TMC 10 - Muscle EC coupling and related disorders

Question 1

how is calcium regulated in muscle?

Answer 1

• muscle contracts in response to intracellular Ca in the myoplasm
• normal/resting intracellular Ca is low
• Muscle contraction – Rapid increase in Ca concentration within the myoplasm
• Muscle relaxation – quick reduction in Ca
• A neuronal signal from nervous system causes depolarisation of the T-tubule
• DHPR protein senses voltage change and leads to a conformational change in DHPR
• DHPR is linked to the RYR1 Ca2+ release channels - conformational change in DHPR causes RYR1 Ca release channels in the SR to open
• Large amount of Ca released by these channels – causing contraction in the muscle cells

Question 2

What is SR?

Answer 2

Sarcoplasmic reticulum – SR – a specialised Ca storage compartment
- surrounds myofibres
- supplies Ca2+ for muscle contraction

Question 3

Transverse tubules (T tubules)

Answer 3

They are invaginations of the muscle plasma membrane (the sarcolemma).

Question 4

What is excitation-contraction coupling?

Answer 4

CONTRACTION:
- A neuronal signal from nervous system causes depolarisation of the T-tubule
- DHPR protein senses voltage change and leads to a conformational change in DHPR
- DHPR is linked to the RYR1 Ca2+ release channels - conformational change in DHPR causes RYR1 Ca release channels in the SR to open
- Large amount of Ca released by these channels – causing contraction in the muscle cells

RELAXATION:
- Occurs when Ca is pumped back into the SR and out of the cell
- occurs rapidly after contraction
- Ca 2+ is pumped back into the SR by a calcium pump called the Ca2+ ATPase
- This pumps Ca 2+ up a conc. gradient thus requires ATP
- Pumps 2 Ca 2+ for every 1 ATP
- Some of the Ca2+ pumped out of cell by Na+/Ca2+ exchanger in plasma memb.

The coupling between neuronal excitation and contraction through the DHPR and RYR1 Ca2+ channel
resulting in Ca2+ release and muscle contraction is called excitation-contraction coupling.

Question 5

Familial Hypertrophic cardiomyopathy (FHCM or HCM)

Answer 5

• most common familial (inherited) heart disease.
• common cause of sudden cardiac arrest / sudden death in
  young people & athletes

Question 6

FHCM – incidence + inheritance

Answer 6

• Incidence: 1 in 500, male and female affected equally.
• Inheritance: autosomal dominant i.e. 50% will pass it on to each child.

Question 7

FHCM – Phenotype

Answer 7

• heart muscle cells enlarge (hypertrophy)
• cause the walls of the ventricles (usually the left ventricle) to thicken and can block blood flow.
• can also affect the heart’s mitral valve, causing blood to leak backward through the valve.

Question 8

FHCM – symptoms

Answer 8

Symptoms:
include chest pain, dizziness, shortness of breath, fainting, or serious arrhythmias which result from disruption of the heart’s electrical signals.

Question 9

FHCM – Genetic

Answer 9

• usually caused by a change of an amino acid in the myosin protein.
• Change is due to a missense mutation (replacement of one amino acid with a different amino acid)
• Change is due to replacement of amino acid in the MYH7 gene (beta-myosin heavy chain gene)

Question 10

Malignant hyperthermia (MH)

Answer 10

a pharmacogenetic disorder where susceptible individuals react to certain types of anaesthetic
example: halothane and sevoflurane.

Question 11

Central Core Disease (CCD)

Answer 11

CCD is a non progressive muscle weakness disorder.

Question 12

Catecholaminergic polymorphic ventricular tachycardia (CPVT)
and
arrhythmogenic right ventricular cardiomyopathy (ARVC)