (for refilling SR)

Question 29

How do intracellular sources of calcium regulate smooth muscle contraction?

Answer 29

Sarcoplasmic reticulum pathways for Ca2+ release

1) Inositol 1,4,5 triphosphate (IP3) receptors
2) Ryanodine receptors (although these usually cause relaxation)

Question 30

What is different between smooth and skeletal muscle cross-bridge cycling?

Answer 30

ATPase activity of mysoin head in stage 2 is necessary for cross-bridge binding to actin.

Smooth muscle - ATPase activity of myosin head requires a phosphorylation event.

Question 31

Explain how smooth muscle contraction is regulated.

Answer 31

Through the phosphorylation of regulatory protein on myosin.

Myosin light chain (regulatory light chain) goes between dephosphorylated (inactive) and phosphorylated (active)

When activated (through myosin light chain kinase) becomes thick filament and increases ATPase activity of myosin.

Turns back to inactive throguh myosin phosphatase.

Question 32

What is the process of MLCK (myosin light chain kinase)?

Answer 32

Calcium binds to Calmodulin (CaM) and forms Ca2+-CaM (calcium calmodulin), this activates MLCK causing contraction. cAMP and protein kinase A (PKA) inhibit MLCK dephosphrylating the myosin light chain causing relaxation.

Question 33

What is the process of MLCP (myosin light chain phosphatase)?

Answer 33

Nitric oxide is a key vasodilator
Nitric acid activates cGMP this in turn activates protein kinase G (PKG).
Activates myosin phosphatase.
Causes muscle relaxation.

Question 34

How do G-protein coupled receptors regulate smooth muscle function?

Answer 34

• Gq-R raises IP3 which raises calcium levels activating MLCK
• Gs-R raises cAMP levels inhibiting MLCK
• Gi-R lowers cAMP levels inhibiting MLCK
• Gq-R also raises Rho-kinase which inhibits MLCP
• NO increases cGMP which activates MLCP

Question 35

Explain the pharmalogical control of smooth muscle contraction

Answer 35

Stimulation of contraction occurs by increasing intracellular calcium or by increasing sensitivity of myofilaments to calcium.

Intracellular calcium:
- Antagonists of Gaq coupled receptors that activate PLC - calium release from SR
- Increased opening of coltage gated calcium channels
- Agonists of ligand gated channels tht are calcium permeable and/ or cause depolarisation

Increased sensitivity to calcium increased by:
- Increased MLCK activity or decreased myosin phosphatase activity

Question 36

Explain the pharmalogical control of smooth muscle relaxation

Answer 36

Relaxation occurs by reducing intracellular calcium or by inhibiting cross-bridge cycling

Intracellular calcium regulation:
- Calcium channel blockers (e.g. dihydropyridines such as nifedipine)
- Drugs and agonists of Gas coupled receptors that activate potassium channels causing memebrane hyperpolarisation and decreased opening of voltage gated calcium channels
- Agonists of Gas coupled receptors - activated of PKA leads to phosphorylation and inhibition of MLCK

Cross-bridge cycling inhibition:
- Drugs that elevate cGMP, which reduces intracellular calium and inhibits myosin cross bridge cycling
e.g. 1) guanylyl cyclase activators (nitric oxide, nitrates) 2) cGMP phosphoduesterase inhibitors (sildenafil/ viagra)