Skeletal muscle diseases: Pharmacological therapies (Lecture 16) Flashcards
What is IL-15?
A myokine naturally released from muscle during muscle contractions.
What does Il-15 do?
Increases muscle glucose uptake and lowers rate of deterioration of contractile protein.
*May play a role in metabolic adaptation of muscle to physical activity
What effect did IL-15 have on dystrophic mice?
IL-15 improved specific force of mdx’s diaphragm by decreasing rate of fibrosis.
What is poloxamer-188?
Synthetic non-toxic, non-ionic, membrane sealant.
How does poloxamer-188 work?
It is a membrane-like structure that can incorporate itself into cell membranes and ‘plug’ holes in torn membranes.
What evidence is there that poloxamer is a good treatment for muscular dystrophy?
Poloxamer prevented blue dye infiltration
What happens when there are high calcium levels following dystrophin deficiency?
Calpain’s are activated and ROS are increased resulting in chronic inflammation, apoptosis, and necrosis
What happens on the macroscopic scale when calpains are activated and ROS are released?
myofibers degenerate and there is a decreased regenerative capacity.
Fibrosis
Loss of viable muscle fibers
Muscle functional impairment
What causes impairment of calcium homeostasis?
impaired SERCA function
What is the mdx mouse?
Most widely used model for DMD.
It lacks dystrophin
What was the effect of higher SERCA levels in the SR?
Higher SERCA levels in the SR dramatically reduced fibrosis and muscle damage.
How could SERCA pump be preserved in the sarcoplasmic reticulum?
Heat Shock Proteins
How do Hsp proteins protect SERCA?
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.
What happened following Hsp72 treatment?
Blue dye infiltration was reduced
Muscle damage was reduced
Creatine kinase levels were reduced
Fibrosis was reduced
Muscle force was improved
What drug can potentially upregulate Hsp72?
BGP-15
What other methods can upregulate Hsp72?
Heat therapy
Which method to upregulate Hsp72 is better?
BGP-15 produces dramatic reduction in muscle damage in the long term
What effects did BGP-15 have on dko mice?
Decrease in kyphosis
Decrease in Creatine Kinase levels
Decrease in collagen infiltration
Increase in specific force
What is the problem with Hsp72?
Hsp72 treatment needs to be done early. It slows pathology development but does not reverse it.
What happened when BGP-15 was used in later age?
No changes were observed to skeletal muscle and diaphragm muscle.
Heart defects were reduced.
What agents could be used to reduce fibrosis in muscle?
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.
What happened to mdx mice given tranilast?
31% reduction in fibrosis in diaphragm.
Muscle function was not improved.
