Module 5 - cell signalling

Question 1

Muscular dystrophy

Answer 1

group of disorders, progressive muscle weakness and loss of muscle tissue
unrecoverable, damage replaced with scar tissue

Question 2

Duchenne Muscular Dystrophy

Answer 2

Pseudohypertrophy 
X-chromosome Xp21 (Dystrophin gene)
X-linked recessive
Predominantly in males
Rarely in females w/ Turner (XO) or Turner mosaic syndromes
1/3500 live male births

Question 3

Pseudohypertrophy

Answer 3

Increased mass, muscle damage, replaced with scar tissue

Question 4

Dystrophin function

Answer 4

transmission of force to extracellular matrix

Question 5

Dystroglycan complex

Answer 5

Transmembrane linkage between ECM and cytoskeleton
Provides structural integrity to muscle tissues
Possibly an agrin receptor and reduces agrin-induced clustering at NMJ

dystrophin, dystroglycan (alpha and beta), sarcoglycans (a, b, y, o), syntrophins (a, B1), dystrobrevins (a, b), sarcospan, laminin-a2 (merosin)

Question 6

Muscular dystrophy - 2 main types

Answer 6

Due to mutations in various genes related to dystrophin associated complex (DAC)

Major:
DMD - total absence of dystrophin, lethal, leads to cardiac and respiratory failure (failure of diaphragm)
Becker dystrophy (BMD) - milder myopathy, some alterations and absence of dystrophin

Minor: exercise intolerance, limb girdle weakness (LGMD1C; 2A-E), cardiomyopathy. Linked to late onset diseases

Question 7

DMD

Answer 7

Lethal, childhood, assoc w/ marked deficiency or total absence of dystrophin
Early symptoms - difficulty running, frequent floors, enlargement of calf muscles(body tries to compensate for loss of muscle strength; muscle tissued eventually replaced by fat and connective tissue = pseudo hypertrophy)

at 3-6 years, weakness becomes more apparent

6-11 years, strength of limb and torso muscles decreases steadily until ambulation is lost

During second decade: sig. weakness of respiratory muscles

death: 10-29 years old, mean 18.3
phases: early, intermediate (scoliosis), late (wheelchair)

Question 8

Becker dystrophy

Answer 8

mild myopathy, better prognosis
same mutated GENE but different MUTATION
later onset (20s/30s), slower progression
weakening and wasting of hip muscles first, and pelvic area, thighs and shoulders

Question 9

Treatment (BMD?)

Answer 9

Stretching, motion exercise
OT
physical therapy
aquatic therapy
not too much exercise! can't recover from damage

Question 10

Treatment (DMD)

Answer 10

Breathing: O2 therapy, ventilator, scoliosis surgery, tracheotomy

Mobility: physical therapy, surgery on tight joints, prednisone, non-steroidal medications (delays puberty), wheelchair

Question 11

State of nuclei and fibre dimension

Answer 11

Normal: nuclei = subsarcolemmal
Regenerated muscle fibres: nuclei = internalised
Dystrophic: some fibres very large, some very small - both fibre hypertrophy and atrophy present

Weak muscle = branched fibre, contraction causes splitting, makes a weak point due to branching

Question 12

Histopathology of DMD muscle

Answer 12

Degeneration <> regeneration
> Inflammation - fibrosis
> Exhaust replicative pool - fibre loss

Question 13

What causes dystrophy?

Answer 13

Dystrophin assoc complex functions as a protein scaffolding that protects sarcolemma from rupture by stress during muscle contraction (mechanical hypothesis)

Question 14

Mechanical hypothesis

Answer 14

Muscle stretch during contractions = greater damage (eccentric contractions)
dystrophic fibres prone to damage when exposed to hypotonic solutions
prevention of usage in DMD muscle = delays damage

Question 15

Model of DMD?

Answer 15

mdx mice
spontaneous mutation of dystrophin gene = deletion of same protein in DMD
mdx mice show milder phenotype

Question 16

Stretch contraction

Answer 16

when muscle increases tension and length at same time = immediate weakness, days to recover
causes muscle damage!

more damage in mdx mic vs. control when tetanic force contractions (increased lengthening)

however no sig. damage in SLOW-TWITCH muscle

Question 17

Dystrophy - alternative hypothesis

Answer 17

Disruption of DAC causes primarily an increased leak of EC Ca into muscle fibre by increasing opening of Ca2+ channels in membrane&raquo_space; activation of Ca-activated neutral proteases (calpains) and fibre necrosis

Calcium hypothesis!

Question 18

Calcium hypothesis

Answer 18

Elevated IC [Ca2+] in resting muscle from DMD
Early degradation of titin (due to cal pains) - these maintain alignment of myosin filaments in the middle of the sarcomere. Can also be explained by mechanical hypothesis (contraction can destroy membrane&raquo_space; increase in IC [Ca2+])

Question 19

Gene therapy

Answer 19

Deliver to all striated muscles (skeletal and cardiac)?

Created gutted virus - has own genes removed, carries only dystrophin genes

Question 20

Cons of gene therapy

Answer 20

Muscle tissue = large, relatively impenetrable
Viruses can provoke immune sys., destroy muscle fibres with new genes
Gene size (really big)
Secondary injections
Scaling - mouse to human
Gene replacement only benefits young boys with DMD - pre- or mild damage
Need different approach for older patients

Question 21

Rippling muscle disease

Answer 21

autosomal dominant
generally benign symptoms of hyperexcitability, muscle soreness and slowness of movement after rest
most common: mechanically stim. rolling contracture
assoc wi/ mutation in caveolin-3 gene (plasma membrane protein) - decreases resistance on AP propagation
due to APs propagating solely within t-system networks

Question 22

t-tubules

Answer 22

ensure uniform contraction and release of calcium everywhere - repeating through to sarcomere
SR - releases Ca to bind to contractile proteins to release a force

Question 23

Transverse t tubules

Answer 23

conduct APs throughout muscle fibre, house moleculr machinery for ECC (creates signalling microdomain by forming a junction with the SR terminal cistern)

Question 24

Longitudinal

Answer 24

links transverse tubules, provides storage area for small molecules during fatigue

Question 25

Subsarcolemmal

Answer 25

provides pathway from sarcolemma (surface membrane) to the transverse tubules for the APs

Question 26

Rolling contractures - cable theory

Answer 26

Swollen t-system due to mutations
AP propagation rate increaes
silent in surface EMG
conducted by APs that travel solely through t-sys without breaking out to the sarcolemma (low amplitude electrical signal) - cannot reach threshold to activate AP (high Na+ channel densities)

Question 27

Space flight - physiological effects

Answer 27

Space motion sickness, fluid redistribution to upper body and head&raquo_space; increased neg Ca++ balance, increased renal stone risk, decreased muscle strength
neurovestibular dysfunction
decreased CV efficiency, blood plasma and bone density, increased radiation doses

Question 28

17 day spaceflight

Answer 28

Structural changes - skeletal structure, z line streaming - misaligned sarcomeres, loss of thin filaments, increased lipid droplets, mitochondria morphology changes

Question 29

Gravity muscle

Answer 29

slow twitch, type I, opposes gravity, required less in microgravity environment
skeletal muscles remodel after a few days