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+ CAPS 301: Muscle, Bodily Fluid, Cardio > Muscle – DMD, BMD > Flashcards

Muscle – DMD, BMD Flashcards

1
Q

What is botox?

A

toxin produced by bacterium Clostridium botulinum

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2
Q

How does botox lead to botulism?

A

botox inhibits fusion of synaptic vesicles with presynaptic membrane

inhibits ACh release by axon terminals, which leads to botulism

no endplate potential, therefore no muscle contraction – state of relaxation

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3
Q

What does botulism cause?

A

muscular paralysis
respiratory failure
death

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4
Q

What happens when people get botox?

A

freeze muscles in face – remove wrinkles and emotional responses

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5
Q

What are Duchenne (DMD) and Becker (BMD) Muscular Dystrophies characterized by?

A
  • weakening of skeletal muscles
  • progressive wasting of muscles
  • mental retardation
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6
Q

What type of disease is DMD and BMD?

A

genetic diseases caused by mutations in dystrophin gene located on X chromosome

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7
Q

What is dystrophin protein?

A

cytoplasmic protein that plays role in linking actin cytoskeleton with basal lamina

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8
Q

How is DMD and BMD inherited?

A

from carrier mother

  • ¼ chance of having son with DMD
  • ¼ chance of having carrier daughter
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9
Q

What are symptoms of DMD and BMD?

A
  • mostly affects boys
  • first signs appear around ages 3-5, especially people with DMD
  • waddling walk
  • walking on tiptoes
  • curvature of spine
  • enlarged calf muscles – pseudohypertrophy
  • progression of muscle weakness
  • use of wheelchair between age of 8-12 (people with DMD)
  • limited fine movements
  • development of scoliosis (curvature of spine)
  • breathing difficulties
  • death occurs before age of 20 from heart failure or pneumonia
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10
Q

Where is the dystrophin gene?

A

on short arm of X chromosome

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11
Q

What does the dystrophin gene produce?

A

large dystrophin protein

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12
Q

Where is the actin binding domain of the dystrophin protien?

A

NH2 terminal

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13
Q

What are the regions of the dystrophin protein?

A
  • 4 hinge regions
  • 24 rod-like domains
  • cysteine-rich domain
  • actin binding domain
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14
Q

What happens if there is mutation in dystrophin gene?

A

results in stop codon – truncated protein

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15
Q

What types of mutation will result in stop codon in dystrophin gene?

A

any mutation (exon deletion, base substitution, etc.)

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16
Q

What happens to truncated dystrophin proteins?

A

don’t live long in the cell because it will be targeted by degradation enzymes

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17
Q

What happens if a mutation in the dystrophin gene does not result in stop codon?

A

synthesis of a shorter, but still functional, dystrophin protein

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18
Q

What does the dystroglycan-containing complex (dystrophin-associated protein complex) link?

A

links actin cytoskeleton to basal lamina

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19
Q

How does the dystroglycan-containing complex link actin cytoskeleton to basal lamina?

A
  • dystrophin binds to actin cytoskeleton via its NH2 terminal
  • dystrophin binds to 𝛽-dystroglycan via cysteine-rich domain
  • 𝛽-dystroglycan binds to 𝛼-dystroglycan (extracellular)
  • laminin-2 (component of basal lamina) binds to 𝛼-dystroglycan
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20
Q

When are muscle fibers more prone to injury and tears?

A

when performing tasks requiring muscle contraction

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21
Q

Describe the link between tears, contraction-induced injuries, and dystrophin.

A
  • dystrophin is structural protein that makes sure there’s a cross-talk link between inside and outside of cell
  • in DMD, no dystrophin – severed link between inside and outside of cell
  • when muscle fibre twitches and contracts, muscle fibre eventually breaks down and dies
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22
Q

Describe the dystrophin protein and its fate in normal individuals.

A

functional dystrophin protein

  • binds to actin via NH2 terminal
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23
Q

Describe the dystrophin protein and its fate in individuals with DMD.

A

truncated dystrophin protein

targeted by degradation enzymes

24
Q

Describe the dystrophin protein and its fate in individuals with BMD.

A

partially functional dystrophin protein

  • can still bind actin cytoskeleton (maintain link between basal lamina and actin cytoskeleton)
25
Q

What does lack of dystrophin (DMD) result in?

A

infiltration of connective and adipose tissues

26
Q

Where are connective tissues?

