Summary of events during skeletal muscle contraction

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Summary of events during skeletal muscle
contraction
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Rest

• actin and myosin uncoupled
• calcium stored in SR

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Excitation

• nerve impulse generated
• ACH released from the vesicles
• sarcolemma depolarized
• muscle impulse transmitted through the fiber
• calcium released from the cisternae
• calcium binds to troponin
• actin binding sites activated
• myosin ATPase activated

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Contraction

• Myosin cross-bridges swivel
• Release ADP Pi
• Actin slides over myosin

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Regeneration

• ATP attaches to myosin
• actin and myosin dissociate
• ATP ? ADP Pi
• contraction process repeats

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Relaxation

• ACH decomposed by cholinesterase
• nerve impulse stops
• calcium removed by calcium pump
• actin binding sites inhibited (Tn/tropomyosin
  complex returns to original position)
• muscle returns to resting state

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Excitation Contraction Coupling

• process by which myofibrils translate nerve
  impulses into muscle contraction
• depolarization of t-tubule membrane (a change in
  the membrane potential) results in the calcium
  release from the terminal cisternae of the SR
• this results in muscle contraction

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• also know calcium is resequestered in the SR via
  active calcium-ATPase pumps
• not clear is how the change in membrane potential
  of the t-tubule system is communicated into the
  SR to cause calcium release

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Structure and Function of the Triad

• t-tubules and SR communicate at the triad
  junction
• a ryanodine receptor is a large protein complex
  which is the release channel of the sarcoplasmic
  calcium, located at the t-tubule SR junction
• the receptor has two parts channel region and a
  large cytoplasmic region

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• within t-tubule is another protein complex,
  believed to be the voltage sensor which controls
  the opening and closing of the ryanodine
  receptor, this is the DHP or dihydropyridine
  receptor complex
• hypothesized ryanodine receptor and the DHP
  receptor interact with each other to cause the
  action potential to induce calcium release from
  the SR

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Theories of Communication

• Calcium-induced tubule membranes
• Voltage-induced changes in the t-tubule
• Changes in the voltage gradient

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Calcium induced tubule membranes

• Cause an opening of the calcium channel calcium
  released
• stimulation of t-tubule induces a release of
  calcium ions from the gates within the SR

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• Con block calcium release channels of the cell
  membrane does not inhibit calcium release from
  the SR
• Nor reduce tension development
• Also, amount of calcium needed to induce release
  is not clear (may not be physiologic)

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Voltage-induced changes in the t-tubule

• induce the formation of D-myosinositol
  1,4,5-triphosphate (IP3)
• IP3 then increases the permeability of the SR
  membranes to cause calcium release

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• Pros elevated IP3 production has been
  demonstrated in skeletal muscle following
  electrical stimulation
• Release of calcium in skinned fibers induced by
  IP3
• An augmented muscle response following inhibition
  of IP3 breakdown
• A reduction of IP3 release from RBCs
• Cons is the concentration of IP3 necessary for
  activation and is its rate of activation
  physiologic?

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Changes in the voltage gradient

• Activation of calcium is due to perturbation of
  the normal H gradient across the SR membranes
• Cons the pH changes during muscle contraction
  may be too small to induce the necessary
  gradients in order to stimulate calcium release

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Hypothesized Mechanisms for ECC

• Calcium-induced calcium release
• Chemical intermediate
• Allosteric Interaction

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Calcium induced calcium release

• stimulation of t-tubules causes a small amount of
  calcium to cross the t-tubule membrane
• an amount insufficient to cause muscle
  contraction
• This induces the release of additional calcium in
  greater amounts, from the SR (calcium channels
  are open)

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• Cons blocking the DHP channels of the t-tubule
  membrane does not inhibit calcium release from
  the SR
• Or decrease force development
• Are the amounts of calcium required physiologic?

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Chemical Intermediate

• voltage-induced changes in the t-tubules induce
  the formation of inositol 1,4,5 triphosphate
  (InsP3)
• IP3 then increases the permeability of the SR
  membranes to cause calcium release

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• Pros after electrical stimulation, there is an
  elevated production IP3
• The release of calcium in skinned fibers induced
  by IP3
• If IP3 release from the RBCs is inhibited, there
  is a reduction of calcium transients in skeletal
  muscle
• If IP3 breakdown is inhibited, there is an
  augmented skeletal muscle response

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• Cons is the concentration of IP3 necessary for
  activation?
• Is its rate of activation physiologic?

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Allosteric Interaction Hypothesis (aka, Plunger
Hypothesis)

• there is a mechanical or allosteric link between
  DHP channels of the t-tubules and the ryanodine
  channels of the SR (junctional foot proteins)
• There is a foot structure composed primarily of
  SR calcium channel proteins clustered next to the
  t-tubule membrane called channel protein or
  electron dense feet

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• This suggests a role for protein-protein
  interactions to transmit the depolarization
  signal across the junction. Most popular
  mechanism of signal transmission is a variant of
  the plunger hypothesis
• Imagine a mobile positive charge in the t-tubule
  membrane (it may be associated with the DHP
  voltage sensor)

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• The charge is connected by a rod to a plug in the
  calcium release channel of the SR
• Depolarization of the t-tubule membrane causes
  charge movement in the t-tubule membrane
• Results in the unplugging of the SR calcium
  release channel

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• Suspect that the mobile charge is contained
  within specific amino acids contained within a
  segment of the DHP receptor complex
• Ryanodine receptor complex has a large
  cytoplasmic portion spanning the gap between
  membranes, and able to contact the voltage
  sensors of the DHP complex

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Skeletal Muscle Fiber Types

• not all skeletal muscle has the same biochemical
  or functional characteristics
• are generally classified according to their
  primary dependence on different metabolic
  pathways for the production of ATP.

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Nomenclature based on

• Myosin ATPase pH lability histochemical staining
• Glycolytic staining
• Oxidative staining

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Fiber sub-types

• Type I, SO (slow oxidative), red fibers, slow
• Type IIa FOG (fast oxidative glycolytic),
  intermediate fibers
• Type IIb FG (fast glycolytic), white, fast

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• Type IIc rare, undifferentiated fiber, perhaps
  found during re-innervation or motor unit
  transformation, between I and IIa on the
  continuum of metabolic potential
• Type IIx, not classified

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Slow twitch fibers

• fatigue resistant, good for prolonged exercise
• primarily synthesized ATP via aerobic energy
  transfer
• recruited for aerobic activities such as
  prolonged moderate exercise
• have a smaller resting membrane potential,
  -50-70mv, versus 80-90mv in fast muscle

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• longer latency period due to less extensive SR
• low activity of myosin ATPase
• slow speed of contraction
• low glycolytic capacity
• increased size and number of mitochondria

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• higher levels of myoglobin
• higher concentrations of mitochondrial enzymes
• increased blood flow -- increased capillarization

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Fast twitch fibers

• activated in short-term, sprint activities, and
  forceful contractions which rely primarily on
  anaerobic metabolism for energy
• important in stop and go and change of pace
  activities
• more extensive SR
• greater capability for electrochemical AP
  transmission (due to increased SR)

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• high activity level of myosin ATPase
• rapid SR calcium release and uptake
• high rate of cross-bridge turnover development
• intrinsic speed of contraction and tension is 2-3
  times that of ST fibers
• primarily use the glycolytic system for energy
  transfer