Role Of Creatine Kinase In Muscle Biology Essay

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1a. It has been pointed out (Pocock and Richards 2006, pp. 87-88) that the role of creatine kinase (CK) in muscle is to catalyse the reversible reaction of creatine phosphate, adenosine diphosephate (ADP) and H+ to produce creatine and more importantly adenosine triphosphate (ATP), the level of which needs to be maintained during contraction.

1b. The rise in serum CK levels is resultant of rhabdomyolysis, symptomatic of malignant hyperthermia (MH), which primarily brings about rapid necrotic damage to skeletal muscle fibres. This damage leads to the release of CK from the damaged muscle fibres into the bloodstream (Cervellin et al. 2010).

2. As CK levels rose:

Serum potassium concentration to increase also as a result of rhabdomyolysis which also causes the release of K+ ion into the bloodstream from the ruptured muscle (Hopkins 2000).

Blood pH would drop.

Serum phosphate concentration will increase.

Serum calcium concentration will increase.

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Explanation to blood pH, serum phosphate and calcium concentrations:

These will increase because whilst a MHS patient goes tachycardic and excessive muscle contraction occurs as a result increased sarcoplasmic reticulum (SR) Ca2+ channels releasing Ca2+ into the myoplasm (Krause et al. 2004; Girard et al. 2002). Therefore excessive ATP is used leading to higher intracellular CK levels to replace the ATP deficit, and also as a result of the prolonged excitation-contraction coupling from increased Ca2+, the cells respire anaerobically building up H+ ions and phosphate ions too (Pocock and Richards 2006, pp. 87-88). Consequentially when rhabdomyolysis occurs the excessive Ca2+ ions, H+ ions and phosphates in the muscle cells leak out into the extracellular space (Cervellin et al. 2010).

3. No, because ketamine reduces the Ca2+ ions released in skeletal muscle and despite the patient possibly experiencing tachycardia and hypertension these are just normal symptoms of ketamine use because of ketamine's cardiostimulant properties (Hopkins 2000).

4. Caffeine and halothane are the two drugs utilised and an equivocal result can be reached when the test results come back as positive with caffeine, having a caffeine concentration of 2.0 mmol l-1 or lower, but negative with halothane, having a halothane concentration greater than 0.44 mmol l-1. Plus vice versa having a negative caffeine result, having a caffeine threshold concentration of 3.0 mmol l-1 or greater, and having a positive result for the halothane, having a threshold concentration of 0.44 mmol l-1 or less (European Malignant Hyperthermia Group)

5.

6. The majority of malignant hyperthermia susceptible (MHS) patients display disruption to Ca2+ ions homeostasis (Balog et al. 2001, pp. 2050-2058). A mutation of the RYR1 is responsible for this defect, for instance, in the normal functioning receptor it has an A-site which has a high affinity to Ca2+ ions leading to its opening and an I-site which has a low affinity for Ca2+ leading to its closing. Also Mg2+ normally can affect either A- or I-sites of the RYR1 receptor causing it to close. However in MHS individuals with a mutation to the RYR1 gene affinity for Mg2+ at either sites is substantially depreciated therefore a greater amount of Ca2+ is released resultant of reduced activation and increased deactivation thresholds. Consequentially a large amount of ATP is utilised to reabsorb the Ca2+causing excess heat generation and anaerobic respiration and this leads to the muscle cells having depleted ATP supplies hence damaging the cell and these ruptures lead to cellular constituents exuding from the cell such as K+ ions, creatine kinase (hence increased serum H+ lowering pH), lactate and phosphates, all symptomatic of MH and sequential to lactic acidosis (Balog et al. 2001, pp. 2050-2058; Yang et al. 2003, pp. 25722-25730).

7.

Central Core Disease (Robinson et al. 2006)

King-Denborough Syndrome (Davis et al. 2002)

Duchenne Muscular Dystrophy (Dreissen 2008)

Glycogen Storage Disease (Bollig et al. 2005)

Mitochondrial Myopathies (Dreissen 2008)

8a. Template strand: 5' - GAGTTCTTCT - 3'

Resultant mRNA: 5' - CUCAAGAAGA - 3'

8b. Using a genetic code table it was possible to translate the DNA sequence of the mutation RYR1 gene producing this:

EKLDVAPKRDVEGMGPPEIKYRESLCFVQHVASGLWLTYAAPDPKALRLGVLKK

In comparison to the given protein sequence it is clear to see that a Glycine had been substituted with an Arginine. Therefore this is a substitution mutation of R for G.

