Skeletal muscle diseases: Pharmacological therapies (Lecture 15)

Question 1

What is the gene regulation hypothesis for muscle fiber necrosis?

Answer 1

Failure of certain molecules to be localized to the muscle membrane when DGC components are absent prevents proper signalling molecules from being incorporated into the muscle

Question 2

What is the vascular hypothesis for muscle fiber necrosis?

Answer 2

NO produced in muscle cells by the neuronal form of NO synthase which is normally incorporated into the DGC complex is now free and is trapped in the cell making it unable to dilate blood vessels. Leading to ischaemia.

Question 3

What is evidence that supports the vascular hypothesis?

Answer 3

nNOS KO mice do not have muscle disease so nNOS may play a direct role.

Question 4

What is the inflammatory hypothesis for muscle fiber necrosis?

Answer 4

Muscles in DMD patients exhibit coordinated activity of numerous components of a chronic inflammatory response.

Question 5

Why is inflammation important for successful regeneration?

Answer 5

Macrophage derived factors during this response activates satellite cells.

Question 6

What could go wrong during regeneration of muscle cells via satellite cells?

Answer 6

Too little, too long, too short, to much inflammation could all interfere with optimal regeneration. This is the result of compromised inflammatory signature

Question 7

What is fibrosis?

Answer 7

Abnormal and unresolvable chronic increase in connective tissue that interferes with function.

Question 8

What causes fibrosis?

Answer 8

increase in connective tissue that replaces contractile tissue.

Question 9

What are the negative effects of fibrosis in muscle cells?

Answer 9

Creates a physical barrier that limits efficacy of drug, cell and gene based therapies.

replaces contractile material

abnormal and unresolvable.

Question 10

What is necessary for maximum effectiveness of a pharmaceutical intervention for muscular dystrophy?

Answer 10

Treating as soon as possible.

Question 11

What are the types of methods by with muscular dystrophy can be treated?

Answer 11

Correction of genetic defects.

Cell therapy (myoblast transfer therapy)

Prevention of the phenotypic defect (generally via pharmacological therapies)

Question 12

What are some therapeutic approaches that have been trialed for DMD?

Answer 12

Corticosteroids

Anabolic agents

Myostatin inhibition

Growth factors

Ca2+ channel blockers

Membrane sealants

proteasome inhibitors

anti-inflammatory drugs

anti-fibrotic agents

antioxidants

amino acids as well as other nutritional approaches

Question 13

Why are animal models necessary?

Answer 13

Understanding the disease process is easier with animals

Multiple and invasive samples can be obtained in large amounts

Can manipulate system to investigate disease mechanisms

Developing treatments (test drugs to modify disease progression and to test novel therapies)

Question 14

What are the limitations of using animal models?

Answer 14

Species are different (some aspects of physiology are different)

quantity of muscle

quantity of the agent used

metabolism

Safety

Cost

Question 15

What are corticosteroids and what do they do?

Answer 15

Corticosteroids (prednisone for example) decrease muscle fiber size.

Used to counter the effects of chronic inflammation and to preserve existing muscle fibers.

Treated DMD patients experience increase in strength following this treatment compared to untreated DMD as a result.

As a result theydelay the need for wheelchair.

Question 16

How do corticosteroids work?

Answer 16

They decrease inflammation resulting in slow fibrosis in the muscles.

• Smaller fiber size could result in reduced ongoing damage to dystrophic muscle.
• Upregulate compensatory proteins (eg utrophin) or modify muscle fiber phenotype

Question 17

What are the side effects of corticosteroids?

Answer 17

Weight gain; fluid retention; and high blood pressure.

Ulcers; growth inhibition as a result

*This is the best treatment for this condition at the moment. Defined as the gold standard

Question 18

What is VBP15?

Answer 18

An alternative anti-inflammatory drug to prednisolone and has less side effects.

Question 19

What is the function of anabolic agents?

Answer 19

Make the muscles bigger and stronger.

They do this either by increasing muscle protein synthesis, decreases degradation, or both resulting in bigger muscles.

Question 20

What are some examples of muscle anabolic agents?

Answer 20

Anabolic steroids

Growth Hormones

Beta 2 agonists

Growth Factors

Myostatin inhibiting antibodies.

Question 21

What is the result of myostatin inhibition?

Answer 21

Myostatin inhibition results in bigger muscles in animals and humans.

Myostatin KO mice have 3 fold greater muscle mass.

Question 22

What are myostatin levels like in the elderly?

Answer 22

Higher (potentially a contributing factor to sarcopenia)

Question 23

What are the methods by which myostatin inhibition can take place?

Answer 23

Genetic manipulation (KO mice)

Neutralising antibody - pharmacological approach

Question 24

What was the result of myostatin blackade in dystrophic mice?

Answer 24

Reduced pathology

Improvement in size of muscle

Force of contraction was larger

Tetanic forces were improved

Question 25

What are the problems with using IGF-1?

Answer 25

Existing tumour growth?

New tumour formation?

IGF-1 is promising as a therapeutic agent for muscular dystrophy.

Question 26

What was the result of IGF-1 administration to mice?

Answer 26

Improvement in fatigue resistance of the diaphragm and the force produced by muscle strips.

Increase in muscle fiber size and number

Decrease in necrosis of muscle fibers.

Decrease in signalling pathways associated with necrosis.

Enhanced oxidative status and reduced contraction-induced injury.

Question 27

What was the result of upregulation of IGF-1 in transgenic mice?

Answer 27

Upregulation of IGF-1 in transgenic mice resulted in a largermuscle fiber size in mdx mice.

Question 28

What were the benefits of using IGF-1 in dystrophic mice?

Answer 28

Fibrosis inhibition

Hypertrophy of muscle fibers

Improved repair of muscle fibers

This resulted in enhanced muscle survival

Increased oxidative capacity of the muscles.

Question 29

How did IGF-1 administration cause an increase in oxidative capacity of muscle fibers?

Answer 29

IGF-1 induced a shift away from the type 2b muscle to more oxidative muscle types.

Question 30

Why is there an interest in the ideal muscle size for muscular dystrophy?

Answer 30

Small fibers with low forces are typically spared in DMD.

Large muscle fibers create larger forces. However they are also likely to experience more contraction mediated injury.

*Commonly held view is that increasing muscle size has the negative effect of aggravating the dystrophic pathology.

Question 31

What do beta agonists do?

Answer 31

Used traditionally as bronchodilators for treating asthma.

Some have very powerful anabolic effects on muscle in large doses when taken systemically.

Have the potential to reverse muscular atrophy

Question 32

What can beta agonists potentially do for muscle wasting?

Answer 32

Increase muscle mass

Increase fiber size

Increase strength

Increase slow-to-fast muscle fiber transitions

Enhance muscle repair after damage.

Question 33

What did beta agonists do to the stretch response of muscle fibers?

Answer 33

it had a protective effect

Question 34

How did beta agonists so do in treating dystrophic disorders?

Answer 34

They had very limited results so far and some adverse cardiac related events in fasciomuscular dystrophy. More efficacious in duchenne’s and becker’s muscular dystrophy.

Question 35

What was the effect of low intensity exercise training on dystrophic people?

Answer 35

It increased strength modestly. cardiac parameters were improved.

*High intensity exercise should be avoided.

Question 36

What does literature show about immobilising dystrophic muscle?

Answer 36

Immobilisation of muscle caused pathology to get even worse in a study.

Another study showed the opposite effect!

Reason for this was that test models were different.