Muscle Channelopathies

Question 1

What is myotonia

Answer 1

Inherited 
Hyper-excitability of skeletal muscle 
Muscle stiffness 
Lots of inappropriate APs 
Muscles take longer to relax
Myotonic seizures- whole body contraction, can be brief or prolonged and of varying severities

Question 2

Is myotonia fatal

Answer 2

Not in itself, but if a seizure happens at the wrong time this can cause secondary injuries which could lead to death

Question 3

What are the two main classes of Myotonia

Answer 3

Myotonia congenita- mutations in CLCN1 gene which produced CLC1 protein (same family as CLCK)- loss of fucntion
Paramyotonia and K aggrevated myotonia- if the patient ingests too much K. Both are associated with gain of function of the Nav1.4 protein

Question 4

What are the two main classes of myotonia congenita?

Answer 4

Thomson’s autosomal dominant
Becker’s autosomal recessive
Mutations are in the same gene, depends on where the mutation is as to which type you get

Question 5

Why do myotonic seizures occur?

Answer 5

Due to an emotional response- when the patient gets scared

Question 6

What is the role of CL in the muscle action potential?

Answer 6

The Nersnt for Cl is -70mV

If there is a high conductance at rest which helps K set up the resting membrane potential

Question 7

What is the role of the CLC1 protein?

Answer 7

As membrane potential depolarises, the Cl channels increase in open probability and Cl conductance increases to pull the membrane back to the resting potential.
Affects the incidence of APs.

Question 8

What is the effect of mutating the CLC1 channel?

Answer 8

Open probability of much less at the same voltage in the WT.
At resting in WT- 50% of channels are open
In mutants approx 5%.
They are functional but they just don’t function in the normal way. The channels are still voltage dependent- just require a bigger depolarisation to open.
Muscle fibres are hyper-excitable as a result

Question 9

What affect does the mutated CLC1 channel have on the action potential?

Answer 9

ACh levels which would not normally result in an AP do.

Frequency also increased

Question 10

What is the treatment for Myotonia?

Answer 10

Mexiletine. This inhibits Na open phase, and this will decrease the likelihood of an AP firing.
Give a sub-maximal dose however- do not want to inhibit muscles completely

Question 11

What channel is mutated in Paramyotonia and what is the effect of this?

Answer 11

Gain of function in Nav1.4.
Nav in the muscles activate and then inactivate.
Patients have issues with the inactivation gate. Channels fail to close so they get a prolonged depolarisation and thus prolonged contraction of the muscle. They seem to be temperature sensitive

Question 12

What is the effect of cold in Paramyotonia?

Answer 12

Experiments showed that in the cold, the muscle had higher Na concentrations.
The cold slows down the kinetics of channel so there is a greater period of time that the Na can move into the muscle (channel is open for longer time).
In myotonic fibres- higher Na concs because the Nav1.4 is more sensitive to cold.

Question 13

What is malignant hyperthermia

Answer 13

Autosomal dominant
Abnormal response to GAs.
80% death rate
Within minutes the patient is in critical condition after administering GAs

Question 14

What are the symptoms of malignant hyperthermia

Answer 14

Tachycardia 
Tachypnea- increase in breathing rate
Muscle rigidity 
Low plasma O2 which induces anaerobic respiration 
Hypertherimia (if over 42- dead due to denatured proteins) 
Sweating
Acidosis 
Shift in BP

Question 15

Why is there acidosis in Malignant hyperthermia?

Answer 15

Respiratory and lactic acidosis due to lack of oxygen to the respiratory muscles- build up of CO2 and lactic acid as a result of anaerobic respiration

Question 16

What happens to the muscles in malignant hypertherimia if not treated?

Answer 16

There will be breakdown which releases K- so this induces hyperkalaemia which increased neuronal and cardiac excitability which can lead to death

Question 17

Why does malignant hypertherima occur?

Answer 17

Uncontrolled muscle contraction which leads to excessive ATP hydrolysis and this produces heat.
Muscles will also try to replenish the ATP in the stores which requires even more heat.

Question 18

Which ion channel is responsible for malignant hypertherima?

Answer 18

Ryanodine channel in the SR. There is gain of function in this channel- increases the open probability of the channel which increases the Ca conductance into the cell- increased muscle contraction

Question 19

Why was MH selected for in pigs?

Answer 19

Increased muscle contraction meant increased muscle size- this was more profitable.

Question 20

What is INDO-1

Answer 20

A type of fluorescence which is dependent on Ca concentration. Increase fluorescence means increased Ca in intracellular compartment.

Question 21

How was INDO-1 used to study malignant hyperthermia?

Answer 21

In mutant cells there was a rise in fluorescence when halothane was administered.

Question 22

How does the mutant ryanodine cause MH?

Answer 22

Exposure to halothane- the mutants have increased sensitivity to halothane. 
Excess release of Ca from SR 
Enhanced contraction and thus rigidity 
Excess ATP hydrolysis- heat 
Lactic acid production- acidosis 
Increased O2 to make ATP 
Increased production of CO2 so high plasma CO2
Increase ventilation to remove CO2
Increase in HR to supply O2

Question 23

What are the treatments of MH?

Answer 23

Dantrolene- inhibits ryanodine 
IV hydration- patients sweat 
Diuretics to stop the kidneys from being damaged by muscle breakdown products
NaHCO3 to counteract acidosis
Mechanical ventilation