Muscle Diseases Research 1.2 : Pharmacological Therapies I

Question 1

What is the gene regulation hypothesis for dystrophic necrosis?

Answer 1

In the absence of dystrophin, there is a disregulation of other proteins as it is closely associated with them, possibly gene inducing proteins, affecting gene regulation.

Question 2

What is the vascular hypothesis for dystrophic necrosis?

Answer 2

Loss of signalling for oxygen transport via NO in blood vessels.
Creates an oxygen deficient environment, and muscles become ischaemic when working muscles demand oxygen.

Question 3

What happens to mice with an NO knockout?

Answer 3

They dont have a muscular disease.

Question 4

What is the inflammatory hypothesis for dystrophic necrosis?

Answer 4

Disregulation of the normal injury-repair mechanism, excessive inflammatory signature, rise in inflammatory proteins.

Question 5

What is needed to recruit satellite cells? How is this a problem in DMD?

Answer 5

Inflammation needed to recruit satellite cells. Excessive inflammation is seen in DMD and indicates disrgulation.

Question 6

How is fibrosis caused?

Answer 6

Continuous cycle of trauma-repir means replacement of muscle fibres with collagen, which is non-contractile.

Question 7

Why is fibrosis an issue for treatment?

Answer 7

Is a physical barrier betwen drug and muscle.

Isn’t reversible either.

Question 8

What effect does fibrosis have on muscles?

Answer 8

Makes them stiffer and reduces strength.

Question 9

Why does fibrosis affect timing of the intervention?

Answer 9

Fibrosis is irreversible, and prevention of fibrosis needed to efficiently deliver drugs and preserve muscle fibres.

Question 10

Do animal models always translate to humans?

Answer 10

No.

Question 11

What are the functions of corticosteroids?

Answer 11

Maintain/decrease muscle fibre size, and are catabolic.

Question 12

What effect do corticosteroids have on inflammation?

Answer 12

Reduces chronic inflammation.

Question 13

What effect do corticosteroids have on muscle strength?

Answer 13

Small increase, but not directly, rather a preservation of muscle strength.

Question 14

What effect do corticosteroids have on fibrosis?

Answer 14

Slows fibrotic deposition.

Question 15

What are the side effects of corticosteroids (name 4)?

Answer 15

Weight gain, high blood pressure, ulcers and bone growth inhibition.

Question 16

What is the gold standard of DMD treatment?

Answer 16

Corticosteroids

Question 17

What are new DMD drugs compared to as a standard?

Answer 17

Corticosteroids, the gold standard.

Question 18

Does corticosteroid treatment interact with other treatments? If a better drug is found, should it replace corticosteroids? Why?

Answer 18

Yes they do.

The new drug should replace corticosteroids due to its many side effects.

Question 19

How do anabolic agents affect muscle size and susceptibility?

Answer 19

Increases muscle size, and potentially reduce inflammation.

However, may make it more susceptible to damage.

Question 20

What happens to mice with myostatin knockout?

Answer 20

Much bigger muscles.

Question 21

What happens to myostatin with age?

Answer 21

Increases, is a sarcopenia contributor.

Question 22

What is one way to reduce myostatin besides a knockout?

Answer 22

Antibodies to inhibit.

Question 23

What is an anabolic treatment approach to DMD, and when is this normally released? What are some side effects?

Answer 23

IGF1 - growth hormone, released after overload and injury
Increases muscle mass and strength
Side effects include possible tumour formation due to growth effects - less likely
Increase existing tumour growth - more likely

Question 24

How much of an anabolic agent would be administered?

Answer 24

Restored to normal levels, DMD patients may need more.

Question 25

What effect do anabolic agents have on fibrosis?

Answer 25

Inhibition.

Question 26

What effect does IGF1 have on a muscle’s fibre type?

Answer 26

Shifts it away from type 2, towards type 1, which is more oxidative.

Question 27

What is the difference in susceptibility between small and large muscle fibres and why?

Answer 27

Small fibres - low forces, spared in DMD due to low forces

Large fibres - High forces, injured due to trauma

Question 28

What effect can treatment increasing muscle size have on DMD? How can this be tested?

Answer 28

It might aggravate the pathology.
Can be tested using a beta agonist to increase muscle size and strength (high dose).
Shifts muscle from type 1 to type 2, more glycolytic.
Didn’t increase susceptibility, so not an absolute association.

Question 29

Does immobilising muscles help DMD?

Answer 29

No it doesnt, aggravates pathology despite no forces.

Question 30

Can resistance exercise help DMD?

Answer 30

Yes, if at low intensity, such as swimming and general playing.
Can be harmful at high intensity.
Breathing exercises for diaphragm.