8c. The substituted arginine will consequentially change the resultant polypeptide formed during translation and hence altering the function and structure of the produced protein.

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9.

Paternal Grandparents: Maternal Grandparents:

?

?

?

?

Dad (RR)

Ruth (Rr)

Key:

?

Male Grandparent;

(Genotype unknown)

?

Female Grandparent;

(Genotype unknown)

Male MHS (RR);

Female MHS (rr);

Male MHS (Rr);

Female MHS (Rr);

10.

1.

R

r

R

RR

Rr

R

RR

Rr

2.

R

r

r

Rr

rr

r

Rr

rr

3.

R

r

R

RR

Rr

r

Rr

rr

Punnet square 1. 4/4 chance

Punnet square 2. ½ chance

Punnet square 3. ¾ chance

Overall chance of carrying mutation is ¾.

11. Yes because Robinson et al. (2003) points out that there has been evidence to show lack of concordance between results for genetic testing for the RYR1 gene mutations and the IVCT.

12. Nelson et al. (1976) points out that pigs are used for investigation of MH in humans, without high risks to humans, due to susceptible swine having porcine stress syndrome, which can even be induced by exercise and excitement resultant from porcine RYR1 gene mutations leading to porcine MH which is pathophysiologically very similar to that seen in human MH.

13. Dantrolene Sodium is a muscle relaxant specialising in stopping excitation-contraction coupling in muscle cells and does so by the it's binding site binding in within the RYR1 receptor impeding the excessive release of Ca2+ ions from the sarcoplasmic reticulum. Dantrolene does this by stabilising the Ca2+ channel when it binds to the RYR1 receptor, closing the channel (Robinson et al. 2006).

14. Despite there not being a full understanding of the definitive target of Dantrolene it has been suggested by Krause et al. (2004) that the Dantrolene binding site may be located on the RYR1 receptor, which is pivotal in the release of Ca2+ ion from the SR into the myoplasm, and upon it's binding to this receptor Dantrolene is thought to inhibit the efflux of Ca2+ ions via calcium channels decreasing intracellular calcium concentrations hence relaxing the muscle.

An experiment carried out by Zhao et al (2001) provided evidence to back up these suggestions of the presence of Dantrolene reducing myoplasm calcium concentrations comparing normal SR, MHS SR and an appropriate control.

Effect of dantrolene on SR vesicle [3H]ryanodine binding

Kd

Bmax

N

nm

pmol/mg

Normal SR

 Control

112  ± 8.5

11.9  ± 0.3

4

 Dantrolene

303  ± 271-a

11.4  ± 0.5

4

MHS SR

 Control

32  ± 3.31-b

10.9  ± 0.3

4

 Dantrolene

93  ± 6.31-aHYPERLINK "#fn-2"1-b

10.4  ± 0.3

4

MHS SR-AMPPCP

 Control

419  ± 151

10.0  ± 2.1

3

 Dantrolene

317  ± 61

8.8  ± 0.9

3

15. Dantrolene Sodium's poor water solubility is disadvantageous and consequentially introduces clinical difficulties making it harder to prepare the correct intravenous supply for use in an emergency case. This problem is not apparent with Azumolene Sodium which is conversely substantially more water soluble than Dantrolene as a result of the para-nitro-phenole group present in Dantrolene Sodium, part of the reason for Dantrolene's lipophilic nature, being replaced by a para-bromo-phenyl group in Azumolene (Krause et al. 2004).

16. It would be difficult to establish because when one takes into consideration the severity of the disease once an individual is exposed to the inhalation anaesthetics and chemicals that trigger MHS symptoms it would be dangerous to test for susceptibility in humans. Plus the current testing for MHS has not been totally conclusive with uncertainty of concordance between genetic testing and IVCT results (Robinson et al. 2003). Notwithstanding the general increased use of I.V. anaesthesia takes away from the triggering of MH via inhalation anaesthesia (Glahn et al. 2010).