Module 5 - cell signalling Flashcards
Muscular dystrophy
group of disorders, progressive muscle weakness and loss of muscle tissue
unrecoverable, damage replaced with scar tissue
Duchenne Muscular Dystrophy
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
Pseudohypertrophy
Increased mass, muscle damage, replaced with scar tissue
Dystrophin function
transmission of force to extracellular matrix
Dystroglycan complex
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)
Muscular dystrophy - 2 main types
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
DMD
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)
Becker dystrophy
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
Treatment (BMD?)
Stretching, motion exercise OT physical therapy aquatic therapy not too much exercise! can't recover from damage
Treatment (DMD)
Breathing: O2 therapy, ventilator, scoliosis surgery, tracheotomy
Mobility: physical therapy, surgery on tight joints, prednisone, non-steroidal medications (delays puberty), wheelchair
State of nuclei and fibre dimension
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
Histopathology of DMD muscle
Degeneration <> regeneration
> Inflammation - fibrosis
> Exhaust replicative pool - fibre loss
What causes dystrophy?
Dystrophin assoc complex functions as a protein scaffolding that protects sarcolemma from rupture by stress during muscle contraction (mechanical hypothesis)
Mechanical hypothesis
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
Model of DMD?
mdx mice
spontaneous mutation of dystrophin gene = deletion of same protein in DMD
mdx mice show milder phenotype
Stretch contraction
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
Dystrophy - alternative hypothesis
Disruption of DAC causes primarily an increased leak of EC Ca into muscle fibre by increasing opening of Ca2+ channels in membrane»_space; activation of Ca-activated neutral proteases (calpains) and fibre necrosis
Calcium hypothesis!
Calcium hypothesis
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»_space; increase in IC [Ca2+])
Gene therapy
Deliver to all striated muscles (skeletal and cardiac)?
Created gutted virus - has own genes removed, carries only dystrophin genes
Cons of gene therapy
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
Rippling muscle disease
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
t-tubules
ensure uniform contraction and release of calcium everywhere - repeating through to sarcomere
SR - releases Ca to bind to contractile proteins to release a force
Transverse t tubules
conduct APs throughout muscle fibre, house moleculr machinery for ECC (creates signalling microdomain by forming a junction with the SR terminal cistern)
Longitudinal
links transverse tubules, provides storage area for small molecules during fatigue
Subsarcolemmal
provides pathway from sarcolemma (surface membrane) to the transverse tubules for the APs
Rolling contractures - cable theory
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)
Space flight - physiological effects
Space motion sickness, fluid redistribution to upper body and head»_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
17 day spaceflight
Structural changes - skeletal structure, z line streaming - misaligned sarcomeres, loss of thin filaments, increased lipid droplets, mitochondria morphology changes
Gravity muscle
slow twitch, type I, opposes gravity, required less in microgravity environment
skeletal muscles remodel after a few days
