Muscular dystrophy Flashcards
What type of muscle is skeletal muscle?
Voluntary
How many muscles are found in the body?
640
What are the main functions of muscles?
Posture
Locomotion
Muscles are able to regenerate
TRUE or FALSE
TRUE
What is the stem cell found in muscle called?
Satellite cell
What is the smallest unit of muscle?
Myofibrils
What is a collection of myofibrils called?
Fascicles
What is the layer of connective tissue that surrounds the fascicles called?
Perimysium
What is the layer of connective tissue that surrounds each individual muscle fibre?
Endomysium
What is the plasma membrane of the muscle fiber called?
Sarcolemma
What is the cytoplasm of the muscle fiber called?
Sarcoplasma
What is the name of the endoplasmic reticulum of the muscle fiber called?
Sarcoplasmic reticulum
What is the role of the endoplasmic reticulum?
Stores, releases and retrieves calcium ions
What is the name of the functional unit of a skeletal muscle fibre?
Sarcomere
Describe the divisions of muscle
Sarcomere
Myocytes
Fascicles
Muscle
What type of nuclei are found in cells composing skeletal muscle?
Post-mitotic nuclei
Is skeletal muscle innervated?
Yes
Is skeletal muscle vascularised?
Yes
What is muscular dystrophy?
Inherited disorder where strength and muscle bulk gradually decline
What are the different conditions of muscular dystrophy?
Duchenne muscular dystrophy
Becker muscular dystrophy
Emery-Dreifuss muscular dystrophy
Limb-girdle muscular dystrophy
Facioscapulohumeral muscular dystrophy
Myotoic dystrophy
Oculopharyngeal muscular dystrophy
Congenital muscular dystrophy
What characterises the different muscular dystrophies?
Different mutations to the gene coding for the protein complex
What are the differences in presentation between the different muscular dystrophy types?
Different types of muscle affected
Different severity in symptoms
Different onset
Describe the appearance of normal muscle
Fibres are polyglonal
Fibres are tightly packed
Fibres show little variation in size
Nuclei of muscle cells are found on the edge
Describe the appearance of muscle in MD patients
Cells are characterised by necrosis and fibrosis
Diffuse variation in size
Deposition of adipose tissue
Inflammation
Regeneration observed as small cells with large nuclei
More nuclei internally
Abnormal cells with whorled appearances
Split fibres
You can diagnose the type of MD by muscle biopsies
TRUE or FALSE
FALSE
What cells do MD pathologies affect?
Muscle fibres
Satellite cells
Extracellular matrix
Inflammatory cells
Fibroadipogenic cells
What is the consequence of extracellular matrix defects in MD?
Dysfunction in the extracellular matrix consequently affects
- satellite cell niche
- signalling
- physical barrier to stem cells
What is the dystrophin-associated complex?
Protein that spans the cell membrane and whose mutations at different parts of the complex cause different MD pathologies
Which part of the dystrophin-associated complex is affected in DMD?
Dystrophin
Which part of the complex is affected in Becker MD?
Dystrophin
Which part of the complex is affected in Emery-Dreifuss MD?
Emerin
Lamin
Which part of the complex is affected in Limb-girdle MD?
Sarcoglycans
What does DMD stand for?
Duchenne Muscular Dystrophy
What is DMD?
Progressive, muscle-wasting neuromuscular disorder
What proportion of the population is affected by DMD?
1 in 5000 newborn boys
Describe the pathogenesis of DMD
Deficit in dystrophin causes muscle cell death upon contraction
Muscle undergoes successive rounds of degeneration and regeneration
Eventually the muscle tissue is replaced by fibrotic tissue
Why is muscle replaced by fibrotic tissue in DMD?
The muscle regeneration cannot keep up with the degeneration
At what age do patients with DMD lose ambulation?
10-12 years
At what age do patients with DMD die?
Early adulthood (25-30 years)
Advances in treatment have increased the survival in patients
What is the best way to monitor a treatment for MD patients?
Ambulatory assessment
What is an ambulatory assessment?
6 minute walking test
What is fibrotic tissue composed of?
Fat
Connective tissue
What causes the loss of stem cells in muscle of DMD patients?
Not known
Are they lost via apoptosis
Does the pathological environment cause them to not work correctly
What is the main difference between Becker MD and DMD ?
Becker is a milder variant of DMD
What makes Becker MD a milder condition than DMD?
Later onset
Progression of the disease is variable
Loss of walking ability is only seen in 18% of cases
Scoliosis is very uncommon
What mutation causes Becker MD?
Deletion mutations that lead to misshapen dystrophin
Still maintains the reading frame
Loss of amino acids that are not essential to dystrophin function
Dystrophin produced is functional but still semi-functional
What mutation cause DMD?s
Frameshift mutation that cause translation to end earlier on the gene
Loss of amino acids that are essential to dystrophin function
No functional dystrophin is produces
What is the role of dystrophin?
Attaches the dystrophin associated protein complex to the actin of the ECM
Prevents the myocyte cell membrane from ripping apart during the contraction of muscles
What makes the discovery of the dystrophin gene unique?
The gene was discovered before the protein
Where is the dystrophin gene localised?
xp21
What causes the different isoforms of dystrophin found around the body?
Different promoter sequences
Code for different lengths of dystrophin needed in different parts of the body
What happens to the muscle following a lack of dystrophin?
Myofiber degeneration
Satellite cell activation
Muscle regeneration
Altered composition and stiffness of ECM
What are current treatments for DMD patients?
Corticosteroids
Ventilation
Cardiac care
Psychological management
Skeletal management
What are potential therapies for DMD?
Gene therapy through AAVs
Readthrough of stop codons
Antisense oligonucleotides
Stem cells
How does gene therapy through AAVs alleviate DMD presentation?
They lessen the severity of the symptoms by changing the condition from DMD to Becker
Since AAVs are not able to carry the whole gene
The protein is too large
What is the main issue in treating MD?
It is a condition with multi-organ presentation
Many aspects of MD need to be tackled
Which molecules are used in exon skipping?
Antisense oligonucleotides
Describe the process of exon skipping in DMD
Open reading frame disrupted in DMD forms truncated, non-functional dystrophin
Exon responsible for the frameshift mutation is skipped
This restores the reading frame
Forms an internally deleted, partly functional dystrophin
What is the most common mutation that causes DMD?
Out-of-frame deletions
Out-of-frame duplications
Occurs to 70-75% of DMD patients
What is an outcome measure?
Indicates a measure of the result of a system relative to the aim
Used as a measure of the success of a trial
What is normally the primary OM of a clinical trial?
Safety
Why are biochemical OMs of dystrophin patient not good measures of the improvement of a patient?
Tells you if the treatment increases dystrophin levels
Does not necessarily correlate to the functional improvement of a patient
What type of OM is used to assess functional improvement?
Clinical OM
6 minute walk
Why is dystrophin quantification at protein and RNA levels difficult?
Low levels of a very large protein
What are ways to carry out biochemical OMs of treatment modalities used for DMD?
Can asses the exon skipping and dystrophin quantifications by immunohistochemistry and western blotting
What is a disadvantage of AONs?
Ineffectively target the heart
90% of DMD patients suffer cardiac complications
How can we increase the efficacy of AONs targeting the heart?
Conjugate AONs with cell penetrating peptides to enhance cell delivery
What is a disadvantage of using modified AONs?
Increased toxicity
What are targets of DMD therapy?
Premature stop codons
Out of frame deletions or insertions
Absence of functional dystrophin
Loss of regenerative capacity
Loss of muscle mass
Disruption of signalling, inflammation and ROSs
What is a therapy that targets premature stop codons?
Aminoglucoside antibiotics
Read through stop codons
What is a therapy that targets out of frame deletions or insertions?
Exon skipping with antisense oligonucleotides
What is a therapy that targets the absence of functional dystrophin?
Dystrophin gene therapy
Utrophin upregulation
What is a therapy that targets the loss of regenerative capacity?
Stem cell therapy
What is a therapy that targets the loss of muscle mass?
Myostatin blockade
What is a therapy that targets that targets the disruption of signalling, inflammation and reactive oxygen species?
Pharmacological intervention
Examples of drugs used to aid the disrupted signalling, inflammation and ROSs seen in MD
Steroids
Immunosuppressants
Calcium buffering
NF-kB blockade
Anti-oxidants
