Regulation of muscle contraction

Question 1

What is excitation contraction coupling?

Answer 1

• From NMJ, AP propagates along the sarcolemma and the T-tubule system
• The dihydropyridine receptor (DHPR) acts as a voltage sensor and changes shape when the action potential reaches it
  -This conformational shape changes opens up the ryanodine receptors – Ca2+ channels in the terminal cisternae.
• There is release of Ca2+ from the terminal cisternae :
  1. Sarcoplasmic Ca2+ concentration increases 100 fold
  2. From ~100 nM to 10 μM (alternatively 1x10-7 to 1x10-5 M).

Question 2

What is the effect of Ca2+ with contraction?

Answer 2

• Increased intracellular Ca2+ can then interact with troponin C – on the thin filament.
• The conformational change of the troponin complex pulls tropomyosin away from the myosin binding sites on the actin filament.

Question 3

Describe the binding of actin to myosin.

Answer 3

• The phosphorylated myosin head binds to actin filament – forming a cross bridge.
• The subsequent loss of the phosphate reverts the myosin to its natural position and it pulls the actin in towards the M-line: sliding filament hypothesis
• The myosin head hydrolyses ATP and dissociates from the actin
• The released phosphate binds to the myosin head and the myosin returns to the “cocked” position for further cycles.

Question 4

Describe the process of muscle relaxation.

Answer 4

• Occurs when the intracellular Ca2+ levels drop, thus removing the change in troponin and covering the myosin binding sites
• Ca2+ is removed from the cytoplasm by Ca2+ ATPases that actively pump Ca2+ back into the sarcoplasmic reticulum.
• In the sarcoplasmic reticulum the Ca2+ is sequestered by the protein calsequestrin.

Question 5

What is malignant hyperthermia?

Answer 5

• Rare condition caused in some by anaesthesia (halothane) due to an abnormal reaction between anaesthetic agents and the ryanodine receptor.
• Leads to excessive Ca2+ in the sarcoplasm and so muscle contraction (and heat) – treated by the ryanodine receptor antagonist, Dantrolene.
• Classically it is characterised by muscle rigidity and injury, increased SNS activity and hyper-metabolism:
  1. as the body tries to replenish ATP.
  2. If untreated it leads to hyperthermia and possibly death.

Question 6

How is ATP regenerated for cross bridge recycling?

Answer 6

• Muscle cells only contain a small store of ATP, enough for a few secs of contraction.
• recycling is via one of three mechanism:
  1. Creatine phosphate metabolism.
  2. Anaerobic glycolysis (muscle glycogen) .
  3. Aerobic glycolysis.

Question 7

Discuss creatine phosphate metabolism and its relation to ATP.

Answer 7

• Creatine phosphate stores about 5-10x that of ATP.
• Rapidly re-phosphorylates ADP to ATP via the enzyme creatine kinase :
  1. Timescale of seconds
  2. Elevated creatine kinase concentrations are a marker of muscle damage.
• ADP + Creatine-P = ATP + creatine
• At rest creatine phosphate stores are replenished
  – Its metabolite creatinine is marker of renal function.
• Dietary creatine can increase muscle stores

Question 8

Discuss respiration and its relation to ATP.

Answer 8

• Aerobic when the oxygen is sufficient: TCA cycle
• Anaerobic when the oxygen is insufficient: glycolysis and lactate
• Substrates for respiration are circulating glucose, muscle glycogen and triglycerides & fatty acids.
• Large stores of glycogen are broken down and undergo glycolysis
• Fats undergo β-oxidation to acetyl co-A and enter the TCA cycle – triglycerides and fatty acids

Question 9

Glycogen vs Creatine.

Answer 9

• Like creatine phosphate, the utilisation of glycogen stores is rapid: minutes as oppose to hours.
• Glycogen = glucose = ATP for contraction.
• Muscle fatigue is associated with depletion of glycogen stores.
• Lactate build up leads to pain but lactate dehydrogenase is vital to recycle the NAD+ for glycolysis.

Question 10

Discuss the timing of muscle events.

Answer 10

• Each myosin head can cycle up to five times per second – so it can move around 5x11nm/s
• However, because ~500 myosin heads are binding to the same actin filament the rate of contraction can reach 8,000 nm/s (8 μm/s)
• An entire muscle can contract within a tenth of a second

Question 11

Discuss the mechanism of muscle contraction.

Answer 11

• Muscle contraction = force and decrease in length (tension).
• To move an object (load), the muscle fibres of a skeletal muscle must shorten.
• Tension can also be generated when the muscle is contracting against a load that does not move.
• This results in two main types of skeletal muscle contractions:
  1. Isotonic contractions
  2. isometric contractions

Question 12

What is Isotonic contraction?

Answer 12

• Tension increases until it equals the weight to be lifted.
• Then the muscle shortens and the tension stays constant.
• Isotonic = same tension

Question 13

What is Isometric contraction?

Answer 13

• Tension is developed but the overall length of the muscle does not change.
• Isometric = same length.

Question 14

What is eccentric contraction?

Answer 14

• Isotonic contractions are either concentric as in the previous example.
• Alternatively they can be eccentric.
• Eccentric contraction in when tension is developed but the muscle lengthens due to an external force.