Met2

Question 1

1. Glyn could potentially take part in a long distance walk using blood glucose and free fatty acids as sources of energy. It might be expected that increasing free fatty acid delivery to muscles in people with McArdles would lead to increased energy production, but it does not. Why does this not happen? [2 marks]

Answer 1

There is limited availability of TCA intermediates because of limited pyruvate production (cannot break down glycogen) (1 mark) to react with acetyl CoA released from beta oxidation of fatty acids (1 mark).

Question 2

1. What are the differences between the causes of McArdles and Hers diseases. What would be the primary symptom on Hers disease? [3 marks]

Answer 2

• McArdles is caused by the lack of muscle glycogen phosphorylase enzyme in muscle cells [1]
• whereas Hers disease is caused by the lack of the same enzyme but in the liver [1].
• Hers disease results in hypoglyceamia or inability to control blood sugar OR enlarged liver [1 mark]

Question 3

1. The concentration of which two intracellular factors link muscle contraction to glycogen breakdown? [2 marks]

Answer 3

Calcium [1] & AMP levels [1]

Question 4

1. (I) What would you expect the pH to be if measured in the blood of a sprint athlete right after exercise?
   (ii) Explain why?
   (iii) On her admission to A&E, Glyn’s results show no change in pH. Explain why? [3 marks]

Answer 4

I) pH would be lowered (acidosis) [1]

Ii) High level of lactic acid in the blood [½], produced by anaerobic metabolism [½]

Iii) There is little to no lactate produced as there is no glucose source* in the muscle (*glycogen cannot be used) [1]

Question 5

explain causes of McArdles disease

Answer 5

1. Mutation in gene for myophosphorylase (PYGM) on chromosome 11
2. Results in having no glycogen phosphorylase to break down the glycogen storage in their muscle.
3. Unable to release glucose from glycogen in muscle
4. Instead: during aerobic activity, skeletal muscle derives energy from free fatty acids by oxidising them in mitochondria via the beta oxidation pathway to form acetyl co-A. Acetyl co-A goes into the Krebs cycle, leads to production of ATP

Question 7

symptoms & inheritance of McArdles disease?

Answer 7

1. Inheritance:
   
   1. Autosomal recessive: need both copies of gene to have mutation
2. Symptoms:
   
   1. Presentations occur in first decade, but often only diagnosed until rd or 4^th decade
   2. Reversible exercise intolerance
   3. Fatigue
   4. Fixed motor weakness
   5. Acute crisis: severe fatigue and painful muscle cramps triggered by static muscle contractions (lifting weights) or dynamic exercise
   6. Second wind: after about 8 minutes most patients can continue exercise without difficulty
   7. Symptoms worsen with age as aerobic fitness is reduced
   8. Half of all patients have myoglobinuria (dark urine) following intense exercise

Question 8

how do diagnose McArdles?

Answer 8

1. Creatine kinase levels elevated
2. Blood urate levels raised (uric acid): nitrogen from increased proteins break down (damaged cells)
3. DNA testing
4. Muscle biopsy
5. No increase in venous lactic acid after exercise: blood pH levels also don’t decrease
6. Urine myoglobinuria

• *Biopsy**
  
  1. Shows evidence of glycogen build up in the muscle cells

Absence of enzyme myophosphorylase

Question 9

how do u manage McArdles disease? :)

Answer 9

1. Diet rich in protein / keto diet: burning fatty acids instead of glucose into Krebs cycle. Have this enzyme (unlike glycogen phosphorylase)
2. Creatine supplements: increases ATP levels.
3. High blood sugar diet

Question 10

explain causes of Hers disease

Answer 10

1. Mutation in the PYGL gene: codes for glycogen phosphorylase
2. glycogen phosphorylase: converts glycogen  glucose-1-phosphate
3. glycogen phosphorylase only found in liver cells
4. As a result: glycogen builds up in the liver cells: hepatomegaly.

Question 11

inheritance, symptoms, diagnosis and treatment of hers?