A

intercalated between muscle cells and muscle fascicles

27
Q

What happens as a result of infiltration of connective and adipose tissues (due to DMD)?

A

clusters of nuclei of macrophages that have invaded tissue (to digest debris of muscle fibres) have degenerated

28
Q

What is pseudohypertrophy? (ie. of large calf)

A

from outside, we are led to believe there are more muscle fibres, or they’re much larger

but, actually due to lots of connective tissue and adipose tissue that invades muscles – not ‘real’ hypertrophy

29
Q

What is a mdx mouse?

A

mouse that carries spontaneous mutation in exon 23 of dystrophin gene – used as model for DMD

30
Q

What is kyphosis in mdx mouse?

A

more prominent curvature of spine

31
Q

How does kyphosis occur?

A
  • muscles have weakened
  • less muscle fibres – degenerate
  • cannot maintain normal spinal shape
32
Q

What are the 3 main therapeutic strategies for DMD?

A
  • cell therapy
  • pharmacological therapy
  • gene therapy
33
Q

What does pharmacological therapy due?

A

aim to reduce inflammation

34
Q

What is cell therapy?

A

myoblast or stem cell transplantation into skeletal muscles

35
Q

Is cell therapy successful?

A

not very successful in the past

36
Q

How is cell therapy done?

A

skeletal muscles are large, therefore transplantation must be done in many sites

37
Q

What is the downside of cell therapy?

A

generates inflammation due to transplantation done in many sites

38
Q

What is gene therapy?

A

delivery of DNA encoding dystrophin

39
Q

What is the challenge of delivering DNA encoding dystrophin in gene therapy?

A
  • gene is too long to deliver
  • need to find ways to chop gene and express its most significant sequences to end up with some kind of functional protein
40
Q

What are the 2 methods used in gene therapy?

A
  • exon skipping

- CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat)

41
Q

What does pharmacological therapy rely on?

A

relies on use of arginine butyrate

42
Q

What does arginine butyrate do?

A

inhibits histone acetylases (which modulate rate of gene transcription) → increases gene transcription

43
Q

What is utrophin?

A

homolog of dystrophin also expressed in skeletal muscle fibres

44
Q

Describe pharmacological therapy in mdx mouse. State the results.

A

treat mdx with arginine butyrate and look at histology of muscle

much less connective tissue in mdx mouse

45
Q

What is microdystrophin?

A

possible therapeutic strategy for DMD

46
Q

In dystrophin-associated protein complex in mdx muscle expressing microdystrophin:

A
  • deleted rod domain from R4 to R23 → left with NT, hinge 1, R1, R2, hinge 3, R24, hinge 4
  • when DNA sequence encoding microdystrophin was made, some things were able to be restored
47
Q

What is the effect of microdystrophin in mdx mouse?

A

microdystrophin gene delivery using AAVs restores dystrophin expression in mdx mouse

48
Q

What do adeno-associated virus vectors (AAVs) do?

A

packages microdystrophin in order for it to reach the appropriate sites

49
Q

What does microdystrophin delivery do in mdx mouse?

A

corrects dystrophic pathology in mdx mouse

no full-sized fields of macrophage nuclei

at motor level, improvements were marginal

50
Q

What occurs during exon skipping?

A
  • skip sequence where stop codon appears

- use antisense oligonucleotides to mask/block DNA sequence where stop codon appears

51
Q

What are antisense oligonucleotides?

A

sequences of nucleotides that are somewhere around 20 nucleotides

52
Q

Exon Skipping

A
  • skip sequence where stop codon appears

- use antisense oligonucleotides to mask/block DNA sequence where stop codon appears

53
Q

Multi-Exon Skipping Approach

A
  • use multiple antisense oligonucleotides to skip exons
54
Q

What occurs during multi-exon skipping?

A

use multiple antisense oligonucleotides to skip exons

55
Q

What is a limitation of exon skipping?

A

skipping in critical regions

ie. mutation in exon, which encodes portion of cysteine-rich domain (green)

  • without cysteine-rich domain, dystrophin cannot bind to beta dystroglycan
  • non-functional protein
56
Q

What is an out of frame mutation?

A

mutation that disrupts 3-letter reading pattern, creating words that don’t make sense and leading to unreadable sentence

57
Q

What is the general idea of exon skipping?

A

converts unreadable sentence to sentence that makes sense

+ CAPS 301: Muscle, Bodily Fluid, Cardio (13 decks)

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