Skeletal muscle diseases: Pharmacological therapies (Lecture 16)

Question 1

What is IL-15?

Answer 1

A myokine naturally released from muscle during muscle contractions.

Question 2

What does Il-15 do?

Answer 2

Increases muscle glucose uptake and lowers rate of deterioration of contractile protein.

*May play a role in metabolic adaptation of muscle to physical activity

Question 3

What effect did IL-15 have on dystrophic mice?

Answer 3

IL-15 improved specific force of mdx’s diaphragm by decreasing rate of fibrosis.

Question 4

What is poloxamer-188?

Answer 4

Synthetic non-toxic, non-ionic, membrane sealant.

Question 5

How does poloxamer-188 work?

Answer 5

It is a membrane-like structure that can incorporate itself into cell membranes and ‘plug’ holes in torn membranes.

Question 6

What evidence is there that poloxamer is a good treatment for muscular dystrophy?

Answer 6

Poloxamer prevented blue dye infiltration

Question 7

What happens when there are high calcium levels following dystrophin deficiency?

Answer 7

Calpain’s are activated and ROS are increased resulting in chronic inflammation, apoptosis, and necrosis

Question 8

What happens on the macroscopic scale when calpains are activated and ROS are released?

Answer 8

myofibers degenerate and there is a decreased regenerative capacity.

Fibrosis

Loss of viable muscle fibers

Muscle functional impairment

Question 9

What causes impairment of calcium homeostasis?

Answer 9

impaired SERCA function

Question 10

What is the mdx mouse?

Answer 10

Most widely used model for DMD.

It lacks dystrophin

Question 11

What was the effect of higher SERCA levels in the SR?

Answer 11

Higher SERCA levels in the SR dramatically reduced fibrosis and muscle damage.

Question 12

How could SERCA pump be preserved in the sarcoplasmic reticulum?

Answer 12

Heat Shock Proteins

Question 13

How do Hsp proteins protect SERCA?

Answer 13

At high temperature SERCA activity is reduced. Heat Shock Proteins reduce this effect and stabilize nucleotide domain during periods of high temperatures.

Improves [Ca2+] handling through improvements in SERCA function under conditions of stress.

Question 14

What happened following Hsp72 treatment?

Answer 14

Blue dye infiltration was reduced

Muscle damage was reduced

Creatine kinase levels were reduced

Fibrosis was reduced

Muscle force was improved

Question 15

What drug can potentially upregulate Hsp72?

Answer 15

BGP-15

Question 16

What other methods can upregulate Hsp72?

Answer 16

Heat therapy

Question 17

Which method to upregulate Hsp72 is better?

Answer 17

BGP-15 produces dramatic reduction in muscle damage in the long term

Question 18

What effects did BGP-15 have on dko mice?

Answer 18

Decrease in kyphosis

Decrease in Creatine Kinase levels

Decrease in collagen infiltration

Increase in specific force

Question 19

What is the problem with Hsp72?

Answer 19

Hsp72 treatment needs to be done early. It slows pathology development but does not reverse it.

Question 20

What happened when BGP-15 was used in later age?

Answer 20

No changes were observed to skeletal muscle and diaphragm muscle.

Heart defects were reduced.

Question 21

What agents could be used to reduce fibrosis in muscle?

Answer 21

TGF-beta inhibitors/modulators

Tranilast

Orally bioavailable anti-allergenic approved for human use to treat bronchial asthma, atropic dermatitis, and allergc rhinitis.

Base formulation of new drugs for fibrosis in diabetic nephropathy.

Question 22

What happened to mdx mice given tranilast?

Answer 22

31% reduction in fibrosis in diaphragm.

Muscle function was not improved.