Answer 11

1. Inheritance:
   
   1. Autosomal recessive
2. Symptoms
   
   1. Hepatomegaly (enlarged liver)
   2. Increased hepatic glycogen content
   3. Hypoglycaemia (low blood sugar)
   4. Lactic acidosis (increase in lactic acid in the body)
   5. Faintness
   6. Weakness
   7. Delayed puberty
   8. Failure to thrive
3. Diagnosis:
   
   1. Genetic testing of PYGL gene
4. Treatment / Management:
   
   1. Avoid going for long times without eating / lots of small meals glycogen is only broken down in periods of need / hunger
   2. Eat high protein diet
   3. Monitor blood glucose levels

Question 12

in McArdles disease, what is fixed muscle weakness and myoglobinuria? why do they occur? [3]

Answer 12

Fixed muscle weakness = permanent weakness to muscle occurs in 25% of individuals

Myoglobinuria = episodes of myoglobin in blood urine occurs in 50% of individuals.

Result of breakdown of skeletal muscle (rhabdomyolysis).

Question 13

explain why a second wind occurs after 10 mins of excercise in mcardles disease?

Answer 13

Second Wind Phenomenon = a sudden, marked improvement in the tolerance to aerobic, dynamic, large muscle mass exercise (walking or cycling) after about 10 min.

Within the first few minutes of exercise, muscles rely mainly on muscle glycogen, causes patients with McArdle’s severe damage as there is not enough glucose/fat being supplied in the blood

Gradually, vessels vasodilate allowing glucose and fats (free fatty acids) to be used

Achieving second wind can be shortened by administering glucose in blood transfusions.

NOTE: can do intense activity up to 6 seconds due to small store of ATP and phosphocreatine (anaerobic) immediately available. However, this rapidly runs out= glycogen needs to be used and this is not possible.

Question 14

what is sliding filament theory of McArdles disease?

Answer 14

Muscle remains contracted as without ATP the myosin heads remain attached to the actin forming cross bridges and maintaining the muscle in a contracted state. ATP is required to remove myosin heads from actin.

Question 15

what is the funciton of myoglobin? [1]
where is it found? [1]

Answer 15

Myoglobin: found only in muscles. It functions as an oxygen-storage unit, providing oxygen to the working muscles. Only found in the blood if there is muscle damage.

Question 16

what would creatine kinase levels be like in blood tests of mcardles disease patient and why?

(what is the function of creatine kinas)

Answer 16

Creatine Kinase: raised in more than 90% of patients

Function: CK catalyzes the conversion of creatine and utilizes adenosine triphosphate ATP) to create phosphocreatine (PCr) and adenosine diphosphate (ADP).

Released when muscles are broken down (due to rhabdomyolysis)

Question 17

why mgiht urea, K+ be high in mcardles diease patients, but glucose and Na+ be low?

Answer 17

Glucose: is low because it is used up very quickly.

Na+: Less sodium potassium pumps available so sodium low because they are degraded into rhabdomyolysis as well as not being available for use due to needing ATP to function.

K +: High because not enough ATP available to exchange it in the Na+/K+ pump so it is not moved into the muscle and remains high extracellularly (usually sodium moves out, potassium moves in).

Also, high because it cannot be excreted in the kidneys

Can lead to arrhythmia and that is why cardiac monitoring is undertaken.

Urea: Is on the high side due to kidney problems associated with the build-up of myoglobin that can eventually lead to kidney failure. Urea is high due to reduced excretion

Question 18

why does calcium move out of bone & into blood in mcardles?

Answer 18

Calcium: moves out of the bone into the blood and then into the cell to balance the electrochemical gradient that is caused by high sodium intracellularly.

Question 19

what would immediate treatmnent of mcardles disease be ? [3]

Answer 19

Bolus = rehydration through IV infusion and flushing of the kidneys.

Saline at 2X Maintenance = sodium administered at double the normal.
Increases the blood level of sodium extracellularly and corrects imbalance.
Allows for increased absorption of glucose through sodium-glucose transporter
Also, important for the reuptake of water in the gut and therefore hydration.

Dextrose = a sugar that is chemically identical to glucose. It is simple (monosaccharide) and can be used almost immediately by the body for energy and restoring blood glucose (preferred over sucrose as this is first metabolised into glucose before use and is harder to administer.

Question 20

what are sources of ATP during exercise?

Answer 20

Requirement can x100 in exercise. Comes from phosphocreatine first, then muscle glycogen and then blood glucose and fatty acids (think about second wind).

Question 21

blood pH of a McArdle’s disease pt after sudden exertion?

Answer 21

should be normal as lactate not produced

muscular GP not working therefore muscular glycogen not used to produce lactate

Question 22

elevated serum urea indicates what? [2]

Answer 22

indicates failure to excrete nitrogen

or

indication of proteolysis from muscle damage