From Excitation to Contraction

Question 1

NMJ

Answer 1

• Skeletal muscle contracts under nervous system control
• Motor neurons in anterior horns of the spinal cord
• Motor unit – one ventral or anterior horn nerve cell and all the fibers in a muscle that the one nerve cell interacts with or stimulates
• Could be 10 or 100 muscle fibers
• If a muscle has smaller but more numerous motor units, it is capable of more types of speeds and types of contractions
• The smaller muscles of our hands and digits have more motor units with fewer muscle fibers
• Synapse on muscle fiber = NMJ

Question 2

Synapse

Answer 2

• Nerve terminals descend into the muscle fiber but lie outside the plasma membrane (sarcolemma)
• Post-synaptic membrane = motor end plate
• Invagination of muscle membrane = synaptic gutter
• The synaptic gutter is folded which increases surface area
• Sub-neural folds increase surface area
• Ach neurotransmitter

Question 3

Secretion of acetylcholine

Answer 3

• Approximately 125 vesicles – don’t need to remember this number, but its useful to know that there is a set amount of vesicles being dumped
• When the action potential gets to the nerve terminal, theres an influx of calcium
• Voltage gated calcium channels surround linear dense bars in presynaptic membrane
• Calcium influx leads to vesicle fusion and exocytosis

Question 4

Ach effects

Answer 4

• Binds Ach receptor on motor end plate
• Receptors are large complexes of 5 subunits each (2 a,b,g, D), cumulative MW = 275 kDa
• Chemically gated channels requiring binding of 2 Ach molecules
• Channel is a positive ion channel – 2 sodium enter the cell and potassium leaves

Question 5

why is Na the primary ion involved

Answer 5

• Only Na+ and K+ exist in large enough concentrations to matter
• Resting muscle membrane potential (-80-90mV) has a larger “pull” on sodium
• The very negative potential inside the cell is attracting the large amount of sodium ions present outside the cell
• This then drives the membrane potential positive toward the Nernst potential of sodium

Question 6

effect of sodium flux

Answer 6

• End plate potential turns into action potential
• EPPs normally increase membrane potential 50-75mV, more than enough to pass threshold
• EPPs can be altered (curare and botulinum are examples) – interfere with the NMJ

Question 7

Ach

Answer 7

• Acetylcholine is destroyed by acetylcholinesterase in the synaptic cleft.
• Some is also lost to diffusion.
• Choline is then actively transported back into the presynaptic neuron. – so that it can be repackaged and used again

Question 8

Myasthenia gravis

Answer 8

• Autoimmune disease in which autoantibodies destroy Ach receptors. – the pts own immune system targets these receptors and breaks them down
• May be transmitted vertically from affected mother.
• Usually this form resolves once the antibodies degenerate and go away
• Treatment with cholinesterase blockade (neostigmine) allows Ach to accumulate overcoming receptor deficit.
• Discovered accidentally through animal research on rabbits.

Question 9

pathogenesis of myasthenia gravis

Answer 9

• Unknown, possibly viral infection with production of cross reacting autoantibodies
• M:F = 2:3 – expected considering it is autoimmune and autoimmune diseases are more common in women
• Ach receptors must be reduced to 30% for symptoms
• Smooth and cardiac muscles unaffected – function of the gut and heart are preserved – with this, the sensory nerves use NTs other than Ach so they aren’t affected either
• 75% have thymus abnormality and many improve with thymectomy

Question 10

signs and symptoms of myasthenia gravis

Answer 10

• CC initially = specific muscle weakness, esp eye, neck, face
• Diplopia, difficulty swallowing, chewing, speaking
• Symptoms aggravated by emotional/physical stress (illness, mesntruation, etc)
• Mild early symptom: inability to maintain superior gaze, ptosis
• Ice pack test positive approx 80% (cool affected area for 2 minutes, ptosis resolves)

Question 11

Muscle action potential

Answer 11

• Parallels nerve action potential with only quantitative differences
• Resting membrane potential – muscle tends to be lower and duration of AP is longer
• You also have transverse tubules that descend into the muscle like cardiac muscle – spreads the AP into the interior of the muscle near the SR that contains calcium
• AP duration
• Conduction speed
• Spread of AP to interior of cells by transverse tubule system

Question 12

excitation contraction coupling

Answer 12

• T-tubule system – descends down into fiber, runs across plane of myofibrils, closely related to SR inside the muscle
• Runs across plane of myofibrils
• Open to exterior, filled with EC fluids
• Close apposition to sarcopalsmic reticulum
• Mammalian skeletal and cardiac muscles different (single t-tubule in cardiac)
• 2 T tubules per sarcomere in muscle cells
• Action potential triggers calcium release to flow into the SR to trigger muscle contraction

Question 13

to contraction

Answer 13

• AP along t-tubule system stimulates calcium release from SR which binds troponin and exposes attachment sites for myosin heads
• Muscle contraction continues as long as calcium is present
• Calcium pulse usually lasts approx. 1/20 seconds

Question 14

pathophys of atrophy

Answer 14

• Atrophy (loss of muscle fiber mass)
• Disuse atrophy – sedentary lifestyle – bedridden condition
• Denervation atrophy – loss of trophic effect of lower motor neuron

Question 15

dystrophies

Answer 15

• Genetic disorders (> 30 defects known)
• Mixed muscle atrophy, hypertrophy and necrosis
• Muscle fibers replaced by fat and fibrotic material (psuedohypertrophy)
• Pseudohypertrophy is replacement of the muscle fibers with fat or scar tissue
• Characterized by insidious, progressive weakness

Question 16

duchenne MD

Answer 16

• Heritable absence of dystrophin (protein required for muscle structure)
• Males, females have 50% chance of carrying/passing mutation
• Onset of progressive weakness leading to paralysis at 3-5 yr, most lose ability to walk by 12 yo
• Becker MD similar but less severe disorder of dysfunctional dystrophin – pt produces dystrophin but it is not fully functional

Question 17

adult MD

Answer 17

• Fascioscapulohumeral MD – slowly progressive disorder of face, arms, shoulder beginning in teens
• Myotonic – MC adult form characterized by cardiac abnormalities and cataracts, swan neck, drooping eyelids

Question 18

MD

Answer 18

• Mostly affects boys (rarely girls).
• Often brothers or male relatives have same problem.
• First signs appear around ages 3 to 5: the child may seem awkward or clumsy, or he begins to walk ‘tiptoe’ because he cannot put his feet flat. Runs strangely. Falls often.
• Problem gets steadily worse over the next several years.
• Muscle weakness first affects feet, fronts of thighs, hips, belly, shoulders, and elbows. Later, it affects hands, face, and neck muscles. “Walk up” from seated/lying position.
• Most children become unable to walk by age 10.
• May develop a severe curve of the spine.
• Heart and breathing muscles also get weak. Child usually dies before age 20 from heart failure or pneumonia.