Pathophysiology of Skeletal Muscle Contraction

Question 1

what is multiple sclerosis?

Answer 1

nerve myelin sheath degraded by an antibody-mediated attack; autoimmune condition which affects nerve signalling

Question 2

how does multiple sclerosis affect an individual?

Answer 2

damages myelin sheath and dissipates nerve activity

cause sclerotic lesions and leaky blood brain barrier

numbness, tingling, speech and visual problems, urinary incontinence and debilitating muscle weakness

Question 3

causes of multiple sclerosis?

Answer 3

unknown cause - can be triggered by different viruses and other conditions

Question 4

treatment for multiple sclerosis?

Answer 4

no cure - can manage the symptoms, slow progression of disease and improve quality of life

Question 5

what is myasthesia gravis?

Answer 5

autoimmune disease where the alpha 1 subunit of muscarinic nicotinic Ach receptors are targeted

neuronal nAChRs aren’t affected as they don’t have an alpha 1 subunit

Question 6

how does myasthesia gravis affect the surface of skeletal muscle cell membranes?

Answer 6

muscarinic nAChRs are on the small folds of the membrane. when antibodies attack and degrade the alpha 1 subunit, the membrane is smoothed/flattened out

receptors are degraded and internalised, affecting their function

Question 7

how myasthesia gravis affects an individual? (symptoms)

Answer 7

muscle weakness, dropping eyelids, fatigue, difficulty swallowing or talking

Question 8

treatment for myasthesia gravis?

Answer 8

preventing breakdown of Ach using acetylcholinerase inhibitors to enhance neuromuscular transmission

Question 9

what are non-dystrophic myotonias?

Answer 9

a group of genetic disorders characterised by muscle stiffness and delayed relaxation of muscles after contraction

Question 10

cause of non-dystrophic myotonias? mechanism relating to Na+ channels?

Answer 10

• mutations in SCNA4 gene = encodes and affects Na+ channel function. overall increased Na+ channel activity prolongs contraction
• loss of Cl- channel = less activity causes prolonged contraction

Question 11

how does a SCNA4 gene mutation relate to symptoms of non-dystrophic myotonia?

Answer 11

overall increased Na+ channel activity - decreased inactivation rate, increased recovery from inactivation, slower channel deactivation

more Na+ channel activity = prolonged Na+ influx = prolonged contraction and delayed relaxation (myotonia)

Question 12

what is dystrophic myopathy? what is it caused by? who is affected?

Answer 12

a group genetic disorders characterised by progressive muscle weakness and degeneration

caused by mutations in the DMD gene encoding dystrophin - affects reading frame

X-linked gene = females are carriers, men suffer

Question 13

two different types of dystrophic myopathy and how they differ?

Answer 13

Duchenne - a total loss of dystrophin

Becker - reduced/ dysfunctional dystrophin

Question 14

how do mutations of the dystrophin gene affect membrane permeability?

Answer 14

increase membrane permeability to macromolecules, especially during muscle contraction

leads to muscle fibre necrosis, fibrosis and fat infiltration

results in progressive muscle weakness and loss of function

Question 15

describe the molecular mechanisms behind skeletal muscle contraction

Answer 15

motor neurone releases Ach at the neuromuscular junction - Ach binds to a nicotinic Ach receptor on the muscle sarcolemma

two Ach molecules bind to cause a molecular kink - Na+ ICs ions open, Na+ influx = depolarisation generating an AP on the post-synaptic muscle

wave of depolarisation travels down T-tubule into the muscle fibre

t-tubule has a dihydropyridine receptor. AP depolarisation triggers molecular kink, ion channel opening and Ca2+ release from sarcoplasmic reticulum - increase in intracellular Ca2+

calcium binds to troponin-C, causes a conformational change that moves tropomyosin out of the way, exposing the actin-myosin binding site on actin

myosin head forms ATP-dependent cross-bridges at it binds to the actin-myosin binding site

ATP hydrolysis causes myosin head to pivot and generate a power stroke = causes actin filaments to slide towards the centre of the sarcomere = contraction

ATP binds to the myosin head, breaks the cross-bridges and forces myosin to detach

ATP hydrolysed on the myosin head, allows myosin head to reset its position

calcium is removed, tropomyosin returns to its original position, muscle relaxes

Question 16

understand how muscle structure leads to a rise in calcium

Answer 16

sarcolemma and T-tubules allow the AP to penetrate deep into the muscle fibre

sarcoplasmic reticulum = has voltage-sensitive Ca2+ ICs that release Ca2+ with depolarisation, regulate Ca2+ conc in the sarcoplasm

Ca2+ is needed to bind to troponin-C and initiate the contraction process

Question 17

understand the role of ATP hydrolysis in the power-stroke

Answer 17

myosin head forms ATP dependent cross-bridges to the actin-myosin binding site

ATP is hydrolysed to ADP and Pi = provides energy for myosin head to initiate the power stroke, causing the actin filament to slide towards the centre of the sarcomere

ATP binds to myosin head after power stroke = myosin detaches from myosin

ATP hydrolysed again to reset myosin head position

Question 18

describe the structure of voltage-gated Na+ channels

Answer 18

encoded by genes SCNA1-9 = different types found in the heart, nerves and muscle
e.g. nerves = 1,8,7
heart = 5

formed form one large protein with 4 related regions, each with six transmembrane domains

4th domain has positively charged amino acids, is known as the voltage sensor

rapid opening upon depolarisation, voltage sensor domain moves away and the channel is activated

Question 19

name the four pathologies of muscle contraction

Answer 19

multiple sclerosis = antibody-mediated autoimmune attack on nerve myelin sheath, affecting nerve signalling

myasthesia gravis = autoimmune disease targeting the degradation of the alpha-1 subunit of muscular nAchRs

non-dystrophic myotonias = group of genetic disorders; SCNA4 gene mutation prolonging muscle contraction and causing muscle stiffness, with delayed relaxation

dystrophic myopathy = group of genetic disorders; DMD gene mutation causing the complete loss/ reduced function of dystrophin, affecting muscle function