Muscle Diseases Techniques 1.1 : Functional assessments to evaluate therapeutic efficacy Flashcards Preview

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Flashcards in Muscle Diseases Techniques 1.1 : Functional assessments to evaluate therapeutic efficacy Deck (40):

What is DMD caused by?

Complete lack of dystrophin.


Where is dystrophin found?

Around the sarcolemma.


Which parts of the body are more affected in DMD?

Lower extremity and torso more affected than upper limbs.


What is becker's disease?

Like DMD but less severe, some dystrophin present.


What two structures does dystrophin connect?

Connects muscle fibre to the lamina, disperses forces evenly.


What kind of protein can dystrophin act like (name 2`)?

Anchoring protein and possibly signalling.


What happens to mice with dystrophin knockouts regarding lifespan?

Die prematurely.


What happens to other proteins with dystrophin absence?

Compensatory upregulation of the dstrophin like protein, utrophin.


What are mice with upregulated utrophin called?

mdx mice


What are mice with a double knockout of dystrophin and utrophin called?

dko mice.


Is the muscle an endocrine organ?



What is the aim of treating DMD?

Improving both muscle size and functionality. Pure size increase is useless.


Are muscles from mdx mice bigger than wild type mice? How do their strengths compare?

mdx mice muscles are larger, but they have the same strength.
So overall, mdx mice muscles are weaker and fragile given no dystrophin, and lower cross sectional force.


What are some types of non/minimally invasive analysis techniques?

Running, swimming, climbing etc.


What is the vertical hang test, and is it non-invasive? Name a pro and con of this.

It is, and is the latency to fall from a hanging wire.
Cant assess specific muscles, is a crude assessment
Is simple and a natural exercise


What is the grip strength test, and is it non-invasive? Name a pro and con of this.

It is.
Mouse holds onto a bar, and lifted from its tail by the assessor.
Assesses muscle strength, and simple
Can be inaccurate as assessors hold mice differently, cant assess specific muscles


What is the difference between in vitro, in situ and in vivo?

In vitro - isolated from the body - ie cell bath
In situ - Still in the body, as real life as pissble
In vivo - assessing entire muscle group


Name an in vitro technique on muscle, a pro and con.

Muscle cut out, hooked to a force gauge.
pro - directly assesses functionality free of neurovascular influence
con-less physiological assessment


Name an in situ technique on muscle, a pro and con.

Muscles stimulated individually
pro - preserves neurovascular supply, is more physiological
con - technically difficult, menial to carry out, expensive equipment


What is a problem with individual muscle stimulation in situ?

Can be minimally invasive by anaesthetising, but cant do this too often as it might interfere.


Name a technique at the cellular level. What can it assess (name 2). Name a pro and con

Single fibres are assessed, hooked to a force gauge.
Assesses Ca2+ release and uptake
Vmax (velocity of shortening)
pro - cellular level assessment, valuable info
con - technically difficult and expensive


What happens to CK (creatine kinase) levels in damaged muscles and in DMD?

Elevated, indicating muscle trauma.


What does a drug lowering CK levels indicate?

Means its successful in lowering trauma. If CK levels remain, drug most likely isnt working.


How can dye be used to assess damage and drug vbiability?

Damaged muscles let in more dye, more damaged is more dyed.
If a drug works, muscles its affecting must be less dyed.


How can fibrosis levels be used to assess damage levels and drug viability?

Muscles can be dyed for collagen, more damaged muscles are more fibrotic.
If the drug is working, should mean less dye positive fibres.


How can Ca2+ reuptake levels be used to assess damage and drug viability?

Ca2+ reuptake is lowered in damaged fibres. Drug must increase reuptake of Ca2+.


What 4 factors indicate a drug is working?

Lowering CK levels
Lowering dye penetrating membrane
Lowering collagen/fibrosis
Improving Ca2+ reuptake


How can dystrophin's ability to disperse forces be tested?

By electrical stimulation after streching. Isometric contraction force decreases with stretch.


What can be used to assess membrane integrity?



What happens when cells are ruptured in situ, regarding Ca2+ levels? Why is this a problem?

Caq2+ enters the cell from the extracellular matrix. Usually kept very low.


What can be said of isolated dystrophic muscle fibres regarding architecture?

Are wavy and have strange branches. Branches are weak points especially when stretched.


What can be said of the position of the mucei of dystrophic muscle fibres?

They are centrally nucleated, suggesting they are regenerating.


Does muscle damage occur when healthy muscles do isometric contraction? What about dystrophic muscles?

No it doesn't. It does in dystrophic muscles, are inherently fragile, and tear apart.


Why do dystrophic muscles tear apart when contracting? What is a possible cause of this (aside from the lack of dystrophin)?

Some parts of the fibre contract, while others relax, tearing it apart. A failure of the beta plate (neuromuscular junction) could cause this.


What is the mechanical hypothesis for dystrophic necrosis?

Loss of dystroglycan integrity leads to membrane rupture and protein accumulation.


What happens to the force deficit if dystrophic muscles are stretched then stimulated?



What is the calcium hypothesis for dystrophic necrosis?

Influx of Ca2+ intracellularly overwhelms the cell's buffer systems.
High Ca2+ levels for too long activates damaging pathways.
Linked to mechanical hypothesis.


What are the steps of muscle regeneration, and how is it different in DMD?

Contraction induced damage -> Ca2+ homeostasis lost -> muscle degeneration -> muscle regeneration
Normally regeneration is effective
In DMD, works well initially, but trauma is too rleentless and eventually wanes.


What happens if Ca2+ influx is quickly buffered? What happens in DMD?

Damage can be averted, and the muscle fibre preserved.
In DMD, cant be buffered, and once Ca2+ reaches a threshold, damaging pathways are activated.


What effect does the Ca2+ influx have on satellite cells?

If it is unbuffered for a periodof time, satellite cells are activated.